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Masaadeh AH, Eletrebi M, Parajuli B, De Jager N, Bosch DE. Human colitis-associated colorectal carcinoma progression is accompanied by dysbiosis with enriched pathobionts. Gut Microbes 2025; 17:2479774. [PMID: 40094201 PMCID: PMC11917176 DOI: 10.1080/19490976.2025.2479774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/14/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025] Open
Abstract
Dysbiosis and pathobionts contribute to inflammation and the risk of colitis-associated carcinoma (CAC) in animal models, but their roles in humans with this uncommon disease are unknown. We identified microbiome differences in human CAC compared with longstanding inflammatory bowel disease (IBD) and sporadic colorectal carcinoma (CRC). Twenty-four CAC resections were matched with CRC and IBD controls. Methods included histopathology, 16S rDNA metagenomics, and pathobiont-specific qPCR. Beta diversity differed by diagnosis (PERMANOVA p = 0.007). The distinguishing taxa included Akkermansia enriched in CRC, and Bacteroides spp. enriched in IBD. The non-neoplastic mucosae presented distinct beta diversity (p = 0.005), but the CAC/CRC tumor microbiomes were similar (p = 0.7). Within metastases and margins, Enterobacteriaceae were enriched in CAC, and Bacteroidales in CRC. Pathobiont-specific qPCR confirmed a greater frequency of pks+ E. coli and enterotoxigenic Bacteroides fragilis in CAC than IBD. High alpha diversity was associated with active inflammation, advanced cancer stage, and shorter overall survival (log-rank p = 0.008). Mucosal microbiomes distinguish CAC from longstanding IBD, implicating pathobionts as markers for disease progression. Integrating our findings with prior animal model research, pathobionts promote carcinogenesis in IBD patients through genotoxicity and host cell signaling.
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Affiliation(s)
- Amr H. Masaadeh
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Mohamed Eletrebi
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Bishal Parajuli
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nicola De Jager
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Dustin E. Bosch
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, Iowa City, IA, USA
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Lu C, Liu H, Liu T, Sun S, Zheng Y, Ling T, Luo X, E Y, Xu Y, Li J, Liu L, Miao L, Liu Z, Yu C. RIPK2 promotes colorectal cancer metastasis by protecting YAP degradation from ITCH-mediated ubiquitination. Cell Death Dis 2025; 16:248. [PMID: 40185717 PMCID: PMC11971272 DOI: 10.1038/s41419-025-07599-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, making the exploration of metastatic mechanisms crucial for therapeutic advancements. In this study, we identified receptor-interacting protein kinase 2 (RIPK2) as an independent risk factor for poor CRC prognosis. Single-cell RNA sequencing and spatial transcriptomics revealed that a tumor cell cluster with high RIPK2 expression exhibited enhanced metastatic potential, closely linked to bacterial invasion. In vitro and in vivo experiments confirmed that RIPK2 specifically promotes tumor cell migration and invasion, rather than proliferation. Proteomic analysis indicated that RIPK2 knockdown leads to increased proteolysis mediated by ubiquitin, particularly affecting the oncoprotein YAP. Additionally, bacterial invasion of epithelial cells was significantly suppressed in RIPK2 knockdown cells, suggesting a connection to the NOD2-RIPK2 pathway, stimulated by bacterial muramyl dipeptide (MDP). We demonstrated that MDP levels are significantly higher in CRC tissues compared to adjacent non-cancerous tissues, correlating with RIPK2 activation. This activation triggers K63-linked ubiquitination of RIPK2, essential for NF-κB and MAPK pathway activation. Mechanistic studies identified the E3 ubiquitin ligase ITCH as a critical mediator, balancing K63-linked ubiquitination of RIPK2 and K48-linked ubiquitination of YAP, leading to YAP degradation and suppressed CRC metastasis. The stability of YAP could also be disrupted by GSK583, a pharmacological inhibitor of RIPK2, effectively suppressing CRC metastasis. Our findings provide deep insights into RIPK2's role in CRC progression and present a promising target for future therapeutic strategies.
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Affiliation(s)
- Chen Lu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, 211112, Jiangsu, China
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Hongda Liu
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Tianyu Liu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, 211112, Jiangsu, China
| | - Sizheng Sun
- Department of General Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, China
| | - Yanan Zheng
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Tao Ling
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Xiagang Luo
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Yiming E
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Yuting Xu
- Ophthalmic Oncology Department, Nanjing Medical University Eye Hospital, Nanjing, 210008, China
| | - Jie Li
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Lei Liu
- Department of Gastroenterology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Lin Miao
- Medical Centre for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Zhengxia Liu
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China
| | - Chunzhao Yu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, 211112, Jiangsu, China.
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China.
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3
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Zheng Y, Wang K, Mao W, Zhang G, Han X, Li H, Wang Y. Abnormal expression of CDC25C in NSCLC is influenced by transcriptional and RNA N6‑methyladenosine‑mediated post‑transcriptional regulation. Int J Oncol 2025; 66:27. [PMID: 39981934 PMCID: PMC11900934 DOI: 10.3892/ijo.2025.5733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/03/2025] [Indexed: 02/22/2025] Open
Abstract
Non‑small cell lung cancer (NSCLC) exhibits a high incidence and mortality rate worldwide. Elevated cytokinesis cyclin 25 homologous protein C (CDC25C) expression is correlated with a poor prognosis in patients with NSCLC. Transcriptional regulation and post‑transcriptional modification are critical mechanisms governing gene expression, with aberrations in these processes increasingly recognized as pivotal contributors to cancer pathogenesis. The present study elucidated that the transcriptional activator, signal transducer and activator of transcription 3, directly interacts with the CDC25C promoter, thereby modulating its expression. Moreover, multi‑omics analysis was employed to identify the genes involved in the N6‑methyladenosine (m6A) methylation‑mediated post‑transcriptional regulation of CDC25C. The findings indicated that downregulation of alkB homolog 5 RNA demethylase in NSCLC leads to a marked increase in the m6A modification of CDC25C mRNA. It was also shown that YTH N6‑methyladenosine RNA binding protein (YTHDF) 3 and YTHDF2 compete to bind to CDC25C mRNA, thereby promoting or inhibiting its expression. Thus, the present study revealed that dysregulated expression of the CDC25C gene in NSCLC is influenced by multifaceted regulatory layers encompassing both transcriptional and post‑transcriptional mechanisms.
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MESH Headings
- Humans
- Adenosine/analogs & derivatives
- Adenosine/metabolism
- Adenosine/genetics
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Gene Expression Regulation, Neoplastic
- cdc25 Phosphatases/genetics
- cdc25 Phosphatases/metabolism
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Cell Line, Tumor
- RNA Processing, Post-Transcriptional
- Promoter Regions, Genetic
- RNA, Messenger/metabolism
- RNA, Messenger/genetics
- AlkB Homolog 5, RNA Demethylase/genetics
- AlkB Homolog 5, RNA Demethylase/metabolism
- Male
- RNA Splicing Factors/metabolism
- RNA Splicing Factors/genetics
- Female
- Methylation
- Prognosis
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Affiliation(s)
- Yuxin Zheng
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Kefeng Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Wenli Mao
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Guojun Zhang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
- Department of Pharmacy, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Xiaomin Han
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
- Department of Pharmacy, Southern University of Science and Technology Hospital, Shenzhen, Guangdong 518055, P.R. China
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Hualin Li
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
| | - Yukun Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
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4
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Zong Z, Zeng W, Li Y, Wang M, Cao Y, Cheng X, Jin Z, Mao S, Zhu X. Intratumor microbiota and colorectal cancer: Comprehensive and lucid review. Chin J Cancer Res 2024; 36:683-699. [PMID: 39802896 PMCID: PMC11724182 DOI: 10.21147/j.issn.1000-9604.2024.06.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
As a key component of tumor microenvironment, the microbiota has gradually played a key role in cancer research. Particularly in colorectal cancer, the specific population of microbiota within the tumor shows a strong association with the tumor type. Although the existence and potential role of microbiota in tumors have been recognized, the specific associations between the microbiota and tumor tissue and the mechanism of action still need to be further explored. This paper reviews the discovery, origin, and emerging role of the intratumor microbiota in the immune microenvironment and systematically outlines the oncogenic and metastasis-promoting strategies of the intratumor microbiota. Moreover, it comprehensively and holistically evaluates therapeutic strategies and prognostic performance on the basis of the intratumor microbiota, with the goal of providing strong support for future research and clinical practice.
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Affiliation(s)
- Zhen Zong
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Wenjuan Zeng
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Yin Li
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Menghui Wang
- Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Yuke Cao
- School of Ophthalmology and Optometry, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Zhenhua Jin
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Shengxun Mao
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Xingen Zhu
- Department of Neurosurgey, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang 330006, China
- Institute of Neuroscience, Nanchang University, Nanchang 330006, China
- Jiangxi Provincial Health Commission Key Laboratory of Neurological Medicine, Nanchang 330006, China
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5
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Shen J, Lou L, Du X, Zhou B, Xu Y, Mei F, Wu L, Li J, Waisman A, Ruan J, Wang X. YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2. EMBO Rep 2024; 25:4827-4845. [PMID: 39333628 PMCID: PMC11549337 DOI: 10.1038/s44319-024-00276-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 09/03/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.
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Affiliation(s)
- Jiangyun Shen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Liyan Lou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Xue Du
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Bincheng Zhou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Yanqi Xu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Fuqi Mei
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
| | - Liangrong Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China
- Department of Pharmacy, Yiwu Central Hospital, 322099, Yiwu, China
| | - Jianmin Li
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China
| | - Ari Waisman
- Institute for Molecular Medicine, Johannes Gutenberg University Mainz, 55131, Mainz, Germany
| | - Jing Ruan
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, China.
| | - Xu Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health); School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
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6
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Bohm MS, Ramesh AV, Pierre JF, Cook KL, Murphy EA, Makowski L. Fecal microbial transplants as investigative tools in cancer. Am J Physiol Gastrointest Liver Physiol 2024; 327:G711-G726. [PMID: 39301964 PMCID: PMC11559651 DOI: 10.1152/ajpgi.00171.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/22/2024]
Abstract
The gut microbiome plays a critical role in the development, progression, and treatment of cancer. As interest in microbiome-immune-cancer interactions expands, the prevalence of fecal microbial transplant (FMT) models has increased proportionally. However, current literature does not provide adequate details or consistent approaches to allow for necessary rigor and experimental reproducibility. In this review, we evaluate key studies using FMT to investigate the relationship between the gut microbiome and various types of cancer. In addition, we will discuss the common pitfalls of these experiments and methods for improved standardization and validation as the field uses FMT with greater frequency. Finally, this review focuses on the impacts of the gut and extraintestinal microbes, prebiotics, probiotics, and postbiotics in cancer risk and response to therapy across a variety of tumor types.NEW & NOTEWORTHY The microbiome impacts the onset, progression, and therapy response of certain types of cancer. Fecal microbial transplants (FMTs) are an increasingly prevalent tool to test these mechanisms that require standardization by the field.
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Affiliation(s)
- Margaret S Bohm
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Arvind V Ramesh
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Joseph F Pierre
- Department of Nutritional Sciences, College of Agriculture and Life Science, The University of Wisconsin-Madison, Madison, Wisconsin, United States
| | - Katherine L Cook
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
| | - E Angela Murphy
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Liza Makowski
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
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7
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Caruso R, Lo BC, Chen GY, Núñez G. Host-pathobiont interactions in Crohn's disease. Nat Rev Gastroenterol Hepatol 2024:10.1038/s41575-024-00997-y. [PMID: 39448837 DOI: 10.1038/s41575-024-00997-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/26/2024]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Grace Y Chen
- Department of Internal Medicine and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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De Filippo C, Chioccioli S, Meriggi N, Troise AD, Vitali F, Mejia Monroy M, Özsezen S, Tortora K, Balvay A, Maudet C, Naud N, Fouché E, Buisson C, Dupuy J, Bézirard V, Chevolleau S, Tondereau V, Theodorou V, Maslo C, Aubry P, Etienne C, Giovannelli L, Longo V, Scaloni A, Cavalieri D, Bouwman J, Pierre F, Gérard P, Guéraud F, Caderni G. Gut microbiota drives colon cancer risk associated with diet: a comparative analysis of meat-based and pesco-vegetarian diets. MICROBIOME 2024; 12:180. [PMID: 39334498 PMCID: PMC11438057 DOI: 10.1186/s40168-024-01900-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 08/05/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) risk is strongly affected by dietary habits with red and processed meat increasing risk, and foods rich in dietary fibres considered protective. Dietary habits also shape gut microbiota, but the role of the combination between diet, the gut microbiota, and the metabolite profile on CRC risk is still missing an unequivocal characterisation. METHODS To investigate how gut microbiota affects diet-associated CRC risk, we fed Apc-mutated PIRC rats and azoxymethane (AOM)-induced rats the following diets: a high-risk red/processed meat-based diet (MBD), a normalised risk diet (MBD with α-tocopherol, MBDT), a low-risk pesco-vegetarian diet (PVD), and control diet. We then conducted faecal microbiota transplantation (FMT) from PIRC rats to germ-free rats treated with AOM and fed a standard diet for 3 months. We analysed multiple tumour markers and assessed the variations in the faecal microbiota using 16S rRNA gene sequencing together with targeted- and untargeted-metabolomics analyses. RESULTS In both animal models, the PVD group exhibited significantly lower colon tumorigenesis than the MBD ones, consistent with various CRC biomarkers. Faecal microbiota and its metabolites also revealed significant diet-dependent profiles. Intriguingly, when faeces from PIRC rats fed these diets were transplanted into germ-free rats, those transplanted with MBD faeces developed a higher number of preneoplastic lesions together with distinctive diet-related bacterial and metabolic profiles. PVD determines a selection of nine taxonomic markers mainly belonging to Lachnospiraceae and Prevotellaceae families exclusively associated with at least two different animal models, and within these, four taxonomic markers were shared across all the three animal models. An inverse correlation between nonconjugated bile acids and bacterial genera mainly belonging to the Lachnospiraceae and Prevotellaceae families (representative of the PVD group) was present, suggesting a potential mechanism of action for the protective effect of these genera against CRC. CONCLUSIONS These results highlight the protective effects of PVD while reaffirming the carcinogenic properties of MBD diets. In germ-free rats, FMT induced changes reminiscent of dietary effects, including heightened preneoplastic lesions in MBD rats and the transmission of specific diet-related bacterial and metabolic profiles. Importantly, to the best of our knowledge, this is the first study showing that diet-associated cancer risk can be transferred with faeces, establishing gut microbiota as a determinant of diet-associated CRC risk. Therefore, this study marks the pioneering demonstration of faecal transfer as a means of conveying diet-related cancer risk, firmly establishing the gut microbiota as a pivotal factor in diet-associated CRC susceptibility. Video Abstract.
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Grants
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- JTC-2017-7 Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on "Interrelation of the Intestinal Microbiome, Diet and Health"
- Expression of interest # 895 HDHL INTIMIC-Knowledge Platform on food, diet, intestinal microbiomics and human health
- Expression of interest # 895 HDHL INTIMIC-Knowledge Platform on food, diet, intestinal microbiomics and human health
- PE00000003 National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU; Project title "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"
- PE00000003 National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU; Project title "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"
- PE00000003 National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU; Project title "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"
- ECS00000017 European Union - NextGenerationEU - National Recovery and Resilience Plan, Mission 4 Component 2 - Investment 1.5 - THE - Tuscany Health Ecosystem
- ECS00000017 European Union - NextGenerationEU - National Recovery and Resilience Plan, Mission 4 Component 2 - Investment 1.5 - THE - Tuscany Health Ecosystem
- G. Caderni University of Florence (Fondo ex-60%), Italy
- Joint Programming Initiative a Healthy Diet for a Healthy Life-Intestinal Microbiomics (JPI HDHL-INTIMIC) Call for Joint Transnational Research Proposals on “Interrelation of the Intestinal Microbiome, Diet and Health”
- National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Call for tender No. 341 of 15 March 2022 of Italian Ministry of University and Research funded by the European Union – NextGenerationEU; Project title “ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security – Working ON Foods”
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Affiliation(s)
- Carlotta De Filippo
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy.
| | - Sofia Chioccioli
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Niccolò Meriggi
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy
| | - Antonio Dario Troise
- Proteomics, Metabolomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, Portici, Italy
| | - Francesco Vitali
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy
| | - Mariela Mejia Monroy
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Serdar Özsezen
- Netherlands Organisation for Applied Scientific Research, Zeist, Netherlands
| | - Katia Tortora
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Aurélie Balvay
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Claire Maudet
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Nathalie Naud
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Edwin Fouché
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Charline Buisson
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Jacques Dupuy
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Valérie Bézirard
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Sylvie Chevolleau
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
- MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, 31077, France
| | - Valérie Tondereau
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Vassilia Theodorou
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Claire Maslo
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Perrine Aubry
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Camille Etienne
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Lisa Giovannelli
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy
| | - Vincenzo Longo
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy
| | - Andrea Scaloni
- Proteomics, Metabolomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, Portici, Italy
| | | | - Jildau Bouwman
- Netherlands Organisation for Applied Scientific Research, Zeist, Netherlands
| | - Fabrice Pierre
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Philippe Gérard
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Françoise Guéraud
- Toxalim, INRAE, ENVT, INP-Purpan, UPS, Toulouse University, Toulouse, 31027, France
| | - Giovanna Caderni
- Institute of Agricultural Biology and Biotechnology (IBBA), National Research Council (CNR), Pisa, Italy.
- NEUROFARBA Department, Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
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9
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Gurses S, Varghese N, Gupta D. Innate immunity gene Nod2 protects mice from orthotopic breast cancer. Mol Biol Rep 2024; 51:988. [PMID: 39285089 PMCID: PMC11405536 DOI: 10.1007/s11033-024-09927-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Nod2 is involved in innate immune responses to bacteria, regulation of metabolism, and sensitivity to cancer. A Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown. METHODS Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. WT and Nod2-/- mice were injected with 4T1 mammary carcinoma cells and the development of tumors was monitored. A detailed analysis of the tumor transcriptome was performed and genes that were differentially expressed and pathways that were predicted to be altered between WT and Nod2-/- mice were identified. The activation of key signaling molecules involved in metabolism and development of cancer was studied. RESULTS Our data demonstrate that Nod2-/- mice had a higher incidence and larger tumors than WT mice. Nod2-/- mice had increased expression of genes that promote DNA replication and cell division, and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2-/- mice also had lower expression of genes required for adipogenesis and reduced levels of lipids compared with WT mice. The tumors in Nod2-/- mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice. CONCLUSIONS We conclude that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2-/- mice are predicted to have increased DNA replication and cell proliferation and decreased lipid metabolism compared with WT mice.
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Affiliation(s)
- Serdar Gurses
- Indiana University School of Medicine-Northwest, Gary, IN, 46408, USA
- The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Nivya Varghese
- Indiana University School of Medicine-Northwest, Gary, IN, 46408, USA
| | - Dipika Gupta
- Indiana University School of Medicine-Northwest, Gary, IN, 46408, USA.
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10
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Gong X, Wang Z, You J, Gao J, Chen K, Chu J, Sui X, Dang J, Liu X. Pyroptosis-associated genes and tumor immune response in endometrial cancer. Discov Oncol 2024; 15:433. [PMID: 39264524 PMCID: PMC11393226 DOI: 10.1007/s12672-024-01315-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 09/04/2024] [Indexed: 09/13/2024] Open
Abstract
The occurrence and progression of tumors are linked to the process of pyroptosis. However, the precise involvement of pyroptosis-associated genes (PRGs) in endometrial cancer (EC) remains uncertain. 29 PRGs were identified as being either up-regulated or down-regulated in EC. PRGs subgroup analysis demonstrated distinct survival outcomes and diverse responses to chemotherapy and immune checkpoint blockade therapy. A higher expression of GPX4 and NOD2, coupled with lower levels of CASP6, PRKACA, and NLRP2, were found to be significantly associated with higher overall survival (OS) rates (p < 0.05). Conversely, lower expression of NOD2 was linked to lower progression-free survival (p = 0.021) and advanced tumor stage(p = 0.0024). NOD2, NLRP2, and TNM stages were identified as independent prognostic factors (p < 0.001). The LASSO prognostic model exhibited a notable decrease in OS among EC patients in the high-risk score group (ROC-AUC10-years: 0.799, p = 0.00644). Furthermore, NOD2 displayed a positive correlation with the infiltration of immune cells and the expression of immune checkpoints (p < 0.001). GPX4 and CASP6 are significantly associated with TMB and MSI (RTMB = 0.39; RMSI = 0.23). Additionally, a substantial upregulation of NOD2 was confirmed in both EC cells and tissue, indicating a positive relationship between advanced TNM stage (p < 0.0001) and infiltration of M1 phenotype macrophages. Nonetheless, its impact on patient OS did not reach statistical significance (p = 0.141). Our findings have contributed to the advancement of a prognostic model for EC patients. NOD2 receptor-mediated pyroptosis mechanism potentially regulates tumor immunity and promotes the transformation of macrophages from the M2 phenotype to the M1 phenotype, which significantly impacts the progression of EC.
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Affiliation(s)
- Xiaodi Gong
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Zhifeng Wang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Jiahao You
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Jinghai Gao
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Kun Chen
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Jing Chu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Xiaoxin Sui
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Jianhong Dang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Xiaojun Liu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
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11
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Kwon SY, Thi-Thu Ngo H, Son J, Hong Y, Min JJ. Exploiting bacteria for cancer immunotherapy. Nat Rev Clin Oncol 2024; 21:569-589. [PMID: 38840029 DOI: 10.1038/s41571-024-00908-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 06/07/2024]
Abstract
Immunotherapy has revolutionized the treatment of cancer but continues to be constrained by limited response rates, acquired resistance, toxicities and high costs, which necessitates the development of new, innovative strategies. The discovery of a connection between the human microbiota and cancer dates back 4,000 years, when local infection was observed to result in tumour eradication in some individuals. However, the true oncological relevance of the intratumoural microbiota was not recognized until the turn of the twentieth century. The intratumoural microbiota can have pivotal roles in both the pathogenesis and treatment of cancer. In particular, intratumoural bacteria can either promote or inhibit cancer growth via remodelling of the tumour microenvironment. Over the past two decades, remarkable progress has been made preclinically in engineering bacteria as agents for cancer immunotherapy; some of these bacterial products have successfully reached the clinical stages of development. In this Review, we discuss the characteristics of intratumoural bacteria and their intricate interactions with the tumour microenvironment. We also describe the many strategies used to engineer bacteria for use in the treatment of cancer, summarizing contemporary data from completed and ongoing clinical trials. The work described herein highlights the potential of bacteria to transform the landscape of cancer therapy, bridging ancient wisdom with modern scientific innovation.
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Affiliation(s)
- Seong-Young Kwon
- Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Jeonnam, Republic of Korea
- Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Jeonnam, Republic of Korea
| | - Hien Thi-Thu Ngo
- Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Jeonnam, Republic of Korea
- Department of Biomedical Sciences, Chonnam National University Medical School, Jeonnam, Republic of Korea
- Department of Biochemistry, Hanoi Medical University, Hanoi, Vietnam
| | - Jinbae Son
- CNCure Biotech, Jeonnam, Republic of Korea
| | - Yeongjin Hong
- Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Jeonnam, Republic of Korea
- CNCure Biotech, Jeonnam, Republic of Korea
- Department of Microbiology and Immunology, Chonnam National University Medical School, Jeonnam, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University, Jeonnam, Republic of Korea
| | - Jung-Joon Min
- Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Jeonnam, Republic of Korea.
- Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Jeonnam, Republic of Korea.
- Department of Biomedical Sciences, Chonnam National University Medical School, Jeonnam, Republic of Korea.
- CNCure Biotech, Jeonnam, Republic of Korea.
- Department of Microbiology and Immunology, Chonnam National University Medical School, Jeonnam, Republic of Korea.
- National Immunotherapy Innovation Center, Chonnam National University, Jeonnam, Republic of Korea.
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12
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Kong L, Cao Y, He Y, Zhang Y. Role and molecular mechanism of NOD2 in chronic non-communicable diseases. J Mol Med (Berl) 2024; 102:787-799. [PMID: 38740600 DOI: 10.1007/s00109-024-02451-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Nucleotide-binding oligomerization domain containing 2 (NOD2), located in the cell cytoplasm, is a pattern recognition receptor belonging to the innate immune receptor family. It mediates the innate immune response by identifying conserved sequences in bacterial peptide glycans and plays an essential role in maintaining immune system homeostasis. Gene mutations of NOD2 lead to the development of autoimmune diseases such as Crohn's disease and Blau syndrome. Recently, NOD2 has been shown to be associated with the pathogenesis of diabetes, cardiac-cerebral diseases, and cancers. However, the function of NOD2 in these non-communicable diseases (CNCDs) is not well summarized in reviews. Our report mainly discusses the primary function and molecular mechanism of NOD2 as well as its potential clinical significance in CNCDs.
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Affiliation(s)
- Lingjun Kong
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China
| | - Yanhua Cao
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China
| | - Yanan He
- Gamma Knife Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Yahui Zhang
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, Shandong, People's Republic of China.
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13
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Li H, Li H, Stanton C, Ross RP, Zhao J, Chen W, Yang B. Exopolysaccharides Produced by Bifidobacterium longum subsp. longum YS108R Ameliorates DSS-Induced Ulcerative Colitis in Mice by Improving the Gut Barrier and Regulating the Gut Microbiota. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7055-7073. [PMID: 38520351 DOI: 10.1021/acs.jafc.3c06421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/25/2024]
Abstract
Ulcerative colitis (UC) is a major disease that has endangered human health. Our previous study demonstrated that Bifidobacterium longum subsp. longum YS108R, a ropy exopolysaccharide (EPS)-producing bacterium, could alleviate UC in mice, but it is unclear whether EPS is the key substance responsible for its action. In this study, we proposed to investigate the remitting effect of EPS from B. longum subsp. longum YS108R on UC in a DSS-induced UC mouse model. Water extraction and alcohol precipitation were applied to extract EPS from the supernatant of B. longum subsp. longum YS108R culture. Then the animal trial was performed, and the results indicated that YS108R EPS ameliorated colonic pathological damage and the intestinal barrier. YS108R EPS suppressed inflammation via NF-κB signaling pathway inhibition and attenuated oxidative stress via the Nrf2 signaling pathway activation. Remarkably, YS108R EPS regulated gut microbiota, as evidenced by an increase in short-chain fatty acid (SCFA)-producing bacteria and a decline in Gram-negative bacteria, resulting in an increase of propionate and butyrate and a reduction of lipopolysaccharide (LPS). Collectively, YS108R EPS manipulated the intestinal microbiota and its metabolites, which further improved the intestinal barrier and inhibited inflammation and oxidative stress, thereby alleviating UC.
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Affiliation(s)
- Huizhen Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Haitao Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Catherine Stanton
- International Joint Research Center for Probiotics & Gut Health, Jiangnan University, Wuxi, Jiangsu 214122, China
- APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland
- Teagasc Food Research Centre, Moorepark, Fermoy, Cork P61 C996, Ireland
| | - R Paul Ross
- International Joint Research Center for Probiotics & Gut Health, Jiangnan University, Wuxi, Jiangsu 214122, China
- APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Bo Yang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- International Joint Research Center for Probiotics & Gut Health, Jiangnan University, Wuxi, Jiangsu 214122, China
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14
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Sun Y, Wang X, Li L, Zhong C, Zhang Y, Yang X, Li M, Yang C. The role of gut microbiota in intestinal disease: from an oxidative stress perspective. Front Microbiol 2024; 15:1328324. [PMID: 38419631 PMCID: PMC10899708 DOI: 10.3389/fmicb.2024.1328324] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024] Open
Abstract
Recent studies have indicated that gut microbiota-mediated oxidative stress is significantly associated with intestinal diseases such as colorectal cancer, ulcerative colitis, and Crohn's disease. The level of reactive oxygen species (ROS) has been reported to increase when the gut microbiota is dysregulated, especially when several gut bacterial metabolites are present. Although healthy gut microbiota plays a vital role in defending against excessive oxidative stress, intestinal disease is significantly influenced by excessive ROS, and this process is controlled by gut microbiota-mediated immunological responses, DNA damage, and intestinal inflammation. In this review, we discuss the relationship between gut microbiota and intestinal disease from an oxidative stress perspective. In addition, we also provide a summary of the most recent therapeutic approaches for preventing or treating intestinal diseases by modifying gut microbiota.
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Affiliation(s)
- Yiqi Sun
- Surgery of Traditional Chinese Medicine Department, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xurui Wang
- Surgery of Traditional Chinese Medicine Department, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lei Li
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chao Zhong
- Traditional Chinese Medicine Department of Orthopaedic and Traumatic, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu Zhang
- Colorectal and Anal Surgery, Chengdu Anorectal Hospital, Chengdu, China
| | - Xiangdong Yang
- Colorectal and Anal Surgery, Chengdu Anorectal Hospital, Chengdu, China
| | - Mingyue Li
- Special Needs Outpatient Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chao Yang
- Surgery of Traditional Chinese Medicine Department, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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15
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Martin-Gallausiaux C, Salesse L, Garcia-Weber D, Marinelli L, Beguet-Crespel F, Brochard V, Le Gléau C, Jamet A, Doré J, Blottière HM, Arrieumerlou C, Lapaque N. Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. Gut Microbes 2024; 16:2295384. [PMID: 38126163 PMCID: PMC10761154 DOI: 10.1080/19490976.2023.2295384] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
The anaerobic bacterium Fusobacterium nucleatum is significantly associated with human colorectal cancer (CRC) and is considered a significant contributor to the disease. The mechanisms underlying the promotion of intestinal tumor formation by F. nucleatum have only been partially uncovered. Here, we showed that F. nucleatum releases a metabolite into the microenvironment that strongly activates NF-κB in intestinal epithelial cells via the ALPK1/TIFA/TRAF6 pathway. Furthermore, we showed that the released molecule had the biological characteristics of ADP-heptose. We observed that F. nucleatum induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC, BIRC3 and TNFAIP3. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity in vitro. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in Fusobacterium induced-CRC pathogenesis, and identify the role of ADP-H in this process.
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Affiliation(s)
| | - Laurène Salesse
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | | | - Ludovica Marinelli
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | | | - Vincent Brochard
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Camille Le Gléau
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Alexandre Jamet
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Joël Doré
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, Metagenopolis, Jouy-en-Josas, France
| | - Hervé M. Blottière
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, Metagenopolis, Jouy-en-Josas, France
| | | | - Nicolas Lapaque
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
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16
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Carlé C, Boucher D, Morelli L, Larue C, Ovtchinnikova E, Battut L, Boumessid K, Airaud M, Quaranta-Nicaise M, Ravanat JL, Dietrich G, Menard S, Eberl G, Barnich N, Mas E, Carriere M, Al Nabhani Z, Barreau F. Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life. Part Fibre Toxicol 2023; 20:45. [PMID: 37996842 PMCID: PMC10666382 DOI: 10.1186/s12989-023-00555-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/13/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Perinatal exposure to titanium dioxide (TiO2), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel disease (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO2 exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO2 until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2'-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis. RESULTS In pregnant and lactating mice, foodborne TiO2 was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO2 early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO2 also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO2 exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO2-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring. CONCLUSIONS Our findings indicate that foodborne TiO2 consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.
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Affiliation(s)
- Caroline Carlé
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Delphine Boucher
- M2iSH, Université Clermont Auvergne, UMR1071 INSERM, USC INRAE 1382, Clermont-Ferrand, France
| | - Luisa Morelli
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, 3010, Bern, Switzerland
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, 3008, Bern, Switzerland
| | - Camille Larue
- Laboratoire Ecologie Fonctionnelle et Environnement, Université de Toulouse, CNRS, Toulouse, France
| | - Ekaterina Ovtchinnikova
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Louise Battut
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Kawthar Boumessid
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Melvin Airaud
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Muriel Quaranta-Nicaise
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Jean-Luc Ravanat
- Univ. Grenoble-Alpes, CEA, CNRS, IRIG-SyMMES, CIBEST, Grenoble, France
| | - Gilles Dietrich
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Sandrine Menard
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
| | - Gérard Eberl
- Institut Pasteur, Microenvironment and Immunity Unit, 75724, Paris, France
- INSERM U1224, Paris, France
| | - Nicolas Barnich
- M2iSH, Université Clermont Auvergne, UMR1071 INSERM, USC INRAE 1382, Clermont-Ferrand, France
| | - Emmanuel Mas
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France
- Gastroenterology, Hepatology, Nutrition, Diabetology and Hereditary Metabolic Diseases Unit, Hôpital des Enfants, CHU de Toulouse, 31300, Toulouse, France
| | - Marie Carriere
- Univ. Grenoble-Alpes, CEA, CNRS, IRIG-SyMMES, CIBEST, Grenoble, France
| | - Ziad Al Nabhani
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, 3010, Bern, Switzerland.
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, 3008, Bern, Switzerland.
| | - Frédérick Barreau
- Institut de Recherche en Santé Digestive (IRSD), INSERM UMR-1220, Purpan Hospital, CS60039, University of Toulouse, INSERM, INRAE, ENVT, UPS, 31024, Toulouse Cedex 03, France.
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Mehra Y, Chalif J, Mensah-Bonsu C, Spakowicz D, O’Malley DM, Chambers L. The microbiome and ovarian cancer: insights, implications, and therapeutic opportunities. JOURNAL OF CANCER METASTASIS AND TREATMENT 2023. [DOI: 10.20517/2394-4722.2023.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Ovarian cancer is the leading cause of gynecologic cancer death in the United States. Most ovarian cancer patients are diagnosed with advanced-stage disease, which poses a challenge for early detection and effective treatment. At present, cytoreductive surgery and platinum-based chemotherapy are foundational for patients with newly diagnosed ovarian cancer, but unfortunately, most patients will recur and die of their disease. Therefore, there is a significant need to seek innovative, novel approaches for early detection and to overcome chemoresistance for ovarian cancer patients. The microbiome, comprising diverse microbial communities inhabiting various body sites, is vital in maintaining human health. Changes to the diversity and composition of the microbial communities impact the microbiota-host relationship and are linked to diseases, including cancer. The microbiome contributes to carcinogenesis through various mechanisms, including altered host immune response, modulation of DNA repair, upregulation of pro-inflammatory pathways, altered gene expression, and dysregulated estrogen metabolism. Translational and clinical studies have demonstrated that specific microbes contribute to ovarian cancer development and impact chemotherapy’s efficacy. The microbiome is malleable and can be altered through different approaches, including diet, exercise, medications, and fecal microbiota transplantation. This review provides an overview of the current literature regarding ovarian cancer and the microbiome of female reproductive and gastrointestinal tracts, focusing on mechanisms of carcinogenesis and options for modulating the microbiota for cancer prevention and treatment. Advancing our understanding of the complex relationship between the microbiome and ovarian cancer may provide a novel approach for prevention and therapeutic modulation in the future.
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18
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Tian E, Zhou C, Quan S, Su C, Zhang G, Yu Q, Li J, Zhang J. RIPK2 inhibitors for disease therapy: Current status and perspectives. Eur J Med Chem 2023; 259:115683. [PMID: 37531744 DOI: 10.1016/j.ejmech.2023.115683] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/11/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023]
Abstract
Receptor-interacting protein kinase 2 (RIPK2) belongs to the receptor-interacting protein family (RIPs), which is mainly distributed in the cytoplasm. RIPK2 is widely expressed in human tissues, and its mRNA level is highly expressed in the spleen, leukocytes, placenta, testis, and heart. RIPK2 is a dual-specificity kinase with multiple domains, which can interact with tumor necrosis factor receptor (TNFR), and participate in the Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) signaling pathways. It is considered as a vital adapter molecule involved in the innate immunity, adaptive immunity, and apoptosis. Functionally, RIPK2 and its targeted small molecules are of great significance in inflammatory responses, autoimmune diseases and tumors. The present study reviews the molecule structure and biological functions of RIPK2, and its correlation between human diseases. In addition, we focus on the structure-activity relationship of small molecule inhibitors of RIPK2 and their therapeutic potential in human diseases.
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Affiliation(s)
- Erkang Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Changhan Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Shuqi Quan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Chongying Su
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Guanning Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Quanwei Yu
- Joint Research Institution of Altitude Health, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Juan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Jifa Zhang
- Joint Research Institution of Altitude Health, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, 610041, China.
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19
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Garg S, Sharma N, Bharmjeet, Das A. Unraveling the intricate relationship: Influence of microbiome on the host immune system in carcinogenesis. Cancer Rep (Hoboken) 2023; 6:e1892. [PMID: 37706437 PMCID: PMC10644337 DOI: 10.1002/cnr2.1892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/05/2023] [Accepted: 08/17/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Cancer is an outcome of various disrupted or dysregulated metabolic processes like apoptosis, growth, and self-cell transformation. Human anatomy harbors trillions of microbes, and these microbes actively influence all kinds of human metabolic activities, including the human immune response. The immune system which inherently acts as a sentinel against microbes, curiously tolerates and even maintains a distinct normal microflora in our body. This emphasizes the evolutionarily significant role of microbiota in shaping our adaptive immune system and even potentiating its function in chronic ailments like cancers. Microbes interact with the host immune cells and play a part in cancer progression or regression by modulating immune cells, producing immunosuppressants, virulence factors, and genotoxins. RECENT FINDINGS An expanding plethora of studies suggest and support the evidence of microbiome impacting cancer etiology. Several studies also indicate that the microbiome can supplement various cancer therapies, increasing their efficacy. The present review discusses the relationship between bacterial and viral microbiota with cancer, discussing different carcinogenic mechanisms influenced by prokaryotes with special emphasis on their immunomodulatory axis. It also elucidates the potential of the microbiome in transforming the efficacy of immunotherapeutic treatments. CONCLUSION This review offers a thorough overview of the complex interaction between the human immune system and the microbiome and its impact on the development of cancer. The microbiome affects the immune responses as well as progression of tumor transformation, hence microbiome-based therapies can vastly improve the effectiveness of cancer immunotherapies. Individual variations of the microbiome and its dynamic variability in every individual impacts the immune modulation and cancer progression. Therefore, further research is required to understand these underlying processes in detail, so as to design better microbiome-immune system axis in the treatment of cancer.
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Affiliation(s)
- Saksham Garg
- Department of BiotechnologyDelhi Technological UniversityDelhiIndia
| | - Nikita Sharma
- Department of BiotechnologyDelhi Technological UniversityDelhiIndia
| | - Bharmjeet
- Department of BiotechnologyDelhi Technological UniversityDelhiIndia
| | - Asmita Das
- Department of BiotechnologyDelhi Technological UniversityDelhiIndia
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20
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Pai YC, Li YH, Turner JR, Yu LCH. Transepithelial Barrier Dysfunction Drives Microbiota Dysbiosis to Initiate Epithelial Clock-driven Inflammation. J Crohns Colitis 2023; 17:1471-1488. [PMID: 37004200 PMCID: PMC10588795 DOI: 10.1093/ecco-jcc/jjad064] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Indexed: 04/03/2023]
Abstract
BACKGROUND Factors that contribute to inflammatory bowel disease [IBD] pathogenesis include genetic polymorphisms, barrier loss, and microbial dysbiosis. A major knowledge gap exists in the origins of the colitogenic microbiome and its relationship with barrier impairment. Epithelial myosin light chain kinase [MLCK] is a critical regulator of the paracellular barrier, but the effects of MLCK activation on the intraepithelial bacteria [IEB] and dysbiosis are incompletely understood. We hypothesise that MLCK-dependent bacterial endocytosis promotes pathobiont conversion and shapes a colitogenic microbiome. METHODS To explore this, transgenic [Tg] mice with barrier loss induced by intestinal epithelium-specific expression of a constitutively active MLCK were compared with wild-type [WT] mice. RESULTS When progeny of homozygous MLCK-Tg mice were separated after weaning by genotype [Tg/Tg, Tg/WT, WT/WT], increased IEB numbers associated with dysbiosis and more severe colitis were present in Tg/Tg and Tg/WT mice, relative to WT/WT mice. Cohousing with MLCK-Tg mice induced dysbiosis, increased IEB abundance, and exacerbated colitis in WT mice. Conversely, MLCK-Tg mice colonised with WT microbiota at birth displayed increased Escherichia abundance and greater colitis severity by 6 weeks of age. Microarray analysis revealed circadian rhythm disruption in WT mice co-housed with MLCK-Tg mice relative to WT mice housed only with WT mice. This circadian disruption required Rac1/STAT3-dependent microbial invasion but not MLCK activity, and resulted in increased proinflammatory cytokines and glucocorticoid downregulation. CONCLUSIONS The data demonstrate that barrier dysfunction induces dysbiosis and expansion of invasive microbes that lead to circadian disruption and mucosal inflammation. These results suggest that barrier-protective or bacterium-targeted precision medicine approaches may be of benefit to IBD patients.
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Affiliation(s)
- Yu-Chen Pai
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Yi-Hsuan Li
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Jerrold R Turner
- Brigham's Women Hospital, Harvard Medical School, Boston, MA, USA
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
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21
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Chauvin C, Radulovic K, Boulard O, Delacre M, Waldschmitt N, Régnier P, Legris G, Bouchez C, Sleimi MY, Rosenstiel P, Darrasse-Jèze G, Chamaillard M, Poulin LF. Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner. Front Immunol 2023; 14:1252979. [PMID: 37876927 PMCID: PMC10590911 DOI: 10.3389/fimmu.2023.1252979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/14/2023] [Indexed: 10/26/2023] Open
Abstract
Background Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the NOD2 gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC). Methods To ablate Nod2 specifically within the myeloid compartment, we generated LysMCre/+;Nod2fl/fl mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis. Results Upon DSS colitis model, LysMCre/+;Nod2fl/fl mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of LysMCre/+;Nod2fl/fl mice, associated with less expression of Tgfb. Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells. Conclusion Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
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Affiliation(s)
- Camille Chauvin
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
- Institut national de la santé et de la recherche médicale (INSERM) U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Katarina Radulovic
- Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes, France
| | | | - Myriam Delacre
- Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Paul Régnier
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Biotherapy Unit (CIC-BTi), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | | | | | | | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Guillaume Darrasse-Jèze
- Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- Université Paris Cité, Faculté de Médecine, Paris, France
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Iyer K, Erkert L, Becker C. Know your neighbors: microbial recognition at the intestinal barrier and its implications for gut homeostasis and inflammatory bowel disease. Front Cell Dev Biol 2023; 11:1228283. [PMID: 37519301 PMCID: PMC10375050 DOI: 10.3389/fcell.2023.1228283] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/07/2023] [Indexed: 08/01/2023] Open
Abstract
Intestinal epithelial cells (IECs) perform several physiological and metabolic functions at the epithelial barrier. IECs also play an important role in defining the overall immune functions at the mucosal region. Pattern recognition receptors (PRRs) on the cell surface and in other cellular compartments enable them to sense the presence of microbes and microbial products in the intestinal lumen. IECs are thus at the crossroads of mediating a bidirectional interaction between the microbial population and the immune cells present at the intestinal mucosa. This communication between the microbial population, the IECs and the underlying immune cells has a profound impact on the overall health of the host. In this review, we focus on the various PRRs present in different cellular compartments of IECs and discuss the recent developments in the understanding of their role in microbial recognition. Microbial recognition and signaling at the epithelial barrier have implications in the maintenance of intestinal homeostasis, epithelial barrier function, maintenance of commensals, and the overall tolerogenic function of PRRs in the gut mucosa. We also highlight the role of an aberrant microbial sensing at the epithelial barrier in the pathogenesis of inflammatory bowel disease (IBD) and the development of colorectal cancer.
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Affiliation(s)
- Krishna Iyer
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, United States
| | - Lena Erkert
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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23
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Geng Y, Sun YJ, Song H, Miao QJ, Wang YF, Qi JL, Xu XL, Sun JF. Construction and Identification of an NLR-Associated Prognostic Signature Revealing the Heterogeneous Immune Response in Skin Cutaneous Melanoma. Clin Cosmet Investig Dermatol 2023; 16:1623-1639. [PMID: 37396711 PMCID: PMC10312339 DOI: 10.2147/ccid.s410723] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/31/2023] [Indexed: 07/04/2023]
Abstract
Background Skin cutaneous melanoma (SKCM) is the deadliest dermatology tumor. Ongoing researches have confirmed that the NOD-like receptors (NLRs) family are crucial in driving carcinogenesis. However, the function of NLRs signaling pathway-related genes in SKCM remains unclear. Objective To establish and identify an NLRs-related prognostic signature and to explore its predictive power for heterogeneous immune response in SKCM patients. Methods Establishment of the predictive signature using the NLRs-related genes by least absolute shrinkage and selection operator-Cox regression analysis (LASSO-COX algorithm). Through univariate and multivariate COX analyses, NLRs signature's independent predictive effectiveness was proven. CIBERSORT examined the comparative infiltration ratios of 22 distinct types of immune cells. RT-qPCR and immunohistochemistry implemented expression validation for critical NLRs-related prognostic genes in clinical samples. Results The prognostic signature, including 7 genes, was obtained by the LASSO-Cox algorithm. In TCGA and validation cohorts, SKCM patients with higher risk scores had remarkably poorer overall survival. The independent predictive role of this signature was confirmed by multivariate Cox analysis. Additionally, a graphic nomogram demonstrated that the risk score of the NLRs signature has high predictive accuracy. SKCM patients in the low-risk group revealed a distinct immune microenvironment characterized by the significantly activated inflammatory response, interferon-α/γ response, and complement pathways. Indeed, several anti-tumor immune cell types were significantly accumulated in the low-risk group, including M1 macrophage, CD8 T cell, and activated NK cell. It is worth noting that our NLRs prognostic signature could serve as one of the promising biomarkers for predicting response rates to immune checkpoint blockade (ICB) therapy. Furthermore, the results of expression validation (RT-qPCR and IHC) were consistent with the previous analysis. Conclusion A promising NLRs signature with excellent predictive efficacy for SKCM was developed.
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Affiliation(s)
- Yi Geng
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Yu-Jie Sun
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Hao Song
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Qiu-Ju Miao
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Yi-Fei Wang
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Jin-Liang Qi
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, People’s Republic of China
| | - Xiu-Lian Xu
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
| | - Jian-Fang Sun
- Institute of Dermatology, Peking Union Medical College and Chinese Academy of Medical Sciences, Nanjing, 210042, People’s Republic of China
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Chauvin C, Alvarez-Simon D, Radulovic K, Boulard O, Laine W, Delacre M, Waldschmitt N, Segura E, Kluza J, Chamaillard M, Poulin LF. NOD2 in monocytes negatively regulates macrophage development through TNFalpha. Front Immunol 2023; 14:1181823. [PMID: 37415975 PMCID: PMC10320732 DOI: 10.3389/fimmu.2023.1181823] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/23/2023] [Indexed: 07/08/2023] Open
Abstract
Objective It is believed that intestinal recruitment of monocytes from Crohn's Disease (CD) patients who carry NOD2 risk alleles may repeatedly give rise to recruitment of pathogenic macrophages. We investigated an alternative possibility that NOD2 may rather inhibit their differentiation from intravasating monocytes. Design The monocyte fate decision was examined by using germ-free mice, mixed bone marrow chimeras and a culture system yielding macrophages and monocyte-derived dendritic cells (mo-DCs). Results We observed a decrease in the frequency of mo-DCs in the colon of Nod2-deficient mice, despite a similar abundance of monocytes. This decrease was independent of the changes in the gut microbiota and dysbiosis caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted in a Nod2-deficient mixed bone marrow (BM) chimera. The use of pharmacological inhibitors revealed that activation of NOD2 during monocyte-derived cell development, dominantly inhibits mTOR-mediated macrophage differentiation in a TNFα-dependent manner. These observations were supported by the identification of a TNFα-dependent response to muramyl dipeptide (MDP) that is specifically lost when CD14-expressing blood cells bear a frameshift mutation in NOD2. Conclusion NOD2 negatively regulates a macrophage developmental program through a feed-forward loop that could be exploited for overcoming resistance to anti-TNF therapy in CD.
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Affiliation(s)
- Camille Chauvin
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
- INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Daniel Alvarez-Simon
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
| | - Katarina Radulovic
- Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes CEDEX, France
| | | | - William Laine
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France
| | - Myriam Delacre
- U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France
| | - Nadine Waldschmitt
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Elodie Segura
- INSERM U932, Institut Curie, Paris Sciences et Lettres Research University, Paris, France
| | - Jérome Kluza
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France
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Chen K, McCulloch J, Das Neves R, Rodrigues G, Hsieh WT, Gong W, Yoshimura T, Huang J, O'hUigin C, Difilippantonio S, McCollum M, Jones G, Durum SK, Trinchieri G, Wang JM. The beneficial effects of commensal E. coli for colon epithelial cell recovery are related with Formyl peptide receptor 2 (Fpr2) in epithelial cells. Gut Pathog 2023; 15:28. [PMID: 37322488 PMCID: PMC10268441 DOI: 10.1186/s13099-023-00557-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Formyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. Commensal E. coli is known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection between E. coli and Fpr2 in the recovery of colon epithelial cells. RESULTS The deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes of E. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing. E. coli O22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated with E. coli O22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection with E. coli O22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived from E. coli O22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population of E. coli was observed to increase in the colons of Fpr2-/- mice with colitis. CONCLUSION Commensal E. coli O22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products from E. coli induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increased E. coli population in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensal E. coli on colon epithelial cell recovery.
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Affiliation(s)
- Keqiang Chen
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA.
| | - John McCulloch
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Rodrigo Das Neves
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Gisele Rodrigues
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
| | - Wang-Ting Hsieh
- Animal Health Diagnostic Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan
| | - Jiaqiang Huang
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
- College of Life Sciences, Beijing Jiaotong University, Beijing, 100044, People's Republic of China
| | - Colm O'hUigin
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Simone Difilippantonio
- Gnotobiotics Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Matthew McCollum
- Gnotobiotics Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Georgette Jones
- Gnotobiotics Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA
| | - Scott K Durum
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
| | - Giorgio Trinchieri
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Ji Ming Wang
- Laboratory of Cancer Innovation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USA
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Gao J, Wang L, Jiang J, Xu Q, Zeng N, Lu B, Yuan P, Sun K, Zhou H, He X. A probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice. Nat Commun 2023; 14:3338. [PMID: 37286542 PMCID: PMC10247697 DOI: 10.1038/s41467-023-38950-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 05/23/2023] [Indexed: 06/09/2023] Open
Abstract
Secreted proteins are one of the direct molecular mechanisms by which microbiota influence the host, thus constituting a promising field for drug discovery. Here, through bioinformatics-guided screening of the secretome of clinically established probiotics from Lactobacillus, we identify an uncharacterized secreted protein (named LPH here) that is shared by most of these probiotic strains (8/10) and demonstrate that it protects female mice from colitis in multiple models. Functional studies show that LPH is a bi-functional peptidoglycan hydrolase with both N-Acetyl-β-D-muramidase and DL-endopeptidase activities that can generate muramyl dipeptide (MDP), a NOD2 ligand. Different active site mutants of LPH in combination with Nod2 knockout female mice confirm that LPH exerts anti-colitis effects through MDP-NOD2 signaling. Furthermore, we validate that LPH can also exert protective effects on inflammation-associated colorectal cancer in female mice. Our study reports a probiotic enzyme that enhances NOD2 signaling in vivo in female mice and describes a molecular mechanism that may contribute to the effects of traditional Lactobacillus probiotics.
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Affiliation(s)
- Jie Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Jing Jiang
- Department Gerontology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, 610072, Chengdu, Sichuan, China
| | - Qian Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Nianyi Zeng
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Bingyun Lu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, 518101, Shenzhen, Guangdong, China
| | - Peibo Yuan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China
| | - Kai Sun
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China.
- State Key Laboratory of Organ Failure Research, Southern Medical University, 510655, Guangzhou, Guangdong, China.
| | - Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, 510655, Guangzhou, Guangdong, China.
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27
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Tsigalou C, Paraschaki A, Bragazzi NL, Aftzoglou K, Stavropoulou E, Tsakris Z, Vradelis S, Bezirtzoglou E. Alterations of gut microbiome following gastrointestinal surgical procedures and their potential complications. Front Cell Infect Microbiol 2023; 13:1191126. [PMID: 37333847 PMCID: PMC10272562 DOI: 10.3389/fcimb.2023.1191126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/23/2023] [Indexed: 06/20/2023] Open
Abstract
Intestinal microorganisms play a crucial role in shaping the host immunity and maintaining homeostasis. Nevertheless, alterations in gut bacterial composition may occur and these alterations have been linked with the pathogenesis of several diseases. In surgical practice, studies revealed that the microbiome of patients undergoing surgery changes and several post-operative complications seem to be associated with the gut microbiota composition. In this review, we aim to provide an overview of gut microbiota (GM) in surgical disease. We refer to several studies which describe alterations of GM in patients undergoing different types of surgery, we focus on the impacts of peri-operative interventions on GM and the role of GM in development of post-operative complications, such as anastomotic leak. The review aims to enhance comprehension regarding the correlation between GM and surgical procedures based in the current knowledge. However, preoperative and postoperative synthesis of GM needs to be further examined in future studies, so that GM-targeted measures could be assessed and the different surgery complications could be reduced.
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Affiliation(s)
- Christina Tsigalou
- Laboratory of Microbiology, Faculty of Medicine, Democritus University of Thrace, Dragana Campus, Alexandroupolis, Greece
| | - Afroditi Paraschaki
- Department of Biopathology/Microbiology, Faculty of Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Nicola Luigi Bragazzi
- Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON, Canada
| | - K. Aftzoglou
- Medical School, Comenius University, Bratislava, Slovakia
| | - Elisavet Stavropoulou
- Department of Infectious Diseases, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon, Lausanne, Switzerland
| | - Z. Tsakris
- Laboratory of Microbiology, Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - S. Vradelis
- Department of Gastrenterology, Faculty of Medicine, Democritus University of Thrace, Dragana Campus, Alexandroupolis, Greece
| | - Eugenia Bezirtzoglou
- Laboratory of Hygiene and Environmental Protection, Medical School, Democritus University of Thrace, Dragana, Alexandroupolis, Greece
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Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023:10.1038/s41571-023-00766-x. [PMID: 37169888 DOI: 10.1038/s41571-023-00766-x] [Citation(s) in RCA: 252] [Impact Index Per Article: 126.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 05/13/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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29
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Wu J, Zhang D, Zhao M, Zheng X. Gut Microbiota Dysbiosis and Increased NLRP3 Levels in Patients with Pregnancy-Induced Hypertension. Curr Microbiol 2023; 80:168. [PMID: 37024673 PMCID: PMC10079714 DOI: 10.1007/s00284-023-03252-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 03/01/2023] [Indexed: 04/08/2023]
Abstract
Pregnancy-induced hypertension (PIH) is one of the most common diseases, causing high maternal morbidity and mortality. However, the correlation of gut microbiota in PIH has not been reported. Our aim was to characterize the intestinal microbiota of patients with PIH compared with healthy people. We analyzed and compared the gut microbiota communities in the feces of 28 PIH patients with pregnancy(not pre-pregnancy) body mass index (including height and weight)-matched healthy controls using 16S rRNA gene sequencing and then investigate the relationships among gut microbiota, cytokines, and PIH. Compared with the healthy group, microbial α diversity was lower in the PIH group, but not statistically significant different. At the phylum level, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria exhibited obvious differences between the PIH and control groups. LEfSe analysis found 33 differentially abundant taxa between the two groups. The production of pro-inflammatory cytokines in PIH serum or placenta tissues was higher than that of the control group. In addition to alterations in gut microbiota composition, we also found that the Bac_Prevotellaceae, Pre_Prevotella bacteria were positively correlated with NLRP3 level, but negatively correlated with Bac_Bacteroidaceae, Bac_Bacteroides. PIH patients had gut microbiota dysbiosis and increased NLRP3 levels, which will lead to a better understanding of the relationship between the gut microbiota and PIH.
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Affiliation(s)
- Jingjing Wu
- Department of Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Dongmei Zhang
- Department of Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Meijing Zhao
- Department of Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xiaowei Zheng
- Clinical Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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30
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Gu Q, Zou J, Zhou Y, Deng Q. Mechanism of inflammasomes in cancer and targeted therapies. Front Oncol 2023; 13:1133013. [PMID: 37020871 PMCID: PMC10067570 DOI: 10.3389/fonc.2023.1133013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
Inflammasomes, composed of the nucleotide-binding oligomerization domain(NOD)-like receptors (NLRs), are immune-functional protein multimers that are closely linked to the host defense mechanism. When NLRs sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), they assemble into inflammasomes. Inflammasomes can activate various inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and produce a large number of proinflammatory cytokines, which are closely associated with multiple cancers. They can also accelerate the occurrence and development of cancer by providing suitable tumor microenvironments, promoting tumor cell proliferation, and inhibiting tumor cell apoptosis. Therefore, the exploitation of novel targeted drugs against various inflammasomes and proinflammatory cytokines is a new idea for the treatment of cancer. In recent years, more than 50 natural extracts and synthetic small molecule targeted drugs have been reported to be in the research stage or have been applied to the clinic. Herein, we will overview the mechanisms of inflammasomes in common cancers and discuss the therapeutic prospects of natural extracts and synthetic targeted agents.
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Affiliation(s)
- Qingdan Gu
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Jiazhen Zou
- Department of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated 5 Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Ying Zhou
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Qiuchan Deng
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
- *Correspondence: Qiuchan Deng,
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31
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Yang S, Hao S, Ye H, Zhang X. Global research on the crosstalk between intestinal microbiome and colorectal cancer: A visualization analysis. Front Cell Infect Microbiol 2023; 13:1083987. [PMID: 37009513 PMCID: PMC10050574 DOI: 10.3389/fcimb.2023.1083987] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
BackgroundIncreasing evidence has shown that the intestinal microbiome (IM) is highly linked to colorectal cancer (CRC). To investigate scientific output, identify highly cited papers, and explore research hotspots and trends in the field of IM/CRC, we conducted a bibliometric and visualized analysis.MethodsA bibliographic search regarding IM/CRC research (2012-2021) was implemented on October 17, 2022. The terms attached to IM and CRC were searched for in the titles (TI), abstracts (AB), and author keywords (AK). The main information was extracted from the Web of Science Core Collection (WoSCC). Biblioshiny from R packages and VOSviewer were used for data visualization.ResultsA total of 1725 papers related to IM/CRC were retrieved. Publications on IM/CRC have grown rapidly from 2012 to 2021. China and the United States were in the leading position for publications in this field and made the most significant contributions to IM/CRC research. Shanghai Jiao Tong University and Harvard University were the most productive institutions. The high-yield authors were Yu Jun and Fang Jing Yuan. The International Journal of Molecular Sciences published the most papers, whereas Gut had the most citations. Historical citation analysis showed the evolution of IM/CRC research. Current status and hotspots were highlighted using keyword cluster analysis. The hot topics include the effect of IM on tumorigenesis, the effect of IM on CRC treatment, the role of IM in CRC screening, the mechanisms of IM involvement in CRC, and IM modulation for CRC management. Some topics, such as chemotherapy, immunotherapy, Fusobacterium nucleatum and short-chain fatty acids could be the focus of IM/CRC research in the coming years.ConclusionThis research evaluated the global scientific output of IM/CRC research and its quantitative features, identified some significant papers, and gathered information on the status and trends of IM/CRC research, which may shape future paths for academics and practitioners.
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Affiliation(s)
- Shanshan Yang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Shaodong Hao
- Spleen-Stomach Department, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Ye
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
- *Correspondence: Xuezhi Zhang, ; Hui Ye,
| | - Xuezhi Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China
- *Correspondence: Xuezhi Zhang, ; Hui Ye,
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Jang KK, Heaney T, London M, Ding Y, Yeung F, Ercelen D, Chen YH, Axelrad J, Gurunathan S, Marijke Keestra-Gounder A, Griffin ME, Hang HC, Cadwell K. Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.29.526128. [PMID: 36778381 PMCID: PMC9915521 DOI: 10.1101/2023.01.29.526128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium ( Efm ) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1β secretion and increased the proportion of IL-22-producing CD4 + T helper cells and innate lymphoid cells. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
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Schwarz A, Philippsen R, Piticchio SG, Hartmann JN, Häsler R, Rose-John S, Schwarz T. Crosstalk between microbiome, regulatory T cells and HCA2 orchestrates the inflammatory response in a murine psoriasis model. Front Immunol 2023; 14:1038689. [PMID: 36891315 PMCID: PMC9986334 DOI: 10.3389/fimmu.2023.1038689] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/02/2023] [Indexed: 02/22/2023] Open
Abstract
The organ-specific microbiome plays a crucial role in tissue homeostasis, among other things by inducing regulatory T cells (Treg). This applies also to the skin and in this setting short chain fatty acids (SCFA) are relevant. It was demonstrated that topical application of SCFA controls the inflammatory response in the psoriasis-like imiquimod (IMQ)-induced murine skin inflammation model. Since SCFA signal via HCA2, a G-protein coupled receptor, and HCA2 expression is reduced in human lesional psoriatic skin, we studied the effect of HCA2 in this model. HCA2 knock-out (HCA2-KO) mice reacted to IMQ with stronger inflammation, presumably due to an impaired function of Treg. Surprisingly, injection of Treg from HCA2-KO mice even enhanced the IMQ reaction, suggesting that in the absence of HCA2 Treg switch from a suppressive into a proinflammatory type. HCA2-KO mice differed in the composition of the skin microbiome from wild type mice. Co-housing reversed the exaggerated response to IMQ and prevented the alteration of Treg, implying that the microbiome dictates the outcome of the inflammatory reaction. The switch of Treg into a proinflammatory type in HCA2-KO mice could be a downstream phenomenon. This opens the opportunity to reduce the inflammatory tendency in psoriasis by altering the skin microbiome.
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Affiliation(s)
- Agatha Schwarz
- Department of Dermatology and Allergology, University Kiel, Kiel, Germany
| | - Rebecca Philippsen
- Department of Dermatology and Allergology, University Kiel, Kiel, Germany
| | - Serena G Piticchio
- Institute of Clinical Molecular Biology (IKMB), University Kiel, Kiel, Germany.,Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain
| | - Jan N Hartmann
- Department of Dermatology and Allergology, University Kiel, Kiel, Germany
| | - Robert Häsler
- Department of Dermatology and Allergology, University Kiel, Kiel, Germany
| | | | - Thomas Schwarz
- Department of Dermatology and Allergology, University Kiel, Kiel, Germany
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Zhao H, Zhang W, Cheng D, You L, Huang Y, Lu Y. Investigating dysbiosis and microbial treatment strategies in inflammatory bowel disease based on two modified Koch's postulates. Front Med (Lausanne) 2022; 9:1023896. [PMID: 36438062 PMCID: PMC9684636 DOI: 10.3389/fmed.2022.1023896] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/28/2022] [Indexed: 12/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease that occurs in the intestinal tract. It is mainly divided into two subtypes, i.e., the Crohn's disease (CD) and ulcerative colitis (UC). At present, its pathogenesis has not been fully elucidated, but it has been generally believed that the environment, immune disorders, genetic susceptibility, and intestinal microbes are the main factors for the disease pathogenesis. With the development of the sequencing technology, microbial factors have received more and more attention. The gut microbiota is in a state of precise balance with the host, in which the host immune system is tolerant to immunogenic antigens produced by gut commensal microbes. In IBD patients, changes in the balance between pathogenic microorganisms and commensal microbes lead to changes in the composition and diversity of gut microbes, and the balance between microorganisms and the host would be disrupted. This new state is defined as dysbiosis. It has been confirmed, in both clinical and experimental settings, that dysbiosis plays an important role in the occurrence and development of IBD, but the causal relationship between dysbiosis and inflammation has not been elucidated. On the other hand, as a classic research method for pathogen identification, the Koch's postulates sets the standard for verifying the role of pathogens in disease. With the further acknowledgment of the disease pathogenesis, it is realized that the traditional Koch's postulates is not applicable to the etiology research (determination) of infectious diseases. Thus, many researchers have carried out more comprehensive and complex elaboration of Koch's postulates to help people better understand and explain disease pathogenesis through the improved Koch's postulates. Therefore, focusing on the new perspective of the improved Koch's postulates is of great significance for deeply understanding the relationship between dysbiosis and IBD. This article has reviewed the studies on dysbiosis in IBD, the use of microbial agents in the treatment of IBD, and their relationship to the modified Koch's postulates.
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Affiliation(s)
- HanZheng Zhao
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - WenHui Zhang
- Department of Pain Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Die Cheng
- Cancer Research Laboratory, Chengde Medical College, Chengde, China
| | - LiuPing You
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - YueNan Huang
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - YanJie Lu
- Cancer Research Laboratory, Chengde Medical College, Chengde, China
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Bou Zerdan M, Kassab J, Meouchy P, Haroun E, Nehme R, Bou Zerdan M, Fahed G, Petrosino M, Dutta D, Graziano S. The Lung Microbiota and Lung Cancer: A Growing Relationship. Cancers (Basel) 2022; 14:cancers14194813. [PMID: 36230736 PMCID: PMC9563611 DOI: 10.3390/cancers14194813] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/15/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary In the past few years, the microbiota has emerged as a major player in cancer management. The efficacy of chemotherapy or immunotherapy may be influenced by the concomitant use of antibiotics before, during, or shortly after treatment with immune checkpoint inhibitors. Despite this, the mechanism linking the microbiota, host immunity, and malignancies are not clear, and the role of microbiota manipulation and analyses in cancer management is underway. In this manuscript, we discuss the role of the microbiota in the initiation, progression, and treatment outcomes of lung cancer. Abstract The lung is home to a dynamic microbial population crucial to modulating immune balance. Interest in the role of the lung microbiota in disease pathogenesis and treatment has exponentially increased. In lung cancer, early studies suggested an important role of dysbiosis in tumor initiation and progression. These results have helped accelerate research into the lung microbiota as a potential diagnostic marker and therapeutic target. Microbiota signatures could represent diagnostic biomarkers of early-stage disease. Lung microbiota research is in its infancy with a limited number of studies and only single-center studies with a significant methodological variation. Large, multicenter longitudinal studies are needed to establish the clinical potential of this exciting field.
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Affiliation(s)
- Maroun Bou Zerdan
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Department of Hematology and Oncology, Cleveland Clinic Florida, Weston, FL 33326, USA
| | - Joseph Kassab
- Faculty of Medicine, Saint-Joseph University, Beirut 11072180, Lebanon
| | - Paul Meouchy
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut 11072020, Lebanon
| | - Elio Haroun
- Department of Medicine, Division of Hematology and Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Rami Nehme
- Department of Medicine, University of Pavia, 27100 Pavia, Italy
| | - Morgan Bou Zerdan
- Faculty of Medicine, American University of Beirut, Beirut 11072020, Lebanon
| | - Gracia Fahed
- Faculty of Medicine, American University of Beirut, Beirut 11072020, Lebanon
| | - Michael Petrosino
- Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Dibyendu Dutta
- Department of Medicine, Division of Hematology and Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Correspondence: (D.D.); (S.G.)
| | - Stephen Graziano
- Department of Medicine, Division of Hematology and Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
- Correspondence: (D.D.); (S.G.)
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Zhou K, Gu X, Tan H, Yu T, Liu C, Ding Z, Liu J, Shi H. Identification pyroptosis-related gene signature to predict prognosis and associated regulation axis in colon cancer. Front Pharmacol 2022; 13:1004425. [PMID: 36249755 PMCID: PMC9559861 DOI: 10.3389/fphar.2022.1004425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Background: Pyroptosis is an important component of the tumor microenvironment and associated with the occurrence and progression of cancer. As the expression of pyroptosis-related genes and its impact on the prognosis of colon cancer (CC) remains unclear, we constructed and validated a pyroptosis-related genes signature to predict the prognosis of patients with CC. Methods: Microarray datasets and the follow-up clinical information of CC patients were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Candidate genes were screened out for further analysis. Various methods were combined to construct a robust pyroptosis-related genes signature for predicting the prognosis of patients with CC. Based on the gene signature and clinical features, a decision tree and nomogram were developed to improve risk stratification and quantify risk assessment for individual patients. Results: The pyroptosis-related genes signature successfully discriminated CC patients with high-risk in the training cohorts. The prognostic value of this signature was further confirmed in independent validation cohort. Multivariable Cox regression and stratified survival analysis revealed this signature was an independent prognostic factor for CC patients. The decision tree identified risk subgroups powerfully, and the nomogram incorporating the gene signature and clinical risk factors performed well in the calibration plots. Conclusion: Pyroptosis-related genes signature was an independent prognostic factor, and can be used to predict the prognosis of patients with CC.
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Affiliation(s)
- Kexun Zhou
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
| | - Xuyu Gu
- School of Medicine, Southeast University, Nanjing, China
| | - Huaicheng Tan
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
| | - Ting Yu
- Department of Pathology and Laboratory of Pathology, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, China
| | - Chunhua Liu
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
| | - Zhenyu Ding
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
| | - Jiyan Liu
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
| | - Huashan Shi
- Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, China
- Department of Radiotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China
- *Correspondence: Huashan Shi,
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Mao L, Dhar A, Meng G, Fuss I, Montgomery-Recht K, Yang Z, Xu Q, Kitani A, Strober W. Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function. Front Immunol 2022; 13:988862. [PMID: 36189261 PMCID: PMC9520668 DOI: 10.3389/fimmu.2022.988862] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/29/2022] [Indexed: 12/02/2022] Open
Abstract
The studies described here provide an analysis of the pathogenesis of Blau syndrome and thereby the function of NOD2 as seen through the lens of its dysfunction resulting from Blau-associated NOD2 mutations in its nucleotide-binding domain (NBD). As such, this analysis also sheds light on the role of NOD2 risk polymorphisms in the LRR domain occurring in Crohn’s disease. The main finding was that Blau NOD2 mutations precipitate a loss of canonical NOD2 signaling via RIPK2 and that this loss has two consequences: first, it results in defective NOD2 ligand (MDP)-mediated NF-κB activation and second, it disrupts NOD2-mediated cross-regulation whereby NOD2 downregulates concomitant innate (TLR) responses. Strong evidence is also presented favoring the view that NOD2-mediated cross-regulation is under mechanistic control by IRF4 and that failure to up-regulate this factor because of faulty NOD2 signaling is the proximal cause of defective cross-regulation and the latter’s effect on Blau syndrome inflammation. Overall, these studies highlight the role of NOD2 as a regulatory factor and thus provide additional insight into its function in inflammatory disease. Mutations in the nucleotide binding domain of the CARD15 (NOD2) gene underlie the granulomatous inflammation characterizing Blau syndrome (BS). In studies probing the mechanism of this inflammation we show here that NOD2 plasmids expressing various Blau mutations in HEK293 cells result in reduced NOD2 activation of RIPK2 and correspondingly reduced NOD2 activation of NF-κB. These in vitro studies of NOD2 signaling were accompanied by in vivo studies showing that BS-NOD2 also exhibit defects in cross-regulation of innate responses underlying inflammation. Thus, whereas over-expressed intact NOD2 suppresses TNBS-colitis, over-expressed BS-NOD2 does not; in addition, whereas administration of NOD2 ligand (muramyl dipeptide, MDP) suppresses DSS-colitis in Wild Type (WT) mice it fails to do so in homozygous or heterozygous mice bearing a NOD2 Blau mutation. Similarly, mice bearing a Blau mutation exhibit enhanced anti-collagen antibody-induced arthritis. The basis of such cross-regulatory failure was revealed in studies showing that MDP-stimulated cells bearing BS-NOD2 exhibit a reduced capacity to signal via RIPK2 as well as a reduced capacity to up-regulate IRF4, a factor shown previously to mediate NOD2 suppression of NF-κB activation. Indeed, TLR-stimulated cells bearing a Blau mutation exhibited enhanced in vitro cytokine responses that are quieted by lentivirus transduction of IRF4. In addition, enhanced anti-collagen-induced joint inflammation in mice bearing a Blau mutation was accompanied by reduced IRF4 expression in inflamed joint tissue and IRF4 expression was reduced in MDP-stimulated cells from BS patients. Thus, inflammation characterizing Blau syndrome are caused, at least in part, by faulty canonical signaling and reduce IRF4-mediated cross-regulation.
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Affiliation(s)
- Liming Mao
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Atika Dhar
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Guangxun Meng
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- The Center for Microbes, Development and Health, Chinese Academy of Sciences (CAS) Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, China
- Pasteurien College, Soochow University, Suzhou, China
| | - Ivan Fuss
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Kim Montgomery-Recht
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., National Cancer Institute (NCI) Campus at Frederick, Frederick, MD, United States
| | - Zhiqiong Yang
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Qiuyun Xu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Atsushi Kitani
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Warren Strober,
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Qing F, Xie T, Xie L, Guo T, Liu Z. How Gut Microbiota Are Shaped by Pattern Recognition Receptors in Colitis and Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14153821. [PMID: 35954484 PMCID: PMC9367250 DOI: 10.3390/cancers14153821] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 12/21/2022] Open
Abstract
Simple Summary The pathogenesis of intestinal inflammatory disorders such as colitis and colorectal cancer is complicated and dysregulation of gut microbiota is considered an important contributing factor. Inflammation is often initiated by the activation of pattern recognition receptors. However, the relationship between these innate immune receptors and gut microbiota is not fully understood. Here, we show that pattern recognition receptors not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses, but also influence the composition of intestinal microorganisms, thus affecting the development of intestinal inflammation and cancer through various mechanisms. This suggests that the modification of innate immune receptors and relevant molecules could be therapeutic targets for the treatment of colitis and colorectal cancer by regulating gut microbiota. Abstract Disorders of gut microbiota have been closely linked to the occurrence of various intestinal diseases including colitis and colorectal cancer (CRC). Specifically, the production of beneficial bacteria and intestinal metabolites may slow the development of some intestinal diseases. Recently, it has been proposed that pattern recognition receptors (PRRs) not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses but also influence the composition of intestinal microorganisms. However, the mechanisms through which PRRs regulate gut microbiota in the setting of colitis and CRC have rarely been systematically reviewed. Therefore, in this paper, we summarize recent advances in our understanding of how PRRs shape gut microbiota and how this influences the development of colitis and CRC.
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Affiliation(s)
- Furong Qing
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
- School of Graduate, Gannan Medical University, Ganzhou 341000, China
| | - Tao Xie
- Center for Scientific Research, Gannan Medical University, Ganzhou 341000, China
| | - Lu Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Tianfu Guo
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
- Correspondence: (T.G.); (Z.L.)
| | - Zhiping Liu
- Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
- Center for Scientific Research, Gannan Medical University, Ganzhou 341000, China
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
- Correspondence: (T.G.); (Z.L.)
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Ahmad S, Ashktorab H, Brim H, Housseau F. Inflammation, microbiome and colorectal cancer disparity in African-Americans: Are there bugs in the genetics? World J Gastroenterol 2022; 28:2782-2801. [PMID: 35978869 PMCID: PMC9280725 DOI: 10.3748/wjg.v28.i25.2782] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Dysregulated interactions between host inflammation and gut microbiota over the course of life increase the risk of colorectal cancer (CRC). While environmental factors and socio-economic realities of race remain predominant contributors to CRC disparities in African-Americans (AAs), this review focuses on the biological mediators of CRC disparity, namely the under-appreciated influence of inherited ancestral genetic regulation on mucosal innate immunity and its interaction with the microbiome. There remains a poor understanding of mechanisms linking immune-related genetic polymorphisms and microbiome diversity that could influence chronic inflammation and exacerbate CRC disparities in AAs. A better understanding of the relationship between host genetics, bacteria, and CRC pathogenesis will improve the prediction of cancer risk across race/ethnicity groups overall.
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Affiliation(s)
- Sami Ahmad
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21231, United States
| | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20060, United States
| | - Hassan Brim
- Department of Pathology, Howard University, Washington, DC 20060, United States
| | - Franck Housseau
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21231, United States
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40
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Liu Y, Yang M, Tang L, Wang F, Huang S, Liu S, Lei Y, Wang S, Xie Z, Wang W, Zhao X, Tang B, Yang S. TLR4 regulates RORγt + regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila. MICROBIOME 2022; 10:98. [PMID: 35761415 PMCID: PMC9235089 DOI: 10.1186/s40168-022-01296-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/25/2022] [Indexed: 05/05/2023]
Abstract
BACKGROUND Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4-/- mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. METHODS We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4-/- mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila (A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. RESULTS TLR4-/- mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4-/- mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt+ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis. CONCLUSIONS Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Video abstract.
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Affiliation(s)
- Yaojiang Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Min Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Li Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Fengchao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, 400037, China
| | - Shengjie Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Shuang Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Yuanyuan Lei
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Zhuo Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Wei Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China
| | - Xiaoyan Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
| | - Bo Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
| | - Shiming Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Third Military Medical University, 400037, Chongqing, China.
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Selvakumar D, Evans D, Coyte KZ, McLaughlin J, Brass A, Hancock L, Cruickshank S. Understanding the development and function of the gut microbiota in health and inflammation. Frontline Gastroenterol 2022; 13:e13-e21. [PMID: 35812026 PMCID: PMC9234741 DOI: 10.1136/flgastro-2022-102119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/29/2022] [Indexed: 02/04/2023] Open
Abstract
The gut microbiota is known to play an important role in maintaining gut health through a symbiotic relationship with the host. Altered gut microbiota is a common feature of several diseases of the gastrointestinal tract; however, the causal relationship between microbiota and disease pathogenesis is poorly understood. Necrotising enterocolitis (NEC) and inflammatory bowel disease (IBD) are both severe inflammatory diseases affecting the gastrointestinal tract. Although they affect very different patient populations, with NEC primarily being a disease of prematurity and IBD predominantly affecting adults although children can be affected, they both demonstrate common features of gut microbial dysbiosis and a dysregulated host immune response. By comparing and contrasting the changes in gut microbiota, host immune response and function, we aim to highlight common features in diseases that may seem clinically unrelated. Key areas of interest are the role of pattern recognition receptors in altered recognition and responses to the gut microbiota by the host immune system and the associated dysfunctional gut epithelial barrier. The challenge of identifying causal relationships between microbiota and disease is ever-present; however, considering a disease-agnostic approach may help to identify mechanistic pathways shared across several clinical diseases.
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Affiliation(s)
- Deepak Selvakumar
- Department of Colorectal Surgery, Manchester University NHS Foundation Trust, Manchester, UK,Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Dolan Evans
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Katharine Z Coyte
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - John McLaughlin
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK,Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Andy Brass
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Laura Hancock
- Department of Colorectal Surgery, Manchester University NHS Foundation Trust, Manchester, UK,Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Sheena Cruickshank
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Yue C, Gao S, Li S, Xing Z, Qian H, Hu Y, Wang W, Hua C. TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front Immunol 2022; 13:911919. [PMID: 35720417 PMCID: PMC9203892 DOI: 10.3389/fimmu.2022.911919] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/13/2022] [Indexed: 12/19/2022] Open
Abstract
Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.
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Affiliation(s)
- Chenran Yue
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou, China
| | - Shuting Li
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhouhang Xing
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hengrong Qian
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ying Hu
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wenqian Wang
- Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
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43
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Morrison HA, Liu Y, Eden K, Nagai-Singer MA, Wade PA, Allen IC. NLRX1 Deficiency Alters the Gut Microbiome and Is Further Exacerbated by Adherence to a Gluten-Free Diet. Front Immunol 2022; 13:882521. [PMID: 35572547 PMCID: PMC9097893 DOI: 10.3389/fimmu.2022.882521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Abstract
Patients with gluten sensitivities present with dysbiosis of the gut microbiome that is further exacerbated by a strict adherence to a gluten-free diet (GFD). A subtype of patients genetically susceptible to gluten sensitivities are Celiac Disease (CeD) patients, who are carriers of the HLA DR3/DQ2 or HLA DR4/DQ8 haplotypes. Although 85-95% of all CeD patients carry HLA DQ2, up to 25-50% of the world population carry this haplotype with only a minority developing CeD. This suggests that CeD and other gluten sensitivities are mediated by factors beyond genetics. The contribution of innate immune system signaling has been generally understudied in the context of gluten sensitivities. Thus, here we examined the role of NOD-like receptors (NLRs), a subtype of pattern recognition receptors, in maintaining the composition of the gut microbiome in animals maintained on a GFD. Human transcriptomics data revealed significant increases in the gene expression of multiple NLR family members, across functional groups, in patients with active CeD compared to control specimens. However, NLRX1 was uniquely down-regulated during active disease. NLRX1 is a negative regulatory NLR that functions to suppress inflammatory signaling and has been postulate to prevent inflammation-induced dysbiosis. Using Nlrx1-/- mice maintained on either a normal or gluten-free diet, we show that loss of NLRX1 alters the microbiome composition, and a distinctive shift further ensues following adherence to a GFD, including a reciprocal loss of beneficial microbes and increase in opportunistic bacterial populations. Finally, we evaluated the functional impact of an altered gut microbiome by assessing short- and medium-chain fatty acid production. These studies revealed significant differences in a selection of metabolic markers that when paired with 16S rRNA sequencing data could reflect an overall imbalance and loss of immune system homeostasis in the gastrointestinal system.
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Affiliation(s)
- Holly A Morrison
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - Yang Liu
- Eukaryotic Transcriptional Regulation Group, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
| | - Kristin Eden
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.,Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
| | - Margaret A Nagai-Singer
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - Paul A Wade
- Eukaryotic Transcriptional Regulation Group, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, United States
| | - Irving C Allen
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.,Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
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Inczefi O, Bacsur P, Resál T, Keresztes C, Molnár T. The Influence of Nutrition on Intestinal Permeability and the Microbiome in Health and Disease. Front Nutr 2022; 9:718710. [PMID: 35548572 PMCID: PMC9082752 DOI: 10.3389/fnut.2022.718710] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/22/2022] [Indexed: 01/09/2023] Open
Abstract
The leakage of the intestinal barrier and the disruption of the gut microbiome are increasingly recognized as key factors in different pathophysiological conditions, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), chronic liver diseases, obesity, diabetes mellitus, types of cancer, and neuropsychiatric disorders. In this study, the mechanisms leading to dysbiosis and "leaky gut" are reviewed, and a short summary of the current knowledge regarding different diseases is provided. The simplest way to restore intestinal permeability and the microbiota could be ideal nutrition. Further therapeutic options are also available, such as the administration of probiotics or postbiotics or fecal microbiota transplantation.
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Affiliation(s)
- Orsolya Inczefi
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Péter Bacsur
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Resál
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Csilla Keresztes
- Department for Medical Communication and Translation Studies, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary,*Correspondence: Tamás Molnár,
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Hwang J, Rick J, Hsiao J, Hamzavi IH, Shi VY. Microbiome in Hidradenitis Suppurativa: Current Evidence and Practice. CURRENT DERMATOLOGY REPORTS 2022. [DOI: 10.1007/s13671-021-00349-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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46
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Pre-Administration of Berberine Exerts Chemopreventive Effects in AOM/DSS-Induced Colitis-Associated Carcinogenesis Mice via Modulating Inflammation and Intestinal Microbiota. Nutrients 2022; 14:nu14040726. [PMID: 35215376 PMCID: PMC8879943 DOI: 10.3390/nu14040726] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory activation and intestinal flora imbalance play an essential role in the development and progression of colorectal cancer (CRC). Berberine (BBR) has attracted great attention in recent years due to its heath-related benefits in inflammatory disorders and tumors, but the intricate mechanisms have not been fully elucidated. In this study, the effects and the mechanism of BBR on colon cancer were investigated in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis mice model. Our results showed that pre-administration of BBR showed a decrease in weight loss, disease activity index (DAI) score, and the number of colon tumors in mice, compared with the model group. The evidence from pathological examination indicated that the malignancy of intestinal tumors was ameliorated after pre-administration of BBR. Additionally, pre-administration with BBR suppressed the expression of pro-inflammatory factors (interleukin (IL)-6, IL-1β, cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)-α) and the cell-proliferation marker Ki67, while expression of the tight junction proteins (ZO-1 and occludin) were increased in colon tissue. Moreover, the levels of critical pathway proteins involved in the inflammatory process (p-STAT3 and p-JNK) and cell cycle regulation molecules (β-catenin, c-Myc and CylinD1) exhibited lower expression levels. Besides, 16S rRNA sequence analysis indicated that pre-administration of BBR increased the ratio of Firmicutes/Bacteroidetes (F:M) and the relative abundance of potentially beneficial bacteria, while the abundance of cancer-related bacteria was decreased. Gavage with Lactobacillus rhamnosus can improve the anti-tumor effect of BBR. Overall, pre-administration of BBR exerts preventive effects in colon carcinogenesis, and the mechanisms underlying these effects are correlated with the inhibition of inflammation and tumor proliferation and the maintenance of intestinal homeostasis.
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Spalinger MR, Shawki A, Chatterjee P, Canale V, Santos A, Sayoc-Becerra A, Scharl M, Tremblay ML, Borneman J, McCole DF. Autoimmune susceptibility gene PTPN2 is required for clearance of adherent-invasive Escherichia coli by integrating bacterial uptake and lysosomal defence. Gut 2022; 71:89-99. [PMID: 33563644 PMCID: PMC8666829 DOI: 10.1136/gutjnl-2020-323636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/03/2021] [Accepted: 01/19/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Alterations in the intestinal microbiota are linked with a wide range of autoimmune and inflammatory conditions, including inflammatory bowel diseases (IBD), where pathobionts penetrate the intestinal barrier and promote inflammatory reactions. In patients with IBD, the ability of intestinal macrophages to efficiently clear invading pathogens is compromised resulting in increased bacterial translocation and excessive immune reactions. Here, we investigated how an IBD-associated loss-of-function variant in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene, or loss of PTPN2 expression affected the ability of macrophages to respond to invading bacteria. DESIGN IBD patient-derived macrophages with wild-type (WT) PTPN2 or carrying the IBD-associated PTPN2 SNP, peritoneal macrophages from WT and constitutive PTPN2-knockout mice, as well as mice specifically lacking PTPN2 in macrophages were infected with non-invasive K12 Escherichia coli, the human adherent-invasive E. coli (AIEC) LF82, or a novel mouse AIEC (mAIEC) strain. RESULTS Loss of PTPN2 severely compromises the ability of macrophages to clear invading bacteria. Specifically, loss of functional PTPN2 promoted pathobiont invasion/uptake into macrophages and intracellular survival/proliferation by three distinct mechanisms: Increased bacterial uptake was mediated by enhanced expression of carcinoembryonic antigen cellular adhesion molecule (CEACAM)1 and CEACAM6 in PTPN2-deficient cells, while reduced bacterial clearance resulted from defects in autophagy coupled with compromised lysosomal acidification. In vivo, mice lacking PTPN2 in macrophages were more susceptible to mAIEC infection and mAIEC-induced disease. CONCLUSIONS Our findings reveal a tripartite regulatory mechanism by which PTPN2 preserves macrophage antibacterial function, thus crucially contributing to host defence against invading bacteria.
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Affiliation(s)
- Marianne Rebecca Spalinger
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Ali Shawki
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
| | - Pritha Chatterjee
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
| | - Vinicius Canale
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
| | - Alina Santos
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
| | - Anica Sayoc-Becerra
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Michel L Tremblay
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Goodman Cancer Research Centre, Rosalind and Morris Goodman Cancer Research Centre, Montreal, Quebec, Canada
| | - James Borneman
- Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, California, USA
| | - Declan F McCole
- Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, California, USA
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Caparrós E, Wiest R, Scharl M, Rogler G, Gutiérrez Casbas A, Yilmaz B, Wawrzyniak M, Francés R. Dysbiotic microbiota interactions in Crohn's disease. Gut Microbes 2021; 13:1949096. [PMID: 34313550 PMCID: PMC8320851 DOI: 10.1080/19490976.2021.1949096] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.
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Affiliation(s)
- Esther Caparrós
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain
| | - Reiner Wiest
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Ana Gutiérrez Casbas
- Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain
| | - Bahtiyar Yilmaz
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Rubén Francés
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain,CONTACT Rubén Francés Hepatic and Intestinal Immunobiology Group. Departamento De Medicina Clínica, Universidad Miguel Hernández De Elche. Carretera Alicante-Valencia, Km 8,703550San Juan De Alicante
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Pratt M, Forbes JD, Knox NC, Bernstein CN, Van Domselaar G. Microbiome-Mediated Immune Signaling in Inflammatory Bowel Disease and Colorectal Cancer: Support From Meta-omics Data. Front Cell Dev Biol 2021; 9:716604. [PMID: 34869308 PMCID: PMC8635193 DOI: 10.3389/fcell.2021.716604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/31/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic intestinal inflammation and microbial dysbiosis are hallmarks of colorectal cancer (CRC) and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. However, the mechanistic relationship between gut dysbiosis and disease has not yet been fully characterized. Although the “trigger” of intestinal inflammation remains unknown, a wealth of evidence supports the role of the gut microbiome as a mutualistic pseudo-organ that significantly influences intestinal homeostasis and is capable of regulating host immunity. In recent years, culture-independent methods for assessing microbial communities as a whole (termed meta-omics) have grown beyond taxonomic identification and genome characterization (metagenomics) into new fields of research that collectively expand our knowledge of microbiomes. Metatranscriptomics, metaproteomics, and metabolomics are meta-omics techniques that aim to describe and quantify the functional activity of the gut microbiome. Uncovering microbial metabolic contributions in the context of IBD and CRC using these approaches provides insight into how the metabolic microenvironment of the GI tract shapes microbial community structure and how the microbiome, in turn, influences the surrounding ecosystem. Immunological studies in germ-free and wild-type mice have described several host-microbiome interactions that may play a role in autoinflammation. Chronic colitis is a precursor to CRC, and changes in the gut microbiome may be an important link triggering the neoplastic process in chronic colitis. In this review, we describe several microbiome-mediated mechanisms of host immune signaling, such as short-chain fatty acid (SCFA) and bile acid metabolism, inflammasome activation, and cytokine regulation in the context of IBD and CRC, and discuss the supporting role for these mechanisms by meta-omics data.
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Affiliation(s)
- Molly Pratt
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Jessica D Forbes
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Natalie C Knox
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Charles N Bernstein
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.,IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Gary Van Domselaar
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.,National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
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Cao X, Cordova AF, Li L. Therapeutic Interventions Targeting Innate Immune Receptors: A Balancing Act. Chem Rev 2021; 122:3414-3458. [PMID: 34870969 DOI: 10.1021/acs.chemrev.1c00716] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The innate immune system is an organism's first line of defense against an onslaught of internal and external threats. The downstream adaptive immune system has been a popular target for therapeutic intervention, while there is a relative paucity of therapeutics targeting the innate immune system. However, the innate immune system plays a critical role in many human diseases, such as microbial infection, cancer, and autoimmunity, highlighting the need for ongoing therapeutic research. In this review, we discuss the major innate immune pathways and detail the molecular strategies underpinning successful therapeutics targeting each pathway as well as previous and ongoing efforts. We will also discuss any recent discoveries that could inform the development of novel therapeutic strategies. As our understanding of the innate immune system continues to develop, we envision that therapies harnessing the power of the innate immune system will become the mainstay of treatment for a wide variety of human diseases.
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