1
|
Zhang Y, Ji X, Chang K, Yin H, Zhao M, Zhao L. The regulatory effect of chitooligosaccharides on islet inflammation in T2D individuals after islet cell transplantation: the mechanism behind Candida albicans abundance and macrophage polarization. Gut Microbes 2025; 17:2442051. [PMID: 39694919 DOI: 10.1080/19490976.2024.2442051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
Islet cell transplantation (ICT) represents a promising therapeutic approach for addressing diabetes mellitus. However, the islet inflammation during transplantation significantly reduces the surgical outcome rate, which is related to the polarization of macrophages. Chitooligosaccharides (COS) was previously reported which could modulate the immune system, alleviate inflammation, regulate gut microecology, and repair the intestinal barrier. Therefore, we hypothesized COS could relieve pancreatic inflammation by regulating macrophage polarization and gut microbiota. First, 18S rDNA gene sequencing was performed on fecal samples from the ICT population, showing abnormally increased amount of Candida albicans, possibly causing pancreatic inflammation. Functional oligosaccharides responsible for regulating macrophage polarization and inhibiting the growth of Candida albicans were screened. Afterwards, human flora-associated T2D (HMA-T2D) mouse models of gut microbiota were established, and the ability of the selected oligosaccharides were validated in vivo to alleviate inflammation and regulate gut microbiota. The results indicated that ICT significantly decreased the alpha diversity of gut fungal, altered fungal community structures, and increased Candida albicans abundance. Moreover, Candida albicans promoted M1 macrophage polarization, leading to islet inflammation. COS inhibited Candida albicans growth, suppressed the MyD88-NF-κB pathway, activated STAT6, inhibited M1, and promoted M2 macrophage polarization. Furthermore, COS-treated HMA-T2D mice displayed lower M1 macrophage differentiation and higher M2 macrophage numbers. Additionally, COS also enhanced ZO-1 and Occludin mRNA expression, reduced Candida albicans abundance, and balanced gut microecology. This study illustrated that COS modulated macrophage polarization via the MyD88/NF-κB and STAT6 pathways, repaired the intestinal barrier, and reduced Candida albicans abundance to alleviate islet inflammation.
Collapse
Affiliation(s)
- Yayu Zhang
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China
| | - Xiaoguo Ji
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai, China
| | - Kunlin Chang
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China
| | - Hao Yin
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai, China
| | - Mengyao Zhao
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai, China
| | - Liming Zhao
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai, China
- Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCICBT), Shanghai, China
- Organ Transplant Center, Shanghai Changzheng Hospital, Shanghai, China
| |
Collapse
|
2
|
Liu L, Shi J, Wang H, Du H, Yang J, Wei K, Zhou Z, Li M, Huang S, Zhan L, Li G, Lv Y, Shen H, Cai W. The characteristics of tissue microbiota in different anatomical locations and different tissue types of the colorectum in patients with colorectal cancer. mSystems 2025:e0019825. [PMID: 40422085 DOI: 10.1128/msystems.00198-25] [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: 02/10/2025] [Accepted: 04/27/2025] [Indexed: 05/28/2025] Open
Abstract
The gut microbiota is intricately associated with the onset and progression of colorectal cancer (CRC), leading to significant interest in developing prevention and treatment strategies that leverage gut microbiota. In this study, we collected 57 samples from 19 CRC patients, comprising cancerous tissue, paracancerous tissue, and normal mucosa. Utilizing metagenomic sequencing and bioinformatics analysis, we identified differences in the microbiomes and their functional characteristics across the various tissue types. The results indicated that species such as Alistipes putredinis were predominantly found in normal tissues, while Pseudomonas putida was enriched in paracancerous tissue, and Malassezia restricta was prevalent in cancerous tissues. Furthermore, the microbial functions exhibited variability among the different tissue types. Random forest analysis suggested that Moraxella osloensis may be implicated in the onset and progression of colorectal cancer. We also classified the patients into three subgroups based on the anatomical location of the colorectum: right-sided colon, left-sided colon, and rectum. The subgroup analysis revealed that the microbiota enriched in normal mucosa and paracancerous tissue varied across different anatomical sites. These findings not only elucidate the characteristics of the microbiomes in the normal mucosa, paracancerous tissue, and cancerous tissues of CRC patients, thereby providing new potential targets for clinical diagnosis and treatment, but also contribute to the existing microbiome data pertinent to CRC research.IMPORTANCEThis study provides crucial insights into the relationship between gut microbiota and colorectal cancer (CRC) by analyzing microbial communities in different tissue types and anatomical locations of CRC patients. We identified distinct microbial signatures, such as Alistipes putredinis in normal tissues and Malassezia restricta in cancerous tissues, indicating location-specific microbiomes with unique functional attributes. These findings suggest potential new biomarkers or therapeutic targets for CRC. The observed microbiota variations among right-sided colon, left-sided colon, and rectum cancers underscore the heterogeneity of CRC, pointing toward more personalized treatment strategies. By enhancing our understanding of the microbiome's role in CRC, this research paves the way for innovative diagnostic tools and targeted therapies tailored to individual patient profiles. This work is essential for advancing clinical approaches to CRC management.
Collapse
Affiliation(s)
- Lei Liu
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Hui Wang
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Hansong Du
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Jia Yang
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Wei
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Zhuohui Zhou
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Moli Li
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Shuai Huang
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lifang Zhan
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| | - Guolong Li
- School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Yongling Lv
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
- School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Hexiao Shen
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
- School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Wei Cai
- Department of Gastrointestinal Surgery and Intestinal Microenvironment Treatment Center, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Intestinal Microecological Diagnostics, Therapeutics, and Clinical Translation, Wuhan, Hubei, China
| |
Collapse
|
3
|
Tan Q, Cao X, Zou F, Wang H, Xiong L, Deng S. Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance. Biomedicines 2025; 13:1261. [PMID: 40427087 DOI: 10.3390/biomedicines13051261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2025] [Revised: 05/18/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025] Open
Abstract
The intratumoral microbiota, as an important component of the tumor microenvironment, is increasingly recognized as a key factor in regulating responses to cancer immunotherapy. Recent studies have revealed that the intratumoral microbiota is not uniformly distributed but instead exhibits significant spatial heterogeneity, with its distribution patterns influenced by factors such as tumor anatomy, local immune status, and therapeutic interventions. This spatial heterogeneity not only alters the interactions between microbes and the host immune system but may also reshape the immunogenic and immunosuppressive landscapes of tumors. The enrichment or depletion of microbiota in different tumor regions can influence immune cell infiltration patterns, metabolic pathway activities, and immune checkpoint molecule expression, thereby driving the development of resistance to immunotherapy. Moreover, certain bacterial metabolites form concentration gradients between the tumor core and margins, thereby regulating immune cell function. Therefore, understanding and manipulating the spatial distribution of intratumoral microbiota, particularly in resistant patients, holds promise for developing new strategies to overcome immunotherapy resistance. In the future, precise modulation strategies targeting microbial spatial heterogeneity, such as engineered bacterial vectors, probiotic combinations, and phage therapy, may open new avenues for immunotherapy.
Collapse
Affiliation(s)
- Qiwen Tan
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiongjing Cao
- Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Falong Zou
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hanwenchen Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lijuan Xiong
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Nosocomial Infection Management, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shenghe Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
4
|
Abdillah A, Ravaux I, Mokhtari S, Ranque S. Do Malassezia yeasts colonize the guts of people living with HIV? PLoS One 2025; 20:e0322982. [PMID: 40397921 DOI: 10.1371/journal.pone.0322982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 04/01/2025] [Indexed: 05/23/2025] Open
Abstract
Malassezia yeasts are commensals of human skin. In contrast to culture-based studies, metagenomic studies have detected abundant Malassezia reads in the gut, especially in patients living with HIV. Whether Malassezia colonizes and persists in the gut remains an open question. This study aimed to describe the influence of HIV-associated immunodeficiency on gut colonization by Malassezia and to assess whether Malassezia are alive. Stool samples were prospectively collected over one-five visits from ten controls and 23 patients living with HIV (10 had CD4 < 200/mm3 and 13 had CD4 > 500/mm3). Each sample was cultured and subjected to Malassezia viability PCR and both fungal and bacterial metabarcoding. Abundant M. furfur colonies were cultured from an HIV-immunocompromised patient. M. furfur and M. globosa were isolated in very low quantities from healthy volunteers. Viability Malassezia-specific qPCR was positive in three HIV-immunocompromised patients. Metagenomic analyses showed that Malassezia reads were significantly more abundant in immunocompromised patients living with HIV and erratic over time in all participants. Our findings emphasise that Malassezia are rarely cultured from human stool samples, despite the use of specific culture media. Although HIV-related immunosuppression appears to be associated with the presence of Malassezia, these yeasts do not persist and colonise the gut, even in immunocompromised patients.
Collapse
Affiliation(s)
- Abdourahim Abdillah
- Aix-Marseille Université, AP-HM, SSA, RITMES, Marseille, France
- IHU Méditerranée Infection, Marseille, France
| | - Isabelle Ravaux
- Hôpital de Jour, Pôle des Maladies Infectieuses et Tropicales, AP-HM, CHU La Timone, Marseille, France
| | - Saadia Mokhtari
- Hôpital de Jour, Pôle des Maladies Infectieuses et Tropicales, AP-HM, CHU La Timone, Marseille, France
| | - Stéphane Ranque
- Aix-Marseille Université, AP-HM, SSA, RITMES, Marseille, France
- IHU Méditerranée Infection, Marseille, France
| |
Collapse
|
5
|
Zhou YD, Komnick MR, Sepulveda F, Liu G, Nieves-Ortiz E, Meador K, Ndatabaye O, Fatkhullina A, Bozicevich A, Juengel B, Wu-Woods NJ, Naydenkov PM, Kent J, Christiansen N, Madariaga ML, Witkowski P, Ismagilov RF, Esterházy D. Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases. Mucosal Immunol 2025:S1933-0219(25)00050-9. [PMID: 40398680 DOI: 10.1016/j.mucimm.2025.05.003] [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: 10/19/2024] [Revised: 04/21/2025] [Accepted: 05/09/2025] [Indexed: 05/23/2025]
Abstract
The REG/Reg gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in REG/Reg isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as "inducible" and others as "constitutive". Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible Reg members were upregulated in the pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.
Collapse
Affiliation(s)
- Yixuan D Zhou
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Macy R Komnick
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | | | - Grace Liu
- The College, University of Chicago, Chicago, IL, USA
| | - Elida Nieves-Ortiz
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Kelsey Meador
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | | | - Aliia Fatkhullina
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Asha Bozicevich
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Braden Juengel
- The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Natalie J Wu-Woods
- Biology and Bioengineering, California Institute of Technology, Pasadena, CA, USA
| | - Paulina M Naydenkov
- Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, USA
| | - Johnathan Kent
- Department of Surgery, University of Chicago, Chicago, IL, USA
| | | | | | - Piotr Witkowski
- The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Rustem F Ismagilov
- Biology and Bioengineering, California Institute of Technology, Pasadena, CA, USA; Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, USA
| | - Daria Esterházy
- Department of Pathology, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA.
| |
Collapse
|
6
|
Liu C, Ma R, Li H, Pan X, Qian H, Yang T, Tian Y. Akkermansia muciniphila ameliorates fatty liver through microbiota-derived α-ketoisovaleric acid metabolism and hepatic PI3K/Akt signaling. iScience 2025; 28:112458. [PMID: 40343268 PMCID: PMC12059670 DOI: 10.1016/j.isci.2025.112458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/10/2024] [Accepted: 04/11/2025] [Indexed: 05/11/2025] Open
Abstract
Akkermansia muciniphila (Akk) has been shown to improve obesity via gut microbiota, while its effects on modulating gut fungi remain underexplored. This study investigates the effects of Akk on obese mice, focusing on gut fungi, metabolites, and hepatic lipid metabolism. We found that Akk treatment significantly modulated gut fungal diversity, enhanced gut immune responses, and improved fatty liver. Specifically, the abundance of harmful fungi Fusarium decreased. Subsequently, Akk improved hepatic lipid metabolism via the PI3K/Akt pathway, as determined by proteomics analysis. Additionally, an in vitro colonic organoid and microbiota co-culture system confirmed these effects by validating changes in key fungi and metabolites. Crucially, α-ketoisovaleric acid was identified as a pivotal metabolite, as its supplementation significantly improved hepatic lipid metabolism via PI3K/Akt pathway in obese mice. This study highlights Akk's potential as a therapeutic agent for obesity by modulating gut fungi and identifying α-ketoisovaleric acid as a critical metabolite.
Collapse
Affiliation(s)
- Chang Liu
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Rongrong Ma
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Han Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Xiaohua Pan
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
| | - Tianyi Yang
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- Analysis and Testing Center, Jiangnan University, Wuxi 214122, China
| | - Yaoqi Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China
- Analysis and Testing Center, Jiangnan University, Wuxi 214122, China
| |
Collapse
|
7
|
Lipke PN. Not gently down the stream: flow induces amyloid bonding in environmental and pathological fungal biofilms. mBio 2025:e0020325. [PMID: 40377304 DOI: 10.1128/mbio.00203-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025] Open
Abstract
Surface-bound biofilms are the predominant microbial life form in the environment and host organisms. Many biofilms survive and thrive under physical stress from liquid flow in streams, fuel lines, blood, and airways. Strategies for biofilm persistence include shear-dependent adhesion (called catch bonding). In some cases, biofilms are physically strengthened by the formation of cross-β bonds between proteins: the same process that generates amyloids. Cross-β bonds have low dissociation rates. In biofilms, they bind cells to substrates, each other, and the biofilm matrix. Most fungal adhesins include amino acid sequences that can form amyloids. Shear flow activates these adhesins by unfolding pseudo-stable protein domains. The unfolding exposes sequence segments that can form cross-β bonds. These segments interact to form high-avidity adhesin patches on the cell surface. Thus, cross-β bonding is a consequence of flow-induced exposure of the cross-β core sequences. Liquid flow leads to both biofilm establishment through catch bonding and biofilm strengthening through amyloid-like bonds. This shear-dependent induction of biofilm establishment and persistence is a model for many microbial systems.IMPORTANCEThe microbes in biofilms persist in many environments, including industrial and pathological settings. These surface-associated communities show high resistance to antibiotics and microbicides. Biofilms also resist scouring by liquid flow. Amyloid-like cross-β bonds allow the establishment, strengthening, and persistence of many biofilms. This discovery opens a window on the novel use of anti-amyloid strategies to control microbes in biofilms.
Collapse
Affiliation(s)
- Peter N Lipke
- Biology Department, Brooklyn College of the City University of New York, Brooklyn, New York, USA
| |
Collapse
|
8
|
Mizutani H, Fukui S, Oosuka K, Ikeda K, Kobayashi M, Shimada Y, Nakazawa Y, Nishiura Y, Suga D, Moritani I, Yamanaka Y, Inoue H, Nakagawa H, Dohi K, Kaiju H, Takaba K, Wada H, Shiraki K. Biliary microbiome profiling via 16 S rRNA amplicon sequencing in patients with cholangiocarcinoma, pancreatic carcinoma and choledocholithiasis. Sci Rep 2025; 15:16966. [PMID: 40374795 PMCID: PMC12081727 DOI: 10.1038/s41598-025-00976-6] [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: 01/05/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
Recent studies have revealed that oral, gut, and intratumoral microbial dysbiosis significantly affects tumor progression, therapy resistance, and prognosis in cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) patients. However, the biliary microbiome, which directly interacts with malignant tissues, remains poorly understood. In this study, we analyzed the bile microbiota from 17 CCA, 15 PDAC, and 40 choledocholithiasis (CDL) patients using bacterial 16 S rRNA and fungal ITS sequencing. Principal coordinate analysis revealed significant differences in microbial communities between the cancer and CDL groups. The microbial community structure in each group demonstrated a specific pattern. Linear discriminant analysis revealed Streptococcus, Sphingomonas, and Bacillus enrichment in CCA patients, Neisseria, Sphingomonas, and Caulobacter in PDAC patients were more prevalent compared with CDL patients. Caulobacter was more prevalent, wheares Campylobacter was less in PDAC patients than in CCA patients. Fungal DNA was detected in ~ 50% of the samples, with CCA and PDAC patients. KEGG pathway analysis revealed altered metabolic pathways, including peptidoglycan, sphingolipid, and fatty acid metabolism and bile acid metabolism, in CCA and PDAC patients. These findings highlight the potential role of the biliary microbiome in CCA and PDAC pathogenesis, offering new insights into disease mechanisms and biomarkers.
Collapse
Affiliation(s)
- Hiroki Mizutani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Shunsuke Fukui
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Kazuki Oosuka
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Kohei Ikeda
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Mayu Kobayashi
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yasuaki Shimada
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yuuichi Nakazawa
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yuuki Nishiura
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Daisuke Suga
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Isao Moritani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Yutaka Yamanaka
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Hidekazu Inoue
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroyuki Kaiju
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Kei Takaba
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Hideo Wada
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Katsuya Shiraki
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, 5450-132, 510-8561, Mie, Japan.
- Department of Research Center, Mie Prefectural General Medical Center, Yokkaichi, Japan.
| |
Collapse
|
9
|
Zhang X, Fam KT, Dai T, Hang HC. Microbiota mechanisms in cancer progression and therapy. Cell Chem Biol 2025; 32:653-677. [PMID: 40334660 DOI: 10.1016/j.chembiol.2025.04.005] [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: 11/05/2024] [Revised: 03/19/2025] [Accepted: 04/13/2025] [Indexed: 05/09/2025]
Abstract
The composition of the microbiota in patients has been shown to correlate with cancer progression and response to therapy, highlighting unique opportunities to improve patient outcomes. In this review, we discuss the challenges and advancements in understanding the chemical mechanisms of specific microbiota species, pathways, and molecules involved in cancer progression and treatment. We also describe the modulation of cancer and immunotherapy by the microbiota, along with approaches for investigating microbiota enzymes and metabolites. Elucidating these specific microbiota mechanisms and molecules should offer new opportunities for developing enhanced diagnostics and therapeutics to improve outcomes for cancer patients. Nonetheless, many microbiota mechanisms remain to be determined and require innovative chemical genetic approaches.
Collapse
Affiliation(s)
- Xing Zhang
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Kyong Tkhe Fam
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Tingting Dai
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Howard C Hang
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA.
| |
Collapse
|
10
|
Glapiński F, Zając W, Fudalej M, Deptała A, Czerw A, Sygit K, Kozłowski R, Badowska-Kozakiewicz A. The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies. Cancers (Basel) 2025; 17:1599. [PMID: 40427098 DOI: 10.3390/cancers17101599] [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: 04/07/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue.
Collapse
Affiliation(s)
- Franciszek Glapiński
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Weronika Zając
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Remigiusz Kozłowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
| | | |
Collapse
|
11
|
Zhang R, Zhang X, Lau HCH, Yu J. Gut microbiota in cancer initiation, development and therapy. SCIENCE CHINA. LIFE SCIENCES 2025; 68:1283-1308. [PMID: 39821827 DOI: 10.1007/s11427-024-2831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.
Collapse
Affiliation(s)
- Ruyi Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, 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, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
| |
Collapse
|
12
|
Nobels A, van Marcke C, Jordan BF, Van Hul M, Cani PD. The gut microbiome and cancer: from tumorigenesis to therapy. Nat Metab 2025; 7:895-917. [PMID: 40329009 DOI: 10.1038/s42255-025-01287-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 03/20/2025] [Indexed: 05/08/2025]
Abstract
The gut microbiome has a crucial role in cancer development and therapy through its interactions with the immune system and tumour microenvironment. Although evidence links gut microbiota composition to cancer progression, its precise role in modulating treatment responses remains unclear. In this Review, we summarize current knowledge on the gut microbiome's involvement in cancer, covering its role in tumour initiation and progression, interactions with chemotherapy, radiotherapy and targeted therapies, and its influence on cancer immunotherapy. We discuss the impact of microbial metabolites on immune responses, the relationship between specific bacterial species and treatment outcomes, and potential microbiota-based therapeutic strategies, including dietary interventions, probiotics and faecal microbiota transplantation. Understanding these complex microbiota-immune interactions is critical for optimizing cancer therapies. Future research should focus on defining microbial signatures associated with treatment success and developing targeted microbiome modulation strategies to enhance patient outcomes.
Collapse
Affiliation(s)
- Amandine Nobels
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- UCLouvain, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique (IREC), Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium
| | - Cédric van Marcke
- UCLouvain, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique (IREC), Pole of Medical Imaging, Radiotherapy and Oncology (MIRO), Brussels, Belgium
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Bénédicte F Jordan
- UCLouvain, Université catholique de Louvain, Biomedical Magnetic Resonance group (REMA), Louvain Drug Research Institute (LDRI), Brussels, Belgium
| | - Matthias Van Hul
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium.
| | - Patrice D Cani
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium.
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research (IREC), Brussels, Belgium.
| |
Collapse
|
13
|
Chen P, Tian W, Zeng A, Gu H, Zeng J. Regulating Intratumoral Fungi With Hydrogels: A Novel Approach to Modulating the Tumor Microbiome for Cancer Therapy. Cancer Med 2025; 14:e70900. [PMID: 40304214 PMCID: PMC12041943 DOI: 10.1002/cam4.70900] [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: 01/17/2025] [Revised: 03/27/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND Fungi in tumors act as a double-edged sword, potentially worsening or alleviating malignancy based on the ecological balance within the tumor microenvironment (TME). Hydrogels, as innovative drug delivery systems, are poised to redefine treatment paradigms. As advanced biomaterials, they offer a versatile platform for encapsulating and releasing antifungal agents and immunomodulators, responding to the TME's unique demands. METHODS We have conducted and collated numerous relevant reviews and studies in recent years from three aspects: Hydrogels, intra-tumoral fungi, and tumor microbe microenvironment, in the hope of identifying the connections between hydrogels and intra-tumoral microbes. RESULTS This review underscores the crucial role of intra-tumoral microbes, particularly fungi, in tumorigenesis, progression, and treatment efficacy. At the same time, we concentrated on the findings of hydrogels investigations, with their remarkable adaptability to the tumor microenvironment emerge as intelligent drug delivery systems. CONCLUSIONS Hydrogels unique ability to precisely target and modulate the tumor microflora, including fungi, endows them with a significant edge in enhancing treatment efficacy. This innovative approach not only holds great promise for improving cancer therapy outcomes but also paves the way for developing novel strategies to control metastasis and prevent cancer recurrence.
Collapse
Affiliation(s)
- Ping Chen
- Translational Chinese Medicine Key Laboratory of Sichuan ProvinceSichuan‐Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese MedicineSichuan Academy of Chinese Medicine SciencesChengduChina
| | - Weiwei Tian
- Translational Chinese Medicine Key Laboratory of Sichuan ProvinceSichuan‐Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese MedicineSichuan Academy of Chinese Medicine SciencesChengduChina
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan ProvinceSichuan‐Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese MedicineSichuan Academy of Chinese Medicine SciencesChengduChina
| | - Huan Gu
- College of Pharmacy and FoodSouthwest Minzu UniversityChengduChina
| | - Jin Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan ProvinceSichuan‐Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese MedicineSichuan Academy of Chinese Medicine SciencesChengduChina
| |
Collapse
|
14
|
Shen W, Li Z, Wang L, Liu Q, Zhang R, Yao Y, Zhao Z, Ji L. Tumor-resident Malassezia can promote hepatocellular carcinoma development by downregulating bile acid synthesis and modulating tumor microenvironment. Sci Rep 2025; 15:15020. [PMID: 40301518 PMCID: PMC12041395 DOI: 10.1038/s41598-025-99973-y] [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: 01/23/2025] [Accepted: 04/24/2025] [Indexed: 05/01/2025] Open
Abstract
Bacterial dysbiosis coincides with the carcinogenesis in malignancies such as lung and colon cancer, and has recently been suggested to involve in the pathogenesis of hepatocellular carcinoma (HCC). However, the mycobiome has not yet been definitively linked to liver tumorigenesis. Here we showed that the microbiota composition of HCC tumors was distinct from that of the normal adjacent to tumor (NAT) on the basis of richness and beta-diversity indices. Specifically, the fungal community that infiltrated HCC tumors was markedly enriched for Malassezia spp. and genus Malassezia in tumors was substantially more abundant than that in NAT. We also discovered that the relative abundance of genus Malassezia was strongly correlated with the tumor microenvironment (TME) signatures, including stromal and immune components. In addition, tumor-resident Malassezia could inhibit bile acid synthesis by downregulating the expression level of CYP7 A1 and CYP27 A1. To improve clinical usability, we developed a set of Malassezia-related genes, called Malassezia.Sig, which could accurately predict patient survival. Collectively, our work shows that tumor-resident Malasseiza may promote HCC progression by downregulating bile acid synthesis and modulating the TME, although more studies are needed.
Collapse
Affiliation(s)
- Weixi Shen
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Zhihong Li
- Ganzi Tibetan Autonomous Prefecture People's Hospital, Tibet, 850002, China
| | - Lei Wang
- Women's Health Section, Harbin Red Cross Central Hospital, Harbin, 150076, China
| | - Qi Liu
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Renjie Zhang
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yuhua Yao
- School of Mathematics and Statistics, Hainan Normal University, Haikou, 571158, China
| | - Zhicheng Zhao
- The Fourth Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150018, China.
| | - Lei Ji
- Geneis Beijing Co., Ltd, Beijing, 100102, China.
| |
Collapse
|
15
|
Adlakha YK, Chhabra R. The human microbiome: redefining cancer pathogenesis and therapy. Cancer Cell Int 2025; 25:165. [PMID: 40296128 PMCID: PMC12039184 DOI: 10.1186/s12935-025-03787-x] [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: 09/27/2024] [Accepted: 04/11/2025] [Indexed: 04/30/2025] Open
Abstract
The human microbiome has always been an important determinant of health and recently, its role has also been described in cancer. The altered microbiome could aid cancer progression, modulate chemoresistance and significantly alter drug efficacy. The broad implications of microbes in cancer have prompted researchers to investigate the microbe-cancer axis and identify whether modifying the microbiome could sensitize cancer cells for therapy and improve the survival outcome of cancer patients. The preclinical data has shown that enhancing the number of specific microbial species could restore the patients' response to cancer drugs and the microbial biomarkers may play a vital role in cancer diagnostics. The elucidation of detailed interactions of the human microbiota with cancer would not only help identify the novel drug targets but would also enhance the efficacy of existing drugs. The field exploring the emerging roles of microbiome in cancer is at a nascent stage and an in-depth scientific perspective on this topic would make it more accessible to a wider audience. In this review, we discuss the scientific evidence connecting the human microbiome to the origin and progression of cancer. We also discuss the potential mechanisms by which microbiota affects initiation of cancer, metastasis and chemoresistance. We highlight the significance of the microbiome in therapeutic outcome and evaluate the potential of microbe-based cancer therapy.
Collapse
Affiliation(s)
- Yogita K Adlakha
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Sector-125, Noida, Uttar Pradesh, 201303, India.
| | - Ravindresh Chhabra
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India.
| |
Collapse
|
16
|
Gaspar BS, Roşu OA, Enache RM, Manciulea Profir M, Pavelescu LA, Creţoiu SM. Gut Mycobiome: Latest Findings and Current Knowledge Regarding Its Significance in Human Health and Disease. J Fungi (Basel) 2025; 11:333. [PMID: 40422666 DOI: 10.3390/jof11050333] [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: 03/05/2025] [Revised: 04/16/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025] Open
Abstract
The gut mycobiome, the fungal component of the gut microbiota, plays a crucial role in health and disease. Although fungi represent a small fraction of the gut ecosystem, they influence immune responses, gut homeostasis, and disease progression. The mycobiome's composition varies with age, diet, and host factors, and its imbalance has been linked to conditions such as inflammatory bowel disease (IBD) and metabolic disorders. Advances in sequencing have expanded our understanding of gut fungi, but challenges remain due to methodological limitations and high variability between individuals. Emerging therapeutic strategies, including antifungals, probiotics, fecal microbiota transplantation, and dietary interventions, show promise but require further study. This review highlights recent discoveries on the gut mycobiome, its interactions with bacteria, its role in disease, and potential clinical applications. A deeper understanding of fungal contributions to gut health will help develop targeted microbiome-based therapies.
Collapse
Affiliation(s)
- Bogdan Severus Gaspar
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Surgery Clinic, Bucharest Emergency Clinical Hospital, 014461 Bucharest, Romania
| | - Oana Alexandra Roşu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Robert-Mihai Enache
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Monica Manciulea Profir
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania
| | - Luciana Alexandra Pavelescu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Sanda Maria Creţoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| |
Collapse
|
17
|
Verma M, Randhawa S, Bathla M, Teji N, Acharya A. Strategic use of nanomaterials as double-edged therapeutics to control carcinogenesis via regulation of dysbiosis and bacterial infection: current status and future prospects. J Mater Chem B 2025; 13:4770-4790. [PMID: 40192037 DOI: 10.1039/d4tb02409e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
The human microbiome plays a crucial role in modulating health and disease susceptibility through a complex network of interactions with the host. When the delicate balance of this microbial ecosystem is disrupted, it often correlates with the onset of systemic diseases. An over-abundance of pathogenic microorganisms within the microbiome has been implicated as a driving factor in the development of disease conditions such as diabetes, obesity, and chronic infections. It has been observed that microbiome dysbiosis perturbs metabolic, inflammatory, and immunological pathways, potentially facilitating carcinogenesis. Furthermore, the metabolites associated with microbial dysbiosis exert multifaceted effects, including metabolic interference, host DNA damage, and tumor promotion, further underscoring the microbiome's significance in several of the cancers. This new exploration of microbiome involvement in carcinogenesis needs additional patient sample analysis, which could provide new insights into cancer diagnosis and treatment. However, treating these diseases using drugs, traditional methods, etc. has resulted in multi-drug resistance, and this has eventually made the situation worrisome. This review highlights the importance of nanotechnology, which may tackle these pathogenic conditions simultaneously by targeting common receptors present in bacteria and cancer. Herein, we have explained how nanotechnology may come to the forefront for these treatments. It explores the potential of non-antibiotic disinfectants, i.e., nanoparticles (NPs) with dual targeting capabilities against microbes and cancer cells, using mechanisms such as ROS generation and DNA damage while minimizing the chances of drug resistance.
Collapse
Affiliation(s)
- Mohini Verma
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Shiwani Randhawa
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Manik Bathla
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Nandini Teji
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Amitabha Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (H.P.) 176061, India.
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India
| |
Collapse
|
18
|
Mou W, Deng Z, Zhu L, Jiang A, Lin A, Xu L, Deng G, Huang H, Guo Z, Zhu B, Wu S, Yang T, Wang L, Liu Z, Wei T, Zhang J, Cheng L, Huang H, Chen R, Shao Y, Cheng Q, Wang L, Yuan S, Luo P. Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma. SCIENCE ADVANCES 2025; 11:eadu1727. [PMID: 40203108 PMCID: PMC11980860 DOI: 10.1126/sciadv.adu1727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/27/2025] [Indexed: 04/11/2025]
Abstract
The intratumoral mycobiome plays a crucial role in the tumor microenvironment, but its impact on renal cell carcinoma (RCC) remains unclear. We collected and quantitatively profiled the intratumoral mycobiome data from 1044 patients with RCC across four international cohorts, of which 466 patients received immunotherapy. Patients were stratified into mycobiota ecology-depauperate and mycobiota ecology-flourishing (MEF) groups based on fungal abundance. The MEF group had worse prognosis, higher fungal diversity, down-regulated lipid catabolism, and exhausted CD8+ T cells. We developed the intratumoral mycobiota signature and intratumoral mycobiota-related genes expression signature, which robustly predicted prognosis and immunotherapy outcomes in RCC and other cancers. Aspergillus tanneri was identified as a potential key fungal species influencing RCC prognosis. Our findings suggest that the intratumoral mycobiome suppresses lipid catabolism and induces T cell exhaustion in RCC.
Collapse
Affiliation(s)
- Weiming Mou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Donghai County People’s Hospital–Jiangnan University Smart Healthcare Joint Laboratory, Lianyungang 222000, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zhixing Deng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Lingxuan Zhu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Liling Xu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Gengwen Deng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hongsen Huang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zeji Guo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Bang Zhu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shuqi Wu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Tao Yang
- Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lu Wang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ting Wei
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Liang Cheng
- Department of Surgery (Urology), Brown University Warren Alpert Medical School, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, Department of Surgery (Urology), Brown University Warren Alpert Medical School, Lifespan Health, and the Legorreta Cancer Center, Brown University, Providence, RI, USA
| | - Haojie Huang
- Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 311100, China
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 311100, China
- Department of Urology, Mayo Comprehensive Cancer Center, Rochester, MN, USA
| | - Rui Chen
- Department of Urology, Shanghai Jiao Tong University School of Medicine Renji Hospital, Shanghai 200127, China
| | - Yi Shao
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Shuofeng Yuan
- Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518009, China
- Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Donghai County People’s Hospital–Jiangnan University Smart Healthcare Joint Laboratory, Lianyungang 222000, China
- Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| |
Collapse
|
19
|
Garlanda C, Dambra M, Magrini E. Interplay between the complement system and other immune pathways in the tumor microenvironment. Semin Immunol 2025; 78:101951. [PMID: 40209638 DOI: 10.1016/j.smim.2025.101951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/01/2025] [Accepted: 04/01/2025] [Indexed: 04/12/2025]
Abstract
Tumor growth and spread are sustained by the tumor microenvironment. Inflammatory cells and pathways have a fundamental role in the tumor microenvironment, driving or conditioning the functional activation of other leukocyte subsets and favoring evasion of anti-tumor immunity. One of the inflammatory pathways contributing to cancer-related inflammation is the complement system. Complement has long been considered an immune mechanism associated with immunosurveillance. More recently it emerged as a tumor promoting pathway, due to direct effects on cancer cells or indirect effects via immunosuppression driven by myeloid cells. The role of complement in cancer is complex and ambiguous, and depends on the tumor type and stage, as well as other factors including oncogenic drivers, leukocyte infiltration, interactions with other tumor microenvironment components or tumor cells. Other factors of complexity include the source of complement molecules, its canonical or non-canonical extracellular functions, its potential intracellular activation, and the interaction with other systems, such as the coagulation or the microbiome. Preclinical studies generally demonstrate the involvement of complement activation in smouldering inflammation in cancer and promotion of an immunosuppressive environment. These studies paved the way for clinical trials aimed at enhancing the potential of immunotherapy, in particular by targeting complement-dependent myeloid-sustained immunosuppression. However, the complex role of complement in cancer and the multiplicity of complement players may represent stumbling blocks and account for failures of clinical trials, and suggest that further studies are required to identify patient subsets who may benefit from specific complement molecule targeting in combination with conventional therapies or immunotherapy. Here, we will discuss the anti- or pro-tumor role of complement activation in cancer, focusing on the interactions of complement with immune cells within the tumor microenvironment, in particular the myeloid compartment. Furthermore, we will examine the potential of complement targeting in cancer treatment, particularly in the context of macrophage reprogramming.
Collapse
Affiliation(s)
- Cecilia Garlanda
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele 20072, Italy; IRCCS, Humanitas Research Hospital, Milan, Rozzano 20089, Italy.
| | - Monica Dambra
- IRCCS, Humanitas Research Hospital, Milan, Rozzano 20089, Italy
| | - Elena Magrini
- IRCCS, Humanitas Research Hospital, Milan, Rozzano 20089, Italy
| |
Collapse
|
20
|
El Jaddaoui I, Sehli S, Al Idrissi N, Bakri Y, Belyamani L, Ghazal H. The Gut Mycobiome for Precision Medicine. J Fungi (Basel) 2025; 11:279. [PMID: 40278100 PMCID: PMC12028274 DOI: 10.3390/jof11040279] [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: 03/08/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/26/2025] Open
Abstract
The human gastrointestinal tract harbors a vast array of microorganisms, which play essential roles in maintaining metabolic balance and immune function. While bacteria dominate the gut microbiome, fungi represent a much smaller, often overlooked fraction. Despite their relatively low abundance, fungi may significantly influence both health and disease. Advances in next-generation sequencing, metagenomics, metatranscriptomics, metaproteomics, metabolomics, and computational biology have provided novel opportunities to study the gut mycobiome, shedding light on its composition, functional genes, and metabolite interactions. Emerging evidence links fungal dysbiosis to various diseases, including inflammatory bowel disease, colorectal cancer, metabolic disorders, and neurological conditions. The gut mycobiome also presents a promising avenue for precision medicine, particularly in biomarker discovery, disease diagnostics, and targeted therapeutics. Nonetheless, significant challenges remain in effectively integrating gut mycobiome knowledge into clinical practice. This review examines gut fungal microbiota, highlighting analytical methods, associations with human diseases, and its potential role in precision medicine. It also discusses pathways for clinical translation, particularly in diagnosis and treatment, while addressing key barriers to implementation.
Collapse
Affiliation(s)
- Islam El Jaddaoui
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, University Mohammed V, Rabat 10000, Morocco; (I.E.J.); (Y.B.)
- Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat 10000, Morocco
- Laboratory of Precision Medicine & One Health (MedPreOne), School of Medicine, Mohammed VI University of Sciences & Health, Casablanca 82403, Morocco; (S.S.); (N.A.I.)
| | - Sofia Sehli
- Laboratory of Precision Medicine & One Health (MedPreOne), School of Medicine, Mohammed VI University of Sciences & Health, Casablanca 82403, Morocco; (S.S.); (N.A.I.)
| | - Najib Al Idrissi
- Laboratory of Precision Medicine & One Health (MedPreOne), School of Medicine, Mohammed VI University of Sciences & Health, Casablanca 82403, Morocco; (S.S.); (N.A.I.)
| | - Youssef Bakri
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, University Mohammed V, Rabat 10000, Morocco; (I.E.J.); (Y.B.)
- Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat 10000, Morocco
| | - Lahcen Belyamani
- School of Medicine, Mohammed VI University of Sciences & Health, Casablanca 82403, Morocco;
| | - Hassan Ghazal
- Laboratory of Precision Medicine & One Health (MedPreOne), School of Medicine, Mohammed VI University of Sciences & Health, Casablanca 82403, Morocco; (S.S.); (N.A.I.)
- Laboratory of Sports Sciences and Performance Optimization, Royal Institute of Executive Management, Salé 10102, Morocco
- National Center for Scientific and Technical Research, Rabat 10102, Morocco
| |
Collapse
|
21
|
Li T, Wu X, Li X, Chen M. Cancer-associated fungi: An emerging powerful player in cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189287. [PMID: 39971202 DOI: 10.1016/j.bbcan.2025.189287] [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: 04/30/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
The role of the human microbiome in cancer has been extensively studied, focusing mainly on bacteria-host interactions and their impact on tumor development and treatment response. However, fungi, an immune-active component of the human microbiome, have received less attention regarding their roles in cancer. Recent studies have identified the widespread and specific colonization and distribution of fungi in multiple sites in patients across various cancer types. Importantly, host-fungal immune interactions significantly influence immune regulation within the tumor microenvironment. The rapid advancement of immune-checkpoint blockade (ICB)-based cancer immunotherapy creates an urgent need for effective biomarkers and synergistic therapeutic targets. Cancer-associated fungi and their associated antifungal immunity demonstrate significant potential and efficacy in enhancing cancer immunotherapy. This review summarizes and discusses the growing evidence of the functions and mechanisms of commensal and pathogenic cancer-associated fungi in cancer immunotherapy. Additionally, we emphasize the potential of fungi as predictive biomarkers and therapeutic targets in cancer immunotherapy.
Collapse
Affiliation(s)
- Tianhang Li
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China; Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China.
| | - Xiangyu Wu
- Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiangyang Li
- Department of Gastrointestinal Tumor Surgery, Nanjing Tianyinshan Hospital, Affiliated Hospital of China Pharmaceutical University, Nanjing, China.
| | - Ming Chen
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China; Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China.
| |
Collapse
|
22
|
Sulekha Suresh D, Jain T, Dudeja V, Iyer S, Dudeja V. From Microbiome to Malignancy: Unveiling the Gut Microbiome Dynamics in Pancreatic Carcinogenesis. Int J Mol Sci 2025; 26:3112. [PMID: 40243755 PMCID: PMC11988718 DOI: 10.3390/ijms26073112] [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: 02/01/2025] [Revised: 03/01/2025] [Accepted: 03/22/2025] [Indexed: 04/18/2025] Open
Abstract
Pancreatic cancer is a major cause of cancer-associated mortality globally, characterized by a poor prognosis and limited therapeutic response. The current approach for treating pancreatic cancer involves locoregional control with surgical resection and systemic therapy in the form of cytotoxic chemotherapy. However, despite standard-of-care treatment, the outcomes remain dismal. Emerging evidence suggests that the gut microbiota plays a significant role in pancreatic carcinogenesis through dysbiosis, chronic inflammation and immune modulation. Dysbiosis-driven alterations in the gut microbiota composition can disrupt intestinal homeostasis, promote systemic inflammation and create a tumor-permissive microenvironment in the pancreas. Moreover, the gut microbiota modulates the efficacy of systemic therapies, including chemotherapy and immunotherapy, by impacting drug metabolism and shaping the tumor immune landscape. This review is mainly focused on exploring the intricate interplay between the gut microbiota and pancreatic cancer, and also highlighting its dual role in carcinogenesis and the therapeutic response.
Collapse
Affiliation(s)
| | | | | | | | - Vikas Dudeja
- Division of Surgical Oncology, Department of Surgery, The University of Alabama at Birmingham, BDB 573 1808 7th Avenue South, Birmingham, AL 35294, USA; (D.S.S.); (T.J.); (V.D.); (S.I.)
| |
Collapse
|
23
|
Pérez Escriva P, Correia Tavares Bernardino C, Letellier E. De-coding the complex role of microbial metabolites in cancer. Cell Rep 2025; 44:115358. [PMID: 40023841 DOI: 10.1016/j.celrep.2025.115358] [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: 08/09/2024] [Revised: 12/11/2024] [Accepted: 02/06/2025] [Indexed: 03/04/2025] Open
Abstract
The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.
Collapse
Affiliation(s)
- Pau Pérez Escriva
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Catarina Correia Tavares Bernardino
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
| |
Collapse
|
24
|
Paradzik Simunovic M, Degoricija M, Korac-Prlic J, Lesin M, Stanic R, Puljak L, Olujic I, Marin Lovric J, Vucinovic A, Ljubic Z, Thissen J, Reen Kok C, Jaing C, Bucan K, Terzic J. Potential Role of Malassezia restricta in Pterygium Development. Int J Mol Sci 2025; 26:2976. [PMID: 40243577 PMCID: PMC11989039 DOI: 10.3390/ijms26072976] [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: 02/10/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
Pterygium is a condition affecting the ocular surface, marked by a triangular-shaped growth of fibrotic tissue extending from the nasal conjunctiva toward the corneal center, potentially causing visual impairment. While ultraviolet (UV )light exposure is the primary risk factor for pterygium, its underlying cause remains unclear. In order to better understand the true genesis of pterygium development, we investigated pterygium tissue and compared it with healthy conjunctiva controls. Given the eye's direct environmental exposure, we analyzed the microbiota composition using metagenomic sequencing of pterygium tissue to identify microbes potentially associated with this condition. Metagenomic sequencing revealed a higher prevalence of the fungus Malassezia restricta in five pterygium samples, confirmed by in situ hybridization. The CHIT1 gene, which plays a role in antifungal defenses, displayed the highest expression in five pterygium tissue samples compared to healthy conjunctiva controls, suggesting the potential involvement of Malassezia restricta in pterygium development. Gene expression profiling of pterygium highlighted an IL-33 and IL-4 gene expression signature, along with an increased presence of M2 macrophages, emphasizing their role in promoting fibrosis-a hallmark feature of pterygium. The detection of Malassezia restricta in the pterygium samples and associated molecular changes provides novel insights into the ocular microbiome and raises the possibility of Malassezia's involvement in pterygium pathology.
Collapse
Affiliation(s)
| | - Marina Degoricija
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
- Department of Medical Chemistry and Biochemistry, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| | - Jelena Korac-Prlic
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| | - Mladen Lesin
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Robert Stanic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Livia Puljak
- Center for Evidence-Based Medicine and Healthcare, Catholic University of Croatia, 10000 Zagreb, Croatia
| | - Ivana Olujic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Josipa Marin Lovric
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Ana Vucinovic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Zana Ljubic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - James Thissen
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Car Reen Kok
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Crystal Jaing
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Kajo Bucan
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Janos Terzic
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| |
Collapse
|
25
|
Guo X, Shao Y. Role of the oral-gut microbiota axis in pancreatic cancer: a new perspective on tumor pathophysiology, diagnosis, and treatment. Mol Med 2025; 31:103. [PMID: 40102723 PMCID: PMC11917121 DOI: 10.1186/s10020-025-01166-w] [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: 10/06/2024] [Accepted: 03/11/2025] [Indexed: 03/20/2025] Open
Abstract
Pancreatic cancer, one of the most lethal malignancies, remains challenging due to late diagnosis, aggressive progression, and therapeutic resistance. Recent advances have revealed the presence of intratumoral microbiota, predominantly originating from the oral and gut microbiomes, which play pivotal roles in pancreatic cancer pathogenesis. The dynamic interplay between oral and gut microbial communities, termed the "oral-gut microbiota axis," contributes multifacetedly to pancreatic ductal adenocarcinoma (PDAC). Microbial translocation via anatomical or circulatory routes establishes tumor-resident microbiota, driving oncogenesis through metabolic reprogramming, immune regulation, inhibition of apoptosis, chronic inflammation, and dysregulation of the cell cycle. Additionally, intratumoral microbiota promote chemoresistance and immune evasion, further complicating treatment outcomes. Emerging evidence highlights microbial signatures in saliva and fecal samples as promising non-invasive diagnostic biomarkers, while microbial diversity correlates with prognosis. Therapeutic strategies targeting this axis-such as antibiotics, probiotics, and engineered bacteria-demonstrate potential to enhance treatment efficacy. By integrating mechanisms of microbial influence on tumor biology, drug resistance, and therapeutic applications, the oral-gut microbiota axis emerges as a critical regulator of PDAC, offering novel perspectives for early detection, prognostic assessment, and microbiome-based therapeutic interventions.
Collapse
Affiliation(s)
- Xuanchi Guo
- School of Stomatology, Shandong University, No. 44-1 Wenhua West Road, Jinan City, Shandong Province, China.
| | - Yuhan Shao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| |
Collapse
|
26
|
Cheng H, Guo H, Wen C, Sun G, Tang F, Li Y. The dual role of gut microbiota in pancreatic cancer: new insights into onset and treatment. Ther Adv Med Oncol 2025; 17:17588359251324882. [PMID: 40093983 PMCID: PMC11909682 DOI: 10.1177/17588359251324882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Pancreatic cancer ranks among the most lethal digestive malignancies, exhibiting a steadily increasing incidence and mortality worldwide. Despite significant advances in cancer research, the 5-year survival rate remains below 10%, predominantly due to delayed diagnosis and limited therapeutic options. Concurrently, the gut microbiota-an integral component of host physiology-has emerged as a crucial player in the pathogenesis of pancreatic cancer. Mounting evidence indicates that alterations in gut microbial composition and function may influence tumor initiation, progression, and response to therapy. This review provides an in-depth examination of the intricate interplay between the gut microbiome and pancreatic cancer, highlighting potential diagnostic biomarkers and exploring microbiome-targeted therapeutic strategies to improve patient outcomes.
Collapse
Affiliation(s)
- Huijuan Cheng
- School of Life Sciences, Lanzhou University, Lanzhou, Gansu, P.R. China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Hongkai Guo
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Chengming Wen
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Guodong Sun
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, P.R. China
- Department of Medical Affairs, Lanzhou University First Hospital, Lanzhou, Gansu, P.R. China
| | - Futian Tang
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, P.R. China
| | - Yumin Li
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan, Lanzhou, Gansu 730000, P.R. China
| |
Collapse
|
27
|
Sun YY, Liu NN. Mycobiome: an underexplored kingdom in cancer. Microbiol Mol Biol Rev 2025:e0026124. [PMID: 40084887 DOI: 10.1128/mmbr.00261-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025] Open
Abstract
SUMMARYThe human microbiome, including bacteria, fungi, archaea, and viruses, is intimately linked to both health and disease. The relationship between bacteria and disease has received much attention and intensive investigation, while that of the fungal microbiome, also known as mycobiome, has lagged far behind bacteria. There is growing evidence showing mycobiome dysbiosis in cancer patients, and certain cancer-specific fungi may contribute to cancer progression by interacting with both host and bacteria. It was also demonstrated that the role of fungi-derived products in cancer should also not be underestimated. Therefore, investigating how fungal pathogenesis contributes to the onset and spread of cancer would yield crucial information for cancer diagnosis, prevention, and anti-cancer therapy.
Collapse
Affiliation(s)
- Yan-Yan Sun
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning-Ning Liu
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
28
|
Bruno PS, Biggers P, Nuru N, Versaci N, Chirila MI, Darie CC, Neagu AN. Small Biological Fighters Against Cancer: Viruses, Bacteria, Archaea, Fungi, Protozoa, and Microalgae. Biomedicines 2025; 13:665. [PMID: 40149641 PMCID: PMC11940145 DOI: 10.3390/biomedicines13030665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
Despite the progress made in oncological theranostics, cancer remains a global health problem and a leading cause of death worldwide. Multidrug and radiation therapy resistance is an important challenge in cancer treatment. To overcome this great concern in clinical practice, conventional therapies are more and more used in combination with modern approaches to improve the quality of patients' lives. In this review, we emphasize how small biological entities, such as viruses, bacteria, archaea, fungi, protozoans, and microalgae, as well as their related structural compounds and toxins/metabolites/bioactive molecules, can prevent and suppress cancer or regulate malignant initiation, progression, metastasis, and responses to different therapies. All these small biological fighters are free-living or parasitic in nature and, furthermore, viruses, bacteria, archaea, fungi, and protozoans are components of human and animal microbiomes. Recently, polymorphic microbiomes have been recognized as a new emerging hallmark of cancer. Fortunately, there is no limit to the development of novel approaches in cancer biomedicine. Thus, viral vector-based cancer therapies based on genetically engineered viruses, bacteriotherapy, mycotherapy based on anti-cancer fungal bioactive compounds, use of protozoan parasite-derived proteins, nanoarchaeosomes, and microalgae-based microrobots have been more and more used in oncology, promoting biomimetic approaches and biology-inspired strategies to maximize cancer diagnostic and therapy efficiency, leading to an improved patients' quality of life.
Collapse
Affiliation(s)
- Pathea Shawnae Bruno
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (P.B.); (N.N.); (N.V.)
| | - Peter Biggers
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (P.B.); (N.N.); (N.V.)
| | - Niyogushima Nuru
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (P.B.); (N.N.); (N.V.)
| | - Nicholas Versaci
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (P.B.); (N.N.); (N.V.)
| | - Miruna Ioana Chirila
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Bvd. 20A, 700505 Iasi, Romania;
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, University Street No. 16, 700115 Iasi, Romania
| | - Costel C. Darie
- Biochemistry & Proteomics Laboratories, Department of Chemistry and Biochemistry, Clarkson University, Potsdam, NY 13699-5810, USA; (P.S.B.); (P.B.); (N.N.); (N.V.)
| | - Anca-Narcisa Neagu
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iași, Carol I Bvd. 20A, 700505 Iasi, Romania;
| |
Collapse
|
29
|
Srinivasan S, Mehra S, Jinka S, Bianchi A, Singh S, Dosch AR, Amirian H, Krishnamoorthy V, Silva IDC, Patel M, Box EW, Garrido V, Totiger TM, Zhou Z, Ban Y, Datta J, VanSaun M, Merchant N, Nagathihalli NS. Activation of CREB drives acinar cells to ductal reprogramming and promotes pancreatic cancer progression in animal models of alcoholic pancreatitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.01.05.574376. [PMID: 38903082 PMCID: PMC11188065 DOI: 10.1101/2024.01.05.574376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
BACKGROUND & AIMS Alcoholic chronic pancreatitis (ACP) exacerbates pancreatic damage through acinar cell injury, fibroinflammation, and cyclic adenosine monophosphate response element binding protein 1 (CREB) activation, surpassing the damage by alcohol (A) alone or cerulein-induced CP. The molecular cooperativity between CREB and oncogenic Kras G12D/+ (Kras*) in promoting pancreatic cancer progression within the context of ACP remains unclear. METHODS Experimental ACP induction was established in multiple mouse models, with euthanasia during the recovery stage to assess tumor latency. We established CREB deletion (Creb fl/fl ) in Ptf1a CreERTM/+ ;LSL-Kras G12D/+ (KC) genetic mouse models (KCC -/- ). Pancreata from Ptf1a CreERTM/+ , KC, and KCC -/- mice were analyzed using western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing of acinar cell explant cultures and analysis of tissue samples from human pancreatic diseases (CP and pancreatic ductal adenocarcinoma [PDAC]) were conducted. RESULTS ACP induction in KC mice impaired the pancreas' repair mechanism. Acinar cell-derived ductal lesions demonstrated prolonged hyperactivated CREB in acinar-to-ductal metaplasia (ADM)/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and in PDAC. Persistent CREB activation reprogrammed acinar cells, increasing profibrotic inflammation. In ACP-induced models, acinar-specific Creb ablation reduced advanced PanIN lesions, hindered tumor progression, and improved acinar cell function. Pharmacological targeting of CREB significantly reduced the primary tumor burden in a PDAC mouse model with ACP. CONCLUSIONS Our findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB offers a promising strategy to address the clinical need for effective treatments for inflammation-driven pancreatic cancer.
Collapse
Affiliation(s)
- Supriya Srinivasan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Siddharth Mehra
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Sudhakar Jinka
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Anna Bianchi
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Samara Singh
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Austin R Dosch
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Haleh Amirian
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | | | - Iago De Castro Silva
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Manan Patel
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Edmond Worley Box
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Vanessa Garrido
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Tulasigeri M Totiger
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Zhiqun Zhou
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Yuguang Ban
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida
| | - Jashodeep Datta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Nipun Merchant
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Nagaraj S Nagathihalli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| |
Collapse
|
30
|
Ajona D, Cragg MS, Pio R. The complement system in clinical oncology: Applications, limitations and challenges. Semin Immunol 2025; 77:101921. [PMID: 39700788 DOI: 10.1016/j.smim.2024.101921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/06/2024] [Accepted: 12/07/2024] [Indexed: 12/21/2024]
Abstract
The complement system, a key component of innate immunity, is involved in seemingly contradictory aspects of tumor progression and cancer therapy. It can act as an immune effector against cancer and modulate the antitumor activity of certain therapeutic antibodies, but it can also contribute to a tumor-promoting microenvironment. Understanding this dual role should lead to the development of better therapeutic tools, strategies for cancer treatment and biomarkers for the clinical management of cancer patients. Here, we review recent advances in the understanding of the role of complement in cancer, focusing on how these findings are being translated into the clinic. We highlight the activity of therapeutic agents that modulate the complement system, as well as combination therapies that integrate complement modulation with existing therapies. We conclude that the role of complement activation in cancer is a rapidly evolving field with the potential to translate findings into new therapeutic strategies and clinically useful biomarkers.
Collapse
Affiliation(s)
- Daniel Ajona
- Laboratory of Translational Oncology, Program in Solid Tumors, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, Universidad de Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| | - Mark S Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Ruben Pio
- Laboratory of Translational Oncology, Program in Solid Tumors, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, Universidad de Navarra, Pamplona, Spain; Navarra's Health Research Institute (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.
| |
Collapse
|
31
|
Tardy KJ, Kwak HV, Tieniber AD, Mangold AK, Perez JE, Do K, Zeng S, Rossi F, DeMatteo RP. Intratumoral Bacteria are Uncommon in Gastrointestinal Stromal Tumor. Ann Surg Oncol 2025; 32:1504-1510. [PMID: 39578323 PMCID: PMC11811456 DOI: 10.1245/s10434-024-16526-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/30/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common human sarcoma with over 5000 new patients diagnosed in the USA each year. The tumor originates from the interstitial cells of Cajal and forms an intramural lesion most commonly in the stomach or small intestine. The gut microbiome has been linked to other gastrointestinal cancers and a recent paper purported that GISTs contain substantial intratumoral bacteria. The purpose of this study is to further evaluate the presence of bacteria in GISTs. PATIENTS AND METHODS We collected 25 tumor samples of varying size and location from 24 patients under sterile conditions in the operating room immediately following surgical resection. 16S quantitative polymerase chain reaction (qPCR) and 16S ribosomal RNA (rRNA) gene amplicon sequencing were performed to evaluate the bacterial species present in each tumor. Retrospective chart review was performed to determine tumor characteristics, including tumor size, location, imatinib exposure, and mucosal involvement. RESULTS In 23 of the 25 tumor samples, there were fewer than 100 copy numbers of 16S rRNA per uL, indicating an absence of a significant bacterial load. 16S rRNA gene amplicon sequencing of the remaining two samples, one gastric tumor and one duodenal tumor, revealed the presence of normal intestinal bacteria. These two tumors, along with three others, had disruption of the mucosal lining. CONCLUSIONS GISTs generally lack substantial bacteria, except in some cases when the tumor disrupts the mucosa.
Collapse
Affiliation(s)
- Katherine J Tardy
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hyunjee V Kwak
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew D Tieniber
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alina K Mangold
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Juan E Perez
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kevin Do
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Shan Zeng
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ferdinando Rossi
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald P DeMatteo
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
32
|
Kawasaki H, Nussbaum G. Therapeutic potential of garlic, aged garlic extract and garlic‑derived compounds on pancreatic cancer (Review). Biomed Rep 2025; 22:54. [PMID: 39926043 PMCID: PMC11803370 DOI: 10.3892/br.2025.1932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 12/11/2024] [Indexed: 02/11/2025] Open
Abstract
Garlic is a popular ingredient used in cuisines and traditional medicines worldwide. It contains numerous bioactive organosulfur-containing compounds, such as allicin, with reported potential for anticancer and antimicrobial therapy. The biological activity and potential use of garlic and its products have been extensively investigated. Aged garlic extract (AGE) is a product manufactured by aging garlic, and has been shown to have numerous health benefits. It has been previously revealed that several garlic-derived compounds, including AGE, have tumor-suppressive effects in various cancer models. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and carries a dismal prognosis. Recently, numerous tumors, including PDAC, were shown to harbor intracellular bacteria, some of which are oral pathogens. Tumor-associated bacteria have been linked to cancer progression. Garlic may inhibit tumor development, in part, by targeting these bacteria. Although it requires further investigation, pharmacological and antibacterial effects of garlic and its products could offer significant therapeutic benefits for the prevention and treatment of PDAC. In the present review, the therapeutic potential of garlic on PDAC is summarized and discussed.
Collapse
Affiliation(s)
- Hiromichi Kawasaki
- Institute of Biomedical and Oral Research, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
- Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., Akitakata-shi, Hiroshima 739-1195, Japan
| | - Gabriel Nussbaum
- Institute of Biomedical and Oral Research, Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| |
Collapse
|
33
|
Wang R, Li W, Cao H, Zhang L. Decoding the Tumor-Associated Microbiota: From Origins to Nanomedicine Applications in Cancer Therapy. BIOLOGY 2025; 14:243. [PMID: 40136500 PMCID: PMC11940167 DOI: 10.3390/biology14030243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/27/2025]
Abstract
Growing evidence reveals that the tumor microbiome-comprising distinct microbial communities within neoplastic tissues-exerts a profound influence on cancer initiation, progression, and therapeutic response. These microbes actively reshape the tumor microenvironment (TME) through metabolite secretion, the modulation of immune pathways, and direct interactions with host cells, thereby affecting tumor biology and therapeutic outcomes. Despite substantial heterogeneity among cancer types, recent insights underscore the tumor microbiome's potential as both a diagnostic/prognostic biomarker and a targetable component for innovative treatments. In this review, we synthesize emerging knowledge on the mechanistic roles of tumor-associated microbiota in shaping the TME, with a focus on how these discoveries can guide novel therapeutic strategies. We further explore interdisciplinary advances, including the convergence of microbiomics and nanotechnology, to enhance drug delivery, circumvent resistance, and foster TME remodeling. By highlighting these cutting-edge developments, our review underscores the transformative potential of integrating tumor microbiome research into precision oncology and advancing more personalized cancer therapies.
Collapse
Affiliation(s)
- Ruiqi Wang
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; (R.W.); (W.L.)
| | - Weizheng Li
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; (R.W.); (W.L.)
| | - Hongqian Cao
- Department of Health Inspection and Quarantine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Lei Zhang
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; (R.W.); (W.L.)
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| |
Collapse
|
34
|
Liu NN. mSphere of Influence: Seeking the unseen fungi in tumors. mSphere 2025; 10:e0098824. [PMID: 39873489 PMCID: PMC11852992 DOI: 10.1128/msphere.00988-24] [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] [Indexed: 01/30/2025] Open
Abstract
Ningning Liu works in the field of fungal infection and cancer progression, with a particular focus on the mechanism of host-pathogen interaction. In this mSphere of influence article, he reflects on how papers entitled "The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL," by B. Aykut, S. Pushalkar, R. Chen, Q. Li, et al. (Nature 574:264-267, 2019, https://doi.org/10.1038/s41586-019-1608-2), and "A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors," by A. B. Dohlman, J. Klug, M. Mesko, I. H. Gao, et al. (Cell 185:3807-3822.E12, 2022, https://doi.org/10.1016/j.cell.2022.09.015), emphasized the non-negligible role of fungi in the host and demonstrated a connection between fungi and cancer. These researches arouse his interest in seeking the novel fungal pathogen lurking inside tumors and understanding the unexplored mechanisms behind the severe fungal infections in cancer patients.
Collapse
Affiliation(s)
- Ning-Ning Liu
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
35
|
Szóstak N, Budnik M, Tomela K, Handschuh L, Samelak-Czajka A, Pietrzak B, Schmidt M, Kaczmarek M, Galus Ł, Mackiewicz J, Mackiewicz A, Kozlowski P, Philips A. Exploring correlations between gut mycobiome and lymphocytes in melanoma patients undergoing anti-PD-1 therapy. Cancer Immunol Immunother 2025; 74:110. [PMID: 39998665 PMCID: PMC11861499 DOI: 10.1007/s00262-024-03918-9] [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: 07/01/2024] [Accepted: 12/02/2024] [Indexed: 02/27/2025]
Abstract
Research has shown that the microbiome can influence how the immune system responds to melanoma cells, affecting the course of the disease and the outcome of the therapy. Here, we used the metagenomic approach and flow cytometry analyses of blood cells to discover correlations between gut fungi of metastatic melanoma patients enrolled in anti-PD-1 therapy and lymphocytes in their blood.We analyzed the patterns of associations before the first administration of anti-PD-1 therapy (BT, n = 61) and in the third month of the therapy (T3, n = 37), allowing us to track changes during treatment. To understand the possible impact of gut fungi on the efficacy of anti-PD-1 therapy, we analyzed the associations in clinical beneficiaries (CB, n = 37) and non-beneficiaries (NB, n = 24), as well as responders (R, n = 28) and non-responders (NR, n = 33).Patients with LDH < 338 units/L, overall survival (OS) > 12, CB, as well as R, had lower levels of Shannon diversity (p = 0.02, p = 0.05, p = 0.05, and p = 0.03, respectively). We found that the correlation pattern between intestinal fungi and lymphocytes was specific to the type of response, positive or negative. When comparing CB and NB groups, correlations with opposite directions were detected for C. albicans, suggesting a response-specific immune reaction. For CB, M. restricta exhibited a set of correlations with different types of lymphocytes, with prevalent positive correlations, suggesting a robust immune response in the CB group. This result extends our former research, where M. restricta and C. albicans were associated with an increased risk of melanoma progression and a poorer response to anti-PD-1 treatment.
Collapse
Affiliation(s)
- Natalia Szóstak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
| | - Michał Budnik
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Katarzyna Tomela
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Luiza Handschuh
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Samelak-Czajka
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Bernadeta Pietrzak
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Marcin Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, Poznan, Poland
| | - Mariusz Kaczmarek
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Łukasz Galus
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
- Department of Medical and Experimental Oncology, Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Mackiewicz
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
- Department of Medical and Experimental Oncology, Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland
| | - Andrzej Mackiewicz
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866, Poznan, Poland
| | - Piotr Kozlowski
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| | - Anna Philips
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
| |
Collapse
|
36
|
Fang P, Yang J, Zhang H, Shuai D, Li M, Chen L, Liu L. Emerging roles of intratumoral microbiota: a key to novel cancer therapies. Front Oncol 2025; 15:1506577. [PMID: 40071093 PMCID: PMC11893407 DOI: 10.3389/fonc.2025.1506577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/04/2025] [Indexed: 03/14/2025] Open
Abstract
Microorganisms, including bacteria, viruses, and fungi, have been found to play critical roles in tumor microenvironments. Due to their low biomass and other obstacles, the presence of intratumor microbes has been challenging to definitively establish. However, advances in biotechnology have enabled researchers to reveal the association between intratumor microbiota and cancer. Recent studies have shown that tumor tissues, once thought to be sterile, actually contain various microorganisms. Disrupted mucosal barriers and adjacent normal tissues are important sources of intratumor microbiota. Additionally, microbes can invade tumors by traveling through the bloodstream to the tumor site and infiltrating through damaged blood vessels. These intratumor microbiota may promote the initiation and progression of cancers by inducing genomic instability and mutations, affecting epigenetic modifications, activating oncogenic pathways, and promoting inflammatory responses. This review summarizes the latest advancements in this field, including techniques and methods for identifying and culturing intratumor microbiota, their potential sources, functions, and roles in the efficacy of immunotherapy. It explores the relationship between gut microbiota and intratumor microbiota in cancer patients, and whether altering gut microbiota might influence the characteristics of intratumor microbiota and the host immune microenvironment. Additionally, the review discusses the prospects and limitations of utilizing intratumor microbiota in antitumor immunotherapy.
Collapse
Affiliation(s)
- Pengzhong Fang
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jing Yang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Huiyun Zhang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Diankui Shuai
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Min Li
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Lin Chen
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liping Liu
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| |
Collapse
|
37
|
Wang N, Wu S, Huang L, Hu Y, He X, He J, Hu B, Xu Y, Rong Y, Yuan C, Zeng X, Wang F. Intratumoral microbiome: implications for immune modulation and innovative therapeutic strategies in cancer. J Biomed Sci 2025; 32:23. [PMID: 39966840 PMCID: PMC11837407 DOI: 10.1186/s12929-025-01117-x] [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: 09/09/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Recent advancements have revealed the presence of a microbiome within tumor tissues, underscoring the crucial role of the tumor microbiome in the tumor ecosystem. This review delves into the characteristics of the intratumoral microbiome, underscoring its dual role in modulating immune responses and its potential to both suppress and promote tumor growth. We examine state-of-the-art techniques for detecting and analyzing intratumoral bacteria, with a particular focus on their interactions with the immune system and the resulting implications for cancer prognosis and treatment. By elucidating the intricate crosstalk between the intratumoral microbiome and the host immune system, we aim to uncover novel therapeutic strategies that enhance the efficacy of cancer treatments. Additionally, this review addresses the existing challenges and future prospects within this burgeoning field, advocating for the integration of microbiome research into comprehensive cancer therapy frameworks.
Collapse
Affiliation(s)
- Na Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Si Wu
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Lanxiang Huang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yue Hu
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xin He
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jourong He
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ben Hu
- Center for Tumor Precision Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yaqi Xu
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yuan Rong
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Chunhui Yuan
- Department of Laboratory Medicine, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430016, China.
| | - Xiantao Zeng
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Fubing Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, 430071, China.
| |
Collapse
|
38
|
Tebbi CK, Sahakian E, Shah B, Yan J, Mediavilla-Varela M, Patel S. Aspergillus flavus with Mycovirus as an Etiologic Factor for Acute Leukemias in Susceptible Individuals: Evidence and Discussion. Biomedicines 2025; 13:488. [PMID: 40002901 PMCID: PMC11853382 DOI: 10.3390/biomedicines13020488] [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: 01/10/2025] [Revised: 02/03/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Several etiologic factors for the development of acute leukemias have been suggested; however, none is applicable to all cases. We isolated a certain mycovirus-containing Aspergillus flavus (MCAF) from the home of a patient with acute lymphoblastic leukemia. Repeated electron microscopic evaluations proved the existence of mycovirus in this organism. According to chemical analysis, this organism does not produce any aflatoxin, possibly due to its infestation with mycoviruses. We reported that using the ELISA technique, forty pediatric patients with acute lymphoblastic leukemia (ALL) uniformly had antibodies to the products of MCAF. In contrast, three separate groups of controls, consisting of normal blood donors, individuals with solid tumors, and patients with sickle cell disease, were negative. In vitro exposure of mononuclear blood cells from patients with ALL, in full remission, to the products of MCAF induced redevelopment of cell surface phenotypes and genetic markers characteristic of ALL. The controls were negative. The incubation of normal and ALL cell lines with the products of MCAF resulted in significant cellular apoptosis, changes in the cell cycle, and the downregulation of transcription factors, including PAX-5 and Ikaros (75 and 55 kDa). Fungi are widespread in nature, and many contain mycoviruses. Normally, an individual inhales 1 to 10 fungal spores per minute, while farmers can inhale up to 75,000 spores per minute. It is known that farmers and foresters, who are more exposed to fungi, have a higher rate of acute leukemia. In contrast, asthmatics, most of whom are allergic to fungal agents, and individuals working in office settings have a lower rate. One of the theories for the development of acute leukemia suggests a genetic predisposition followed by exposure to an infectious agent. With the above findings, we propose that mycovirus-containing Aspergillus flavus may have an etiological role in leukemogenesis in immune-depressed and genetically susceptible individuals.
Collapse
Affiliation(s)
- Cameron K. Tebbi
- Children’s Cancer Research Group Laboratory, Tampa, FL 33613, USA;
| | - Eva Sahakian
- Moffitt Cancer Center, Tampa, FL 33612, USA; (E.S.); (B.S.); (M.M.-V.)
| | - Bijal Shah
- Moffitt Cancer Center, Tampa, FL 33612, USA; (E.S.); (B.S.); (M.M.-V.)
| | - Jiyu Yan
- Children’s Cancer Research Group Laboratory, Tampa, FL 33613, USA;
| | | | | |
Collapse
|
39
|
Zhang S, Huang J, Jiang Z, Tong H, Ma X, Liu Y. Tumor microbiome: roles in tumor initiation, progression, and therapy. MOLECULAR BIOMEDICINE 2025; 6:9. [PMID: 39921821 PMCID: PMC11807048 DOI: 10.1186/s43556-025-00248-9] [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: 08/02/2024] [Revised: 01/06/2025] [Accepted: 01/21/2025] [Indexed: 02/10/2025] Open
Abstract
Over the past few years, the tumor microbiome is increasingly recognized for its multifaceted involvement in cancer initiation, progression, and metastasis. With the application of 16S ribosomal ribonucleic acid (16S rRNA) sequencing, the intratumoral microbiome, also referred to as tumor-intrinsic or tumor-resident microbiome, has also been found to play a significant role in the tumor microenvironment (TME). Understanding their complex functions is critical for identifying new therapeutic avenues and improving treatment outcomes. This review first summarizes the origins and composition of these microbial communities, emphasizing their adapted diversity across a diverse range of tumor types and stages. Moreover, we outline the general mechanisms by which specific microbes induce tumor initiation, including the activation of carcinogenic pathways, deoxyribonucleic acid (DNA) damage, epigenetic modifications, and chronic inflammation. We further propose the tumor microbiome may evade immunity and promote angiogenesis to support tumor progression, while uncovering specific microbial influences on each step of the metastatic cascade, such as invasion, circulation, and seeding in secondary sites. Additionally, tumor microbiome is closely associated with drug resistance and influences therapeutic efficacy by modulating immune responses, drug metabolism, and apoptotic pathways. Furthermore, we explore innovative microbe-based therapeutic strategies, such as engineered bacteria, oncolytic virotherapy, and other modalities aimed at enhancing immunotherapeutic efficacy, paving the way for microbiome-centered cancer treatment frameworks.
Collapse
Affiliation(s)
- Shengxin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Jing Huang
- Department of Medical Ultrasound, West China Hospital of Sichuan University, 37 Guoxue Lane, Wuhou District, Chengdu, 610041, Sichuan Province, China
| | - Zedong Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Huan Tong
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
| |
Collapse
|
40
|
He R, Qi P, Shu L, Ding Y, Zeng P, Wen G, Xiong Y, Deng H. Dysbiosis and extraintestinal cancers. J Exp Clin Cancer Res 2025; 44:44. [PMID: 39915884 PMCID: PMC11804008 DOI: 10.1186/s13046-025-03313-x] [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: 08/26/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025] Open
Abstract
The gut microbiota plays a crucial role in safeguarding host health and driving the progression of intestinal diseases. Despite recent advances in the remarkable correlation between dysbiosis and extraintestinal cancers, the underlying mechanisms are yet to be fully elucidated. Pathogenic microbiota, along with their metabolites, can undermine the integrity of the gut barrier through inflammatory or metabolic pathways, leading to increased permeability and the translocation of pathogens. The dissemination of pathogens through the circulation may contribute to the establishment of an immune-suppressive environment that promotes carcinogenesis in extraintestinal organs either directly or indirectly. The oncogenic cascade always engages in the disruption of hormonal regulation and inflammatory responses, the induction of genomic instability and mutations, and the dysregulation of adult stem cell proliferation. This review aims to comprehensively summarize the existing evidence that points to the potential role of dysbiosis in the malignant transformation of extraintestinal organs such as the liver, breast, lung, and pancreas. Additionally, we delve into the limitations inherent in current methodologies, particularly the challenges associated with differentiating low loads gut-derived microbiome within tumors from potential sample contamination or symbiotic microorganisms. Although still controversial, an understanding of the contribution of translocated intestinal microbiota and their metabolites to the pathological continuum from chronic inflammation to tumors could offer a novel foundation for the development of targeted therapeutics.
Collapse
Affiliation(s)
- Ruishan He
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China
| | - Pingqian Qi
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China
| | - Linzhen Shu
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China
| | - Yidan Ding
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China
| | - Peng Zeng
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Guosheng Wen
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China
| | - Ying Xiong
- Department of General Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Huan Deng
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, No. 133 South Guangchang Road, Nanchang, Jiangxi Province, 330003, China.
- Tumor Immunology Institute, Nanchang University, Nanchang, 330006, Jiangxi, China.
| |
Collapse
|
41
|
Xu B, Luo Z, Niu X, Li Z, Lu Y, Li J. Fungi, immunosenescence and cancer. Semin Cancer Biol 2025; 109:67-82. [PMID: 39788169 DOI: 10.1016/j.semcancer.2025.01.002] [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: 11/05/2024] [Revised: 12/22/2024] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Fungal microbes are a small but immunoreactive component of the human microbiome, which may influence cancer development, progression and therapeutic response. Immunosenescence is a process of immune dysfunction that occurs with aging, including lymphoid organ remodeling, contributing to alterations in the immune system in the elderly, which plays a critical role in many aspects of cancer. There is evidence for the interactions between fungi and immunosenescence in potentially regulating cancer progression and remodeling the tumor microenvironment (TME). In this review, we summarize potential roles of commensal and pathogenic fungi in modulating cancer-associated processes and provide more-detailed discussions on the mechanisms of which fungi affect tumor biology, including local and distant regulation of the TME, modulating antitumor immune responses and interactions with neighboring bacterial commensals. We also delineate the features of immunosenescence and its influence on cancer development and treatment, and highlight the interactions between fungi and immunosenescence in cancer. We discuss the prospects and challenges for harnessing fungi and immunosenescence in cancer diagnosis and/or treatment. Considering the limited understanding and techniques in conducting such research, we also provide our view on how to overcome challenges faced by the exploration of fungi, immunosenescence and their interactions on tumor biology.
Collapse
Affiliation(s)
- Bin Xu
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China
| | - Zan Luo
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China
| | - Xing Niu
- Experimental Center of BIOQGene, YuanDong International Academy of Life Sciences, 999077, China; Voylin Institute for Translation Medicine, Xiamen, Fujian 361000, China
| | - Zhi Li
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Yeping Lu
- Department of Neurosurgery, The Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China.
| | - Junyu Li
- Department of Radiation Oncology, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China; The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| |
Collapse
|
42
|
Bilal H, Khan MN, Khan S, Shafiq M, Fang W, Zeng Y, Guo Y, Li X, Zhao B, Lv QL, Xu B. Fungal Influences on Cancer Initiation, Progression, and Response to Treatment. Cancer Res 2025; 85:413-423. [PMID: 39589783 DOI: 10.1158/0008-5472.can-24-1609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/13/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drugs, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can affect drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.
Collapse
Affiliation(s)
- Hazrat Bilal
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Muhammad Nadeen Khan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, China
| | - Sabir Khan
- Department of Dermatology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Muhammad Shafiq
- Department of Pharmacology, Research Institute of Clinical Pharmacy, Shantou University Medical College, Shantou, China
| | - Wenjie Fang
- Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yuebin Zeng
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yangzhong Guo
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Xiaohui Li
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bing Zhao
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Qiao-Li Lv
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| | - Bin Xu
- Jiangxi Key Laboratory of Oncology, JXHC Key Laboratory of Tumor Metastasis, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Institute, Nanchang, China
| |
Collapse
|
43
|
Skoulakis A, Skoufos G, Ovsepian A, Hatzigeorgiou AG. Machine learning models reveal microbial signatures in healthy human tissues, challenging the sterility of human organs. Front Microbiol 2025; 15:1512304. [PMID: 39931275 PMCID: PMC11808598 DOI: 10.3389/fmicb.2024.1512304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/16/2024] [Indexed: 02/13/2025] Open
Abstract
Background The presence of microbes within healthy human internal organs still remains under question. Our study endeavors to discern microbial signatures within normal human internal tissues using data from the Genotype-Tissue Expression (GTEx) consortium. Machine learning (ML) models were developed to classify each tissue type based solely on microbial profiles, with the identification of tissue-specific microbial signatures suggesting the presence of distinct microbial communities inside tissues. Methods We analyzed 13,871 normal RNA-seq samples from 28 tissues obtained from the GTEx consortium. Unaligned sequencing reads with the human genome were processed using AGAMEMNON, an algorithm for metagenomic microbial quantification, with a reference database comprising bacterial, archaeal, and viral genomes, alongside fungal transcriptomes. Gradient-boosting ML models were trained to classify each tissue against all others based on its microbial profile. To validate the findings, we analyzed 38 healthy living tissue samples (samples from healthy tissues obtained from living individuals, not deceased) from an independent study, as the GTEx samples were derived from post-mortem biopsies. Results Tissue-specific microbial signatures were identified in 11 out of the 28 tissues while the signatures for 8 tissues (Muscle, Heart, Stomach, Colon tissue, Testis, Blood, Liver, and Bladder tissue) demonstrated resilience to in silico contamination. The models for Heart, Colon tissue, and Liver displayed high discriminatory performance also in the living dataset, suggesting the presence of a tissue-specific microbiome for these tissues even in a living state. Notably, the most crucial features were the fungus Sporisorium graminicola for the heart, the gram-positive bacterium Flavonifractor plautii for the colon tissue, and the gram-negative bacterium Bartonella machadoae for the liver. Conclusion The presence of tissue-specific microbial signatures in certain tissues suggests that these organs are not devoid of microorganisms even in healthy conditions and probably they harbor low-biomass microbial communities unique to each tissue. The discoveries presented here confront the enduring dogma positing the sterility of internal tissues, yet further validation through controlled laboratory experiments is imperative to substantiate this hypothesis. Exploring the microbiome of internal tissues holds promise for elucidating the pathophysiology underlying both health and a spectrum of diseases, including sepsis, inflammation, and cancer.
Collapse
Affiliation(s)
- Anargyros Skoulakis
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | - Giorgos Skoufos
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | - Armen Ovsepian
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | - Artemis G. Hatzigeorgiou
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| |
Collapse
|
44
|
Said SS, Ibrahim WN. Gut Microbiota-Tumor Microenvironment Interactions: Mechanisms and Clinical Implications for Immune Checkpoint Inhibitor Efficacy in Cancer. Cancer Manag Res 2025; 17:171-192. [PMID: 39881948 PMCID: PMC11776928 DOI: 10.2147/cmar.s405590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/21/2024] [Indexed: 01/31/2025] Open
Abstract
Cancer immunotherapy has transformed cancer treatment in recent years, with immune checkpoint inhibitors (ICIs) emerging as a key therapeutic approach. ICIs work by inhibiting the mechanisms that allow tumors to evade immune detection. Although ICIs have shown promising results, especially in solid tumors, patient responses vary widely due to multiple intrinsic and extrinsic factors within the tumor microenvironment. Emerging evidence suggests that the gut microbiota plays a pivotal role in modulating immune responses at the tumor site and may even influence treatment outcomes in cancer patients receiving ICIs. This review explores the complex interactions between the gut microbiota and the tumor microenvironment, examining how these interactions could impact the effectiveness of ICI therapy. Furthermore, we discuss how dysbiosis, an imbalance in gut microbiota composition, may contribute to resistance to ICIs, and highlight microbiota-targeted strategies to potentially overcome this challenge. Additionally, we review recent studies investigating the diagnostic potential of microbiota profiles in cancer patients, considering how microbial markers might aid in early detection and stratification of patient responses to ICIs. By integrating insights from recent preclinical and clinical studies, we aim to shed light on the potential of microbiome modulation as an adjunct to cancer immunotherapy and as a diagnostic tool, paving the way for personalized therapeutic approaches that optimize patient outcomes.
Collapse
Affiliation(s)
- Sawsan Sudqi Said
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Wisam Nabeel Ibrahim
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| |
Collapse
|
45
|
Ghaddar BC, Blaser MJ, De S. Revisiting the cancer microbiome using PRISM. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.21.634087. [PMID: 39896561 PMCID: PMC11785023 DOI: 10.1101/2025.01.21.634087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Recent controversy around the cancer microbiome highlights the need for improved microbial analysis methods for human genomics data. We developed PRISM, a computational approach for precise microorganism identification and decontamination from low-biomass sequencing data. PRISM removes spurious signals and achieves excellent performance when benchmarked on a curated dataset of 62,006 known true- and false-positive taxa. We then use PRISM to detect microbes in 8 cancer types from the CPTAC and TCGA datasets. We identify rich microbiomes in gastrointestinal tract tumors in CPTAC and identify bacteria in a subset of pancreatic tumors that are associated with altered glycoproteomes, more extensive smoking histories, and higher tumor recurrence risk. We find relatively sparse microbes in other cancer types and in TCGA, which we demonstrate may reflect differing sequencing parameters. Overall, PRISM does not replace gold-standard controls, but it enables higher-confidence analyses and reveals tumor-associated microorganisms with potential molecular and clinical significance.
Collapse
Affiliation(s)
- Bassel C. Ghaddar
- Center for Systems and Computational Biology, Rutgers Cancer Institute, Rutgers University; 195 Albany St., New Brunswick, New Jersey 08901
| | - Martin J. Blaser
- Center for Advanced Biotechnology and Medicine, Rutgers University; 679 Hoes Lane West, Piscataway, New Jersey 08854
| | - Subhajyoti De
- Center for Systems and Computational Biology, Rutgers Cancer Institute, Rutgers University; 195 Albany St., New Brunswick, New Jersey 08901
| |
Collapse
|
46
|
Sipos L, Banczerowski P, Juhász J, Fedorcsák I, Berényi G, Makra N, Dunai ZA, Szabó D, Erőss L. Brain Tumors and Beyond: Multi-Compartment Microbiome and Mycobiome Analysis. Int J Mol Sci 2025; 26:991. [PMID: 39940760 PMCID: PMC11817552 DOI: 10.3390/ijms26030991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Brain tumors are frequently diagnosed diseases in which etiology and progression largely depend on mutations and genetic factors. Additionally, recent reports document that the microbiome may influence tumor growth, tumor microenvironment, and response to therapy. Our goal was to examine the extent to which the bacterial composition-microbiota-and fungal composition-mycobiota-characteristic of the tumor and its microenvironment correlate with the composition of the gut and blood microbiota and mycobiota in five randomly selected brain tumor patients. The bacterial composition of the tumor, tumor-adjacent tissue (TAT), blood, and gut samples of the five patients were analyzed by 16S rRNA and ITS-based sequencing in order to determine the bacterial and fungal composition. The gut microbiome and mycobiome composition showed individual and tissue-specific signatures in each patient. The microbiome composition of the blood, TAT, and tumor tissue was very similar in each patient, dominated by Klebsiella, Enterococcus, Blautia, and Lactobacillus spp. In contrast, the mycobiome composition of the blood, TAT, and tumor showed a diverse, individual picture. The most common fungal species in the blood and TAT were Tomentella, Didymosphaeria, Alternaria, Penicillium, Mycosphaerella, and Discosia. The blood and TAT mycobiome were similar to each other but unique and characteristic of the patients. In contrast, in the tumor tissues, Alternaria, Malassezia, Schizophyllum, and Tomentella genus were the most common fungi genus. Our results showed that the presence of fungi in tumors shows a unique pattern that is independent of the pattern observed in the gut, blood, and tumor environment and that the effects of the mycobiome are distinct and cannot be associated with those of the microbiome. Elucidating the role of fungi in tumors and exploring the relationship between fungi and brain tumor types may open up further therapeutic options.
Collapse
Affiliation(s)
- László Sipos
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
| | - Péter Banczerowski
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
| | - János Juhász
- Institute of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, 1083 Budapest, Hungary
| | - Imre Fedorcsák
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
| | - György Berényi
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
| | - Nóra Makra
- Institute of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
| | - Zsuzsanna A. Dunai
- Institute of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
- HUN-REN-SU Human Microbiota Research Group, 1052 Budapest, Hungary
| | - Dóra Szabó
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
- Institute of Medical Microbiology, Semmelweis University, 1089 Budapest, Hungary
- HUN-REN-SU Human Microbiota Research Group, 1052 Budapest, Hungary
| | - Loránd Erőss
- Department of Neurosurgery and Neurointervention, Semmelweis University, 1085 Budapest, Hungary; (L.S.)
| |
Collapse
|
47
|
Fanijavadi S, Jensen LH. Dysbiosis-NK Cell Crosstalk in Pancreatic Cancer: Toward a Unified Biomarker Signature for Improved Clinical Outcomes. Int J Mol Sci 2025; 26:730. [PMID: 39859442 PMCID: PMC11765696 DOI: 10.3390/ijms26020730] [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: 12/18/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance. Recent research shows that the microbiome, including microbial communities in the oral cavity, gut, bile duct, and intratumoral environments, plays a key role in PDAC development, with microbial imbalances (dysbiosis) promoting inflammation, cancer progression, therapy resistance, and treatment side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) cells, which are vital for tumor surveillance, therapy response and treatment-related side effects. Dysbiosis can affect NK cell function, leading to resistance and side effects. We propose that a combined biomarker approach, integrating microbiome composition and NK cell profiles, can help predict treatment resistance and side effects, enabling more personalized therapies. This review examines how dysbiosis contributes to NK cell dysfunction in PDAC and discusses strategies (e.g., antibiotics, probiotics, vaccines) to modulate the microbiome and enhance NK cell function. Targeting dysbiosis could modulate NK cell activity, improve the effectiveness of PDAC treatments, and reduce side effects. However, further research is needed to develop unified NK cell-microbiome interaction-based biomarkers for more precise and effective patient outcomes.
Collapse
Affiliation(s)
- Sara Fanijavadi
- Cancer Polyclinic, Levanger Hospital, 7601 Levanger, Trøndelag, Norway
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
| | - Lars Henrik Jensen
- Department of Oncology, Vejle Hospital, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
- Department of Oncology, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark
| |
Collapse
|
48
|
Ding T, Liu C, Li Z. The mycobiome in human cancer: analytical challenges, molecular mechanisms, and therapeutic implications. Mol Cancer 2025; 24:18. [PMID: 39815314 PMCID: PMC11734361 DOI: 10.1186/s12943-025-02227-8] [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: 11/13/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025] Open
Abstract
The polymorphic microbiome is considered a new hallmark of cancer. Advances in High-Throughput Sequencing have fostered rapid developments in microbiome research. The interaction between cancer cells, immune cells, and microbiota is defined as the immuno-oncology microbiome (IOM) axis. Fungal microbes (the mycobiome), although representing only ∼ 0.1-1% of the microbiome, are a critical immunologically active component of the tumor microbiome. Accumulating evidence suggests a possible involvement of commensal and pathogenic fungi in cancer initiation, progression, and treatment responsiveness. The tumor-associated mycobiome mainly consists of the gut mycobiome, the oral mycobiome, and the intratumoral mycobiome. However, the role of fungi in cancer remains poorly understood, and the diversity and complexity of analytical methods make it challenging to access this field. This review aims to elucidate the causal and complicit roles of mycobiome in cancer development and progression while highlighting the issues that need to be addressed in executing such research. We systematically summarize the advantages and limitations of current fungal detection and analysis methods. We enumerate and integrate these recent findings into our current understanding of the tumor mycobiome, accompanied by the prospect of novel and exhilarating clinical implications.
Collapse
Affiliation(s)
- Ting Ding
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, Sichuan Province, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Chang Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, Sichuan Province, 610041, China
| | - Zhengyu Li
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, Sichuan Province, 610041, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China.
| |
Collapse
|
49
|
Pagac MP, Davient B, Plado LA, Lam HYI, Lee SM, Ravikrishnan A, Chua WLE, Muralidharan S, Sridharan A, Irudayaswamy AS, Srinivas R, Wearne S, Mohamed Naim AN, Ho EXP, Ng HQA, Kwah JS, Png E, Bendt AK, Wenk MR, Torta F, Nagarajan N, Common J, Chong YS, Tham EH, Shek LPC, Loo EXL, Chambers J, Yew YW, Loh M, Dawson TL. Life stage impact on the human skin ecosystem: lipids and the microbial community. NPJ Biofilms Microbiomes 2025; 11:13. [PMID: 39800795 PMCID: PMC11725588 DOI: 10.1038/s41522-025-00652-7] [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: 02/22/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
Sebaceous free fatty acids are metabolized by multiple skin microbes into bioactive lipid mediators termed oxylipins. This study investigated correlations between skin oxylipins and microbes on the superficial skin of pre-pubescent children (N = 36) and adults (N = 100), including pre- (N = 25) and post-menopausal females (N = 25). Lipidomics and metagenomics revealed that Malassezia restricta positively correlated with the oxylipin 9,10-DiHOME on adult skin and negatively correlated with its precursor, 9,10-EpOME, on pre-pubescent skin. Co-culturing Malassezia with keratinocytes demonstrated a link between 9,10-DiHOME and pro-inflammatory cytokines IL-1β and IL-6 production. We also observed strong correlations between other skin oxylipins and microbial taxa, highlighting life stage differences in sebum production and microbial community composition. Our findings imply a complex host-microbe communication system mediated by lipid metabolism occurring on human skin, warranting further research into its role in skin health and disease and paving the way towards novel therapeutic targets and treatments.
Collapse
Grants
- This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore - NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore. This study was also supported by Agency for Science, Technology and Research (A*STAR) BMRC EDB IAF-PP grant (H17/01/a0/004) (TD); Skin Research Institute of Singapore, IAF-PP (HBMS) grant; Asian Skin Microbiome Program IAF-PP grants (H18/01/a0/016) (TD) and (H22/J1/a0/040). HELIOS study (NTU IRB: 2016-11-030) is supported by the Singapore Ministry of Health’s National Medical Research Council under its OF-LCG funding scheme (NMRC Project Ref. MOH-000271-00), STaR funding scheme (NMRC Project Ref. NMRC/STaR/0028/2017) and intramural funding from Nanyang Technological University, Lee Kong Chian School of Medicine and the National Healthcare Group. The HELIOS study team is also supported by a team of outstanding operational and administrative staff.
- "This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore - NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore. This study was also supported by Agency for Science, Technology and Research (A*STAR) BMRC EDB IAF-PP grant (H17/01/a0/004) (TD); Skin Research Institute of Singapore, IAF-PP (HBMS) grant; Asian Skin Microbiome Program IAF-PP grants (H18/01/a0/016) (TD) and (H22/J1/a0/040). HELIOS study (NTU IRB: 2016-11-030) is supported by the Singapore Ministry of Health’s National Medical Research Council under its OF-LCG funding scheme (NMRC Project Ref. MOH-000271-00), STaR funding scheme (NMRC Project Ref. NMRC/STaR/0028/2017) and intramural funding from Nanyang Technological University, Lee Kong Chian School of Medicine and the National Healthcare Group. The HELIOS study team is also supported by a team of outstanding operational and administrative staff."
Collapse
Affiliation(s)
- Martin P Pagac
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
- DSM-Firmenich, Perfumery and Beauty, Wurmisweg 576, Kaiseraugst, Switzerland
| | - Bala Davient
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Luca Antonio Plado
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
- Laboratory for Lipidomics and Lipid Biology, University of Manchester, Division of Pharmacy and Optometry, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Hilbert Yuen In Lam
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Dr, Singapore, Singapore
| | - Shi Mun Lee
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Aarthi Ravikrishnan
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - Wee Ling Esther Chua
- SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Sneha Muralidharan
- SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Aishwarya Sridharan
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Antony S Irudayaswamy
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Ramasamy Srinivas
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
- Cellivate Technologies, Singapore, Singapore
| | - Stephen Wearne
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Ahmad Nazri Mohamed Naim
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - Eliza Xin Pei Ho
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - H Q Amanda Ng
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - Junmei Samantha Kwah
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - Eileen Png
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - Anne K Bendt
- SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Markus R Wenk
- SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Precision Medicine Translational Research Programme and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Federico Torta
- SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Precision Medicine Translational Research Programme and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Niranjan Nagarajan
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
| | - John Common
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore
| | - Yap Seng Chong
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, Republic of Singapore
| | - Elizabeth Huiwen Tham
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Khoo Teck Puat-National University Children's Medical Institute, National University Health System (NUHS), Singapore, Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lynette Pei-Chi Shek
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Khoo Teck Puat-National University Children's Medical Institute, National University Health System (NUHS), Singapore, Singapore
| | - Evelyn Xiu Ling Loo
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, Republic of Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John Chambers
- Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, Singapore, Singapore
| | - Yik Weng Yew
- Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, Singapore, Singapore
| | - Marie Loh
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, Singapore, Singapore
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK
- National Skin Centre, Singapore, Singapore
| | - Thomas L Dawson
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) & Skin Research Institute of Singapore (SRIS), Singapore, Republic of Singapore.
- Department of Drug Discovery, College of Pharmacy, Medical University of South Carolina, Charleston, USA.
| |
Collapse
|
50
|
Zhao MQ, Fan MY, Cui MY, Chen SM, Wang JJ, Lu YY, Jiang QL. Profile of intestinal fungal microbiota in acute pancreatitis patients and healthy individuals. Gut Pathog 2025; 17:1. [PMID: 39780261 PMCID: PMC11716059 DOI: 10.1186/s13099-024-00675-z] [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: 11/19/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
OBJECTIVE The gut is involved in the development of acute pancreatitis (AP). Increased focus is being given to the role of gut microbiota in the pathogenesis of AP. Nevertheless, there is currently no available evidence regarding the composition of fungal microorganisms in the intestines of patients with AP. METHODS In this study, we sequenced ITS rRNA gene amplicons and examined the intestinal fungal microbiota in feces from 11 AP patients (the test group) and 15 healthy people (the control group). Additionally, we examined the relationship between fungus and clinical and biochemical markers. RESULTS Results showed a decline in alpha diversity in AP patients. The overall fungal microbiota in the test group was significantly different from that of the control group (P < 0.05). In both groups, the fecal fungal microbiota was dominated by Ascomycota and Basidiomycota phyla. At the genus level, the abundance of Candida was significantly higher in the test group and the abundances of Penicillium, Auricularia, unclassified Eurotiomycetes, Epicoccum and Vishniacozyma were significantly lower. Furthermore, AP patients had a significant decrease in the GMHI score and a significant increase in the MDI index. The co-abundance networks of gut fungus in AP patients showed more interactions and mostly positive correlations than in the control group. There was a strong positive link between Aspergillus and WBC counts, while There was a strong link between unclassified Rozellomycota and IL-6. CONCLUSION Our study provides the first empirical evidence that AP patients have different fecal fungal microbiota, which raises the possibility that mycobiota contribute to the etiology and progression of AP.
Collapse
Affiliation(s)
- Meng-Qi Zhao
- Department of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 800 Huangjiahuayuan Road, Shanghai, 201803, China
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Miao-Yan Fan
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Meng-Yan Cui
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Su-Min Chen
- Department of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 800 Huangjiahuayuan Road, Shanghai, 201803, China
| | - Jing-Jing Wang
- Shanghai Key Laboratory of Pancreatic Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Ying-Ying Lu
- Department of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 800 Huangjiahuayuan Road, Shanghai, 201803, China.
- Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201620, China.
| | - Qiao-Li Jiang
- Department of Gastroenterology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 800 Huangjiahuayuan Road, Shanghai, 201803, China.
| |
Collapse
|