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Jacobsen GE, Gonzalez EE, Mendygral P, Faust KM, Hazime H, Fernandez I, Santander AM, Quintero MA, Jiang C, Damas OM, Deshpande AR, Kerman DH, Proksell S, Sendzischew Shane M, Sussman DA, Ghaddar B, Cickovsk T, Abreu MT. Deep Sequencing of Crohn's Disease Lamina Propria Phagocytes Identifies Pathobionts and Correlates With Pro-Inflammatory Gene Expression. Inflamm Bowel Dis 2025; 31:1203-1219. [PMID: 39951038 PMCID: PMC12069990 DOI: 10.1093/ibd/izae316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Indexed: 05/14/2025]
Abstract
BACKGROUND Crohn's disease (CD) is characterized by an inflammatory response to gut microbiota. Macrophages and dendritic cells play an active role in CD inflammation. Specific microbiota have been implicated in the pathogenesis of ileal CD. We investigated the phagocyte-associated microbiome using an unbiased sequencing approach to identify potential pathobionts and elucidate the host response to these microbes. METHODS We collected ileal and colonic mucosal biopsies from CD patients and controls without inflammatory bowel disease (IBD), isolated lamina propria phagocytes (CD11b+ cells), and performed deep RNA sequencing (n = 37). Reads were mapped to the human genome for host gene expression analysis and a prokaryotic database for microbiome taxonomic and metatranscriptomic profiling. Results were confirmed in a second IBD cohort (n = 17). Lysed lamina propria cells were plated for bacterial culturing; isolated colonies underwent whole genome sequencing (n = 11). RESULTS Crohn's disease ileal phagocytes contained higher relative abundances of Escherichia coli, Ruminococcus gnavus, and Enterocloster spp. than those from controls. CD phagocyte-associated microbes had increased expression of lipopolysaccharide (LPS) biosynthesis pathways. Phagocytes with a higher pathobiont burden showed increased expression of pro-inflammatory and antimicrobial genes, including PI3 (antimicrobial peptide) and BPIFB1 (LPS-binding molecule). E. coli isolated from the CD lamina propria had more flagellar motility and antibiotic resistance genes than control-derived strains. CONCLUSIONS Lamina propria resident phagocytes harbor bacterial strains that may act as pathobionts in CD. Our findings shed light on the role of pathobionts and the immune response in CD pathogenesis and suggest new targets for therapies.
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Affiliation(s)
- Gillian E Jacobsen
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Eddy E Gonzalez
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Payton Mendygral
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Katerina M Faust
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Hajar Hazime
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Irina Fernandez
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ana M Santander
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria A Quintero
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Chunsu Jiang
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Oriana M Damas
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Amar R Deshpande
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - David H Kerman
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Siobhan Proksell
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Morgan Sendzischew Shane
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel A Sussman
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Bassel Ghaddar
- Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Trevor Cickovsk
- Bioinformatics Research Group (BioRG), Knight Foundation School of Computing and Information Sciences, Florida International University, Miami, FL, USA
| | - Maria T Abreu
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, Crohn’s and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Li N, Zhao C, Zhang P, Wu S, Dou X, Xu S, Zhang X, Peng C, Xie Y, Huang S, Zhou L, Shen Y, Wang L, Wang J, Yu C. The role of gut microbiota associated metabolites in digestive disorders. ENGINEERED REGENERATION 2024; 5:228-246. [DOI: 10.1016/j.engreg.2024.04.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025] Open
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Guo Y, Kitamoto S, Caballero-Flores G, Kim Y, Watanabe D, Sugihara K, Núñez G, Alteri CJ, Inohara N, Kamada N. Oral pathobiont Klebsiella chaperon usher pili provide site-specific adaptation for the inflamed gut mucosa. Gut Microbes 2024; 16:2333463. [PMID: 38545880 PMCID: PMC10984132 DOI: 10.1080/19490976.2024.2333463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/04/2024] Open
Abstract
The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived Klebsiella spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral Klebsiella strain to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. We find that K. aerogenes, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named "locus of colonization in the inflamed gut (LIG)" that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among K. aerogenes strains, and these genes are also present in several other Klebsiella species. The Tn screening revealed that the LIG locus is required for the adaptation of K. aerogenes in its ectopic niche. In particular, we determined K. aerogenes employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.
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Affiliation(s)
- Yijie Guo
- Department of Psychiatry and Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Sho Kitamoto
- WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Gustavo Caballero-Flores
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA
| | - Yeji Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Daisuke Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kohei Sugihara
- WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Gabriel Núñez
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | - Naohiro Inohara
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
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Wu R, Xiong R, Li Y, Chen J, Yan R. Gut microbiome, metabolome, host immunity associated with inflammatory bowel disease and intervention of fecal microbiota transplantation. J Autoimmun 2023; 141:103062. [PMID: 37246133 DOI: 10.1016/j.jaut.2023.103062] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/30/2023]
Abstract
Gut dysbiosis has been associated with inflammatory bowel disease (IBD), one of the most common gastrointestinal diseases. The microbial communities play essential roles in host physiology, with profound effects on immune homeostasis, directly or via their metabolites and/or components. There are increasing clinical trials applying fecal microbiota transplantation (FMT) with Crohn's disease (CD) and ulcerative colitis (UC). The restoration of dysbiotic gut microbiome is considered as one of the mechanisms of FMT therapy. In this work, latest advances in the alterations in gut microbiome and metabolome features in IBD patients and experimental mechanistic understanding on their contribution to the immune dysfunction were reviewed. Then, the therapeutic outcomes of FMT on IBD were summarized based on clinical remission, endoscopic remission and histological remission of 27 clinical trials retrieved from PubMed which have been registered on ClinicalTrials.gov with the results been published in the past 10 years. Although FMT is established as an effective therapy for both subtypes of IBD, the promising outcomes are not always achieved. Among the 27 studies, only 11 studies performed gut microbiome profiling, 5 reported immune response alterations and 3 carried out metabolome analysis. Generally, FMT partially restored typical changes in IBD, resulted in increased α-diversity and species richness in responders and similar but less pronounced shifts of patient microbial and metabolomics profiles toward donor profiles. Measurements of immune responses to FMT mainly focused on T cells and revealed divergent effects on pro-/anti-inflammatory functions. The very limited information and the extremely confounding factors in the designs of the FMT trials significantly hindered a reasonable conclusion on the mechanistic involvement of gut microbiota and metabolites in clinical outcomes and an analysis of the inconsistencies.
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Affiliation(s)
- Rongrong Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
| | - Rui Xiong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
| | - Yan Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
| | - Junru Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
| | - Ru Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
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Zhou X, Hu M, Luo J, Xie B, Ma P, Wu G, Xue F. Resistant effects determination of Lactobacillus supplementation on broilers to consecutive hydrogen sulfide exposure. Poult Sci 2023; 102:103102. [PMID: 37783191 PMCID: PMC10551555 DOI: 10.1016/j.psj.2023.103102] [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: 06/11/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 10/04/2023] Open
Abstract
Hydrogen sulfide (H2S) is one of the most irritant gases present in rearing stalls that suppress broilers' healthy growth, which is seriously required an effective alleviation method. In this study, Lactobacillus was supplemented to investigate the alleviative effects on broilers reared under consecutive H2S exposure. A total of 180 healthy 1-day-old male AA broilers with similar body weight (40.8 ± 1.0 g) were randomly allotted into the control treatment (CON), the hydrogen sulfide treatment (H2S), and the Lactobacillus supplement under H2S exposure treatment (LAC) for a 42-d-long feeding process. Growth and carcass performances, immunity-related parameters, intestinal development and cecal microbial communities, and blood metabolites were measured. Results showed that Lactobacillus supplement significantly increased the body weight gain (BWG) while reduced the mortality rate, abdominal fat and bursa of fabricius weight during the whole rearing time compared with H2S treatment (P < 0.05). Serum LPS, IL-1β, IL-2, and IL-6 contents were observed significantly increased after H2S treatment while remarkably decreased after Lactobacillus supplementation(P < 0.05). Intestinal morphology results showed a significant higher in the development of ileum villus height (P < 0.05). Cecal microbiota results showed the bacterial composition was significantly altered after Lactobacillus supplement (P < 0.05). Specifically, Lactobacillus supplement significantly decreased the relative abundance of Faecalibacterium, while significantly proliferated the relative abundance of Lactobacillus, Bifidobacterium, Clostridium, and Campylobacter (P<0.05). Metabolic results indicated that Lactobacillus supplement may alleviate the harmful effects caused by H2S through regulating the pyrimidine metabolism, starch and sucrose metabolism, fructose and mannose degradation, and beta-alanine metabolism. In summary, Lactobacillus supplement effectively increased BWG and decreased mortality rate of broilers under H2S exposure by enhancing the body's immune capacity, proliferating beneficial microbes (e.g., Lactobacillus and Bifidobacterium), and regulating the physiological pyrimidine metabolism, starch and sucrose metabolism, and beta-alanine metabolism.
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Affiliation(s)
- Xiao Zhou
- School of Mathematics, Physics and Optoelectronic Engineering, Hubei University of Automotive Technology, Shiyan, Hubei 442002, China
| | - Meijun Hu
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Jiahui Luo
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Binghong Xie
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Pengyun Ma
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Guoyun Wu
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Fuguang Xue
- Nanchang key laboratory of animal health and safety production, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China.
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Siniagina MN, Laikov AV, Markelova MI, Boulygina EA, Khusnutdinova DR, Abdulkhakov SR, Grigoryeva TV. Competitive ability of <i>Escherichia coli</i> strains in the intestinal microbiota of patients with Crohn's disease and healthy volunteers: physiological, biochemical and genetic characteristics. JOURNAL OF MICROBIOLOGY, EPIDEMIOLOGY AND IMMUNOBIOLOGY 2023. [DOI: 10.36233/0372-9311-192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Introduction. Crohn's disease (CD) is a chronic inflammation of various parts of the gastrointestinal tract with an increased proportion of Escherichia coli. However, the role of E. coli in disease remains unclear.
This study aims to evaluate the competitive abilities of E. coli strains from CD patients and healthy volunteers, and to identify the biochemical and genetic determinants underlying these features.
Materials and methods. The antagonistic activity was assessed by co-cultivation of 11 clinical E. coli strains inhibiting the growth of the K-12, with Enterobacter cloacae, Klebsiella pneumonia and Salmonella enterica. To elucidate the mechanism of antagonistic activity, the evaluation of biochemical properties and a comparative genomic analysis were used.
Results and discussion. Genes of bacteriocin production systems were identified in genomes of 11 strains from CD patients and healthy volunteers active against the E. coli K-12 strain. Three strains from healthy individuals demonstrated activity against several Enterobacteriaceae bacteria. The strains biochemical properties were typical of representatives of E. coli. Strains 1_34_12, active against E. cloacae, and 1_45_11, inhibiting all tested enterobacteria, are phylogenetically related to the laboratory strain K-12. Strain 1_39_1, active against K. pneumonia and S. enterica, is phylogenetically close to the Nissle1917, contains the genes for colibactin biosynthesis and a variant of the fimH gene that increases the adhesive ability of bacteria.
Conclusion. The identified E. coli strains are able to displace Enterobacteriaceae bacteria and can be used to study the bacteria-bacteria and host-bacteria interactions, to understand their role in gut homeostasis and intestinal inflammation.
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Li P, Zheng L, Qi Y, Liu Z, Du E, Wei J, Zhang Z, Guo S, Ding B. Dietary Lactobacillus fermentum and Lactobacillus paracasei improve the intestinal health of broilers challenged with coccidia and Clostridium perfringens. Front Vet Sci 2022; 9:1025677. [PMID: 36590818 PMCID: PMC9797813 DOI: 10.3389/fvets.2022.1025677] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Necrotic enteritis (NE) is a great threat to the intestinal health of broilers, resulting in decreased growth performance and significant economic losses. Lactobacillus fermentum (LF) and Lactobacillus paracasei (LP) exert beneficial effects on intestinal health. The aim of the present study was to investigate the effects of dietary LF and LP on the intestinal health and growth performance of broilers challenged with coccidia and Clostridium perfringens (CCP). The animal trial was carried out using 336 broilers (Ross 308) for 35 days with a completely randomized design. The broilers were divided into 4 groups based on treatment as follows: the control (CTR) group was fed the basal diet and without CCP challenge and the CCP group was fed the basal diet and with CCP challenge. The broilers in the CCP+LF and CCP+LP groups were challenged by CCP, and meanwhile, LF (1 × 109 CFU/g) and LP (1 × 109 CFU/g) were supplemented into the basal diets, respectively. The results showed that the growth performance and the intestinal morphology were negatively affected by the CCP challenge. In addition, the number of coccidia in the intestinal digesta and the relative abundance of Escherichia coli in the cecal digesta were increased. Besides, the mRNA level of IgA in the jejunum was downregulated, and the transcript level of IL-8 was upregulated by the CCP challenge. Dietary LF and LP failed to improve the growth performance of broilers with the CCP challenge. However, they were beneficial for intestinal barrier function. In addition, dietary LF was able to alleviate the downregulation of TGF-β mRNA level in the spleen with CCP challenge and decreased the lesion scores compared with the CCP group. Furthermore, dietary LP alleviated the upregulation of the IL-8 mRNA level in the jejunum with CCP challenge and reduced the number of coccidia in the ileal digesta. In conclusion, dietary LF and LP failed to mitigate the negative effects of CCP infection on growth performance; however, they were able to improve the intestinal health of broilers challenged with CCP by strengthening the intestinal barrier and alleviating inflammation.
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Affiliation(s)
- Peng Li
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Liyun Zheng
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Ya Qi
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Zhipeng Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Encun Du
- Key Laboratory of Animal Embryo Engineering and Molecular Breeding of Hubei Province, Institute of Animal Science and Veterinary Medicine, Hubei Academy of Agricultural Sciences, Wuhan, China
| | - Jintao Wei
- Key Laboratory of Animal Embryo Engineering and Molecular Breeding of Hubei Province, Institute of Animal Science and Veterinary Medicine, Hubei Academy of Agricultural Sciences, Wuhan, China
| | - Zhengfan Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China
| | - Shuangshuang Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China,*Correspondence: Shuangshuang Guo
| | - Binying Ding
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, Hubei, China,Binying Ding
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Zheng L, Duan SL, Dai YC, Wu SC. Role of adherent invasive Escherichia coli in pathogenesis of inflammatory bowel disease. World J Clin Cases 2022; 10:11671-11689. [PMID: 36405271 PMCID: PMC9669839 DOI: 10.12998/wjcc.v10.i32.11671] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 09/04/2022] [Accepted: 10/11/2022] [Indexed: 02/05/2023] Open
Abstract
Gut microbiota imbalances play an important role in inflammatory bowel disease (IBD), but no single pathogenic microorganism critical to IBD that is specific to the IBD terminal ileum mucosa or can invade intestinal epithelial cells has been found. Invasive Escherichia coli (E. coli) adhesion to macrophages is considered to be closely related to the pathogenesis of inflammatory bowel disease. Further study of the specific biological characteristics of adherent invasive E. coli (AIEC) may contribute to a further understanding of IBD pathogenesis. This review explores the relationship between AIEC and the intestinal immune system, discusses the prevalence and relevance of AIEC in Crohn's disease and ulcerative colitis patients, and describes the relationship between AIEC and the disease site, activity, and postoperative recurrence. Finally, we highlight potential therapeutic strategies to attenuate AIEC colonization in the intestinal mucosa, including the use of phage therapy, antibiotics, and anti-adhesion molecules. These strategies may open up new avenues for the prevention and treatment of IBD in the future.
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Affiliation(s)
- Lie Zheng
- Department of Gastroenterology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 322000, Shaanxi Province, China
| | - Sheng-Lei Duan
- Department of Gastroenterology, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 322000, Shaanxi Province, China
| | - Yan-Cheng Dai
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Shi-Cheng Wu
- Department of Proctology, Gansu Academy of Traditional Chinese Medicine, Gansu Hospital of Traditional Chinese Medicine, Lanzhou 730050, Gansu Province, China
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Investigating Causal Relations between Genetic-Related Intermediate Endophenotype and Risk of Chronic Prostatitis: Mendelian Randomization Study. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4560609. [PMID: 36071874 PMCID: PMC9441385 DOI: 10.1155/2022/4560609] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/04/2022] [Accepted: 08/13/2022] [Indexed: 01/02/2023]
Abstract
Objective Prostatitis is a common disease of the male genitourinary system, which seriously disturbs the physical and mental health of male patients. It is related to many factors such as living habits, age, and race, but the etiology has not been fully elucidated. This study investigated whether there is a causal relationship between clinical biochemical indicators (i.e., intermediate phenotype) and prostatitis through Mendelian randomization. The subjects of the study were prostatitis patients and related SNPs in the Guangxi Fangchenggang health examination cohort. Methods According to the requirements of Mendelian randomization (MR), the single nucleotide polymorphisms (SNPs) related to prostatitis patients and 29 common SNPs related to clinical biochemical indicators were analyzed by linkage disequilibrium, and the calculated SNPs were selected. Finally, the related SNPs were analyzed by Mendelian randomization method. Results 15 biochemical indicators such as complement C4, FOL, CRP, HCY, and estradiol have shared chronic prostatitis SNP sites, and five qualified SNPs were finally screened for complement C4. Finally, complement C4 was obtained by Mendelian randomization method (P = 0.039), which was statistically significant. The other 28 clinical endophenotypes were all negative. Conclusion The results show that there was a causal relationship between complement C4 and prostatitis, and the more consistent SNP is rs2075799.
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The Short-Chain Fatty Acids Propionate and Butyrate Augment Adherent-Invasive Escherichia coli Virulence but Repress Inflammation in a Human Intestinal Enteroid Model of Infection. Microbiol Spectr 2021; 9:e0136921. [PMID: 34612688 PMCID: PMC8510176 DOI: 10.1128/spectrum.01369-21] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Short-chain fatty acids (SCFAs), which consist of six or fewer carbons, are fermentation products of the bacterial community that inhabits the intestine. Due to an immunosuppressive effect on intestinal tissue, they have been touted as a therapeutic for inflammatory conditions of the bowel. Here, we study the impact of acetate, propionate, and butyrate, the three most abundant SCFAs in the intestine, on gene expression in the intestinal pathobiont adherent-invasive Escherichia coli. We pair this with adherence, invasion, and inflammation in Caco-2 and human intestinal enteroid (HIE)-derived monolayer models of the intestinal epithelium. We report that propionate and butyrate upregulate transcription of adherent-invasive Escherichia coli (AIEC) flagellar synthesis genes and decrease expression of capsule assembly and transport genes. These changes are predicted to augment AIEC invasiveness. In fact, SCFA supplementation increases AIEC adherence to and invasion of the Caco-2 monolayer but has no effect on these parameters in the HIE model. We attribute this to the anti-inflammatory effect of propionate and butyrate on HIEs but not on Caco-2 cells. We conclude that the potential of SCFAs to increase the virulence of intestinal pathogens should be considered in their use as anti-inflammatory agents. IMPORTANCE The human terminal ileum and colon are colonized by a community of microbes known as the microbiota. Short-chain fatty acids (SCFAs) excreted by bacterial members of the microbiota define the intestinal environment. These constitute an important line of communication within the microbiota and between the microbiota and the host epithelium. In inflammatory conditions of the bowel, SCFAs are often low and there is a preponderance of a conditionally virulent bacterium termed adherent-invasive Escherichia coli (AIEC). A connection between SCFA abundance and AIEC has been suggested. Here, we study AIEC in monoculture and in coculture with human intestinal enteroid-derived monolayers and show that the SCFAs propionate and butyrate increase expression of AIEC virulence genes while concurrently bolstering the intestinal epithelial barrier and reducing intestinal inflammation. While these SCFAs have been promoted as a therapy for inflammatory bowel conditions, our findings demonstrate that their effect on bacterial virulence must be considered.
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Sahu SK, Kulkarni DH, Ozanturk AN, Ma L, Kulkarni HS. Emerging roles of the complement system in host-pathogen interactions. Trends Microbiol 2021; 30:390-402. [PMID: 34600784 DOI: 10.1016/j.tim.2021.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/01/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022]
Abstract
The complement system has historically been entertained as a fluid-phase, hepatically derived system which protects the intravascular space from encapsulated bacteria. However, there has been an increasing appreciation for its role in protection against non-encapsulated pathogens. Specifically, we have an improved understanding of how pathogens are recognized by specific complement proteins, as well as how they trigger and evade them. Additionally, we have an improved understanding of locally derived complement proteins, many of which promote host defense. Moreover, intracellular complement proteins have been identified that facilitate local protection and barrier function despite pathogen invasion. Our review aims to summarize these advances in the field as well as provide an insight into the pathophysiological changes occurring when the system is dysregulated in infection.
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Affiliation(s)
- Sanjaya K Sahu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Devesha H Kulkarni
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Ayse N Ozanturk
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Lina Ma
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Hrishikesh S Kulkarni
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
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Wang J, Jiao H, Zhang X, Zhang Y, Sun N, Yang Y, Wei Y, Hu B, Guo X. Two Enteropathogenic Escherichia coli Strains Representing Novel Serotypes and Investigation of Their Roles in Adhesion. J Microbiol Biotechnol 2021; 31:1191-1199. [PMID: 34261855 PMCID: PMC9705854 DOI: 10.4014/jmb.2105.05016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/05/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Enteropathogenic Escherichia coli (EPEC), which belongs to the attaching and effacing diarrheagenic E. coli strains, is a major causative agent of life-threatening diarrhea in infants in developing countries. Most EPEC isolates correspond to certain O serotypes; however, many strains are nontypeable. Two EPEC strains, EPEC001 and EPEC080, which could not be serotyped during routine detection, were isolated. In this study, we conducted an in-depth characterization of their putative O-antigen gene clusters (O-AGCs) and also performed constructed mutagenesis of the O-AGCs for functional analysis of O-antigen (OAg) synthesis. Sequence analysis revealed that the occurrence of O-AGCs in EPEC001 and E. coli O132 may be mediated by recombination between them, and EPEC080 and E. coli O2/O50 might acquire each O-AGC from uncommon ancestors. We also indicated that OAgknockout bacteria were highly adhesive in vitro, except for the EPEC001 wzy derivative, whose adherent capability was less than that of its wild-type strain, providing direct evidence that OAg plays a key role in EPEC pathogenesis. Together, we identified two EPEC O serotypes in silico and experimentally, and we also studied the adherent capabilities of their OAgs, which highlighted the fundamental and pathogenic role of OAg in EPEC.
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Affiliation(s)
- Jing Wang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China
| | - HongBo Jiao
- LanLing Center for Disease Control and Prevention, 1 City Huibao Road, Lanling 276000, Lanling Shandong, P.R. China
| | - XinFeng Zhang
- Taian Center for Disease Control and Prevention, 33 Changcheng Road, Taian 271000, Shandong, P.R. China
| | - YuanQing Zhang
- Jinan KeJia Medical Laboratory, Inc., 800 Minghu West Road, Jinan 250001, Shandong, P.R. China
| | - Na Sun
- Shandong Center for Disease Control and Prevention, 16992 City Ten Road, Jinan 250014, Shandong, P.R. China
| | - Ying Yang
- Shandong Center for Disease Control and Prevention, 16992 City Ten Road, Jinan 250014, Shandong, P.R. China
| | - Yi Wei
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China
| | - Bin Hu
- Shandong Center for Disease Control and Prevention, 16992 City Ten Road, Jinan 250014, Shandong, P.R. China,Corresponding authors B. Hu Phone: +86-0531-82679738 Fax: +86-531-82679750 E-mail:
| | - Xi Guo
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China,The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, 23 Hongda Street, TEDA, Tianjin 300457, P.R. China,
X. Guo Phone: +86-22-66229574 Fax: +86-22-66229584 E-mail:
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13
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de Sousa Figueiredo MB, Pradel E, George F, Mahieux S, Houcke I, Pottier M, Fradin C, Neut C, Daniel C, Bongiovanni A, Foligné B, Titécat M. Adherent-Invasive and Non-Invasive Escherichia coli Isolates Differ in Their Effects on Caenorhabditis elegans' Lifespan. Microorganisms 2021; 9:microorganisms9091823. [PMID: 34576719 PMCID: PMC8465672 DOI: 10.3390/microorganisms9091823] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/16/2021] [Accepted: 08/24/2021] [Indexed: 01/09/2023] Open
Abstract
The adherent-invasive Escherichia coli (AIEC) pathotype has been implicated in the pathogenesis of inflammatory bowel diseases in general and in Crohn’s disease (CD) in particular. AIEC strains are primarily characterized by their ability to adhere to and invade intestinal epithelial cells. However, the genetic and phenotypic features of AIEC isolates vary greatly as a function of the strain’s clonality, host factors, and the gut microenvironment. It is thus essential to identify the determinants of AIEC pathogenicity and understand their role in intestinal epithelial barrier dysfunction and inflammation. We reasoned that soil nematode Caenorhabditis elegans (a simple but powerful model of host-bacterium interactions) could be used to study the virulence of AIEC vs. non- AIEC E. coli strains. Indeed, we found that the colonization of C. elegans (strain N2) by E. coli impacted survival in a strain-specific manner. Moreover, the AIEC strains’ ability to invade cells in vitro was linked to the median lifespan in C. elegans (strain PX627). However, neither the E. coli intrinsic invasiveness (i.e., the fact for an individual strain to be characterized as invasive or not) nor AIEC’s virulence levels (i.e., the intensity of invasion, established in % from the infectious inoculum) in intestinal epithelial cells was correlated with C. elegans’ lifespan in the killing assay. Nevertheless, AIEC longevity of C. elegans might be a relevant model for screening anti-adhesion drugs and anti-invasive probiotics.
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Affiliation(s)
- Maria Beatriz de Sousa Figueiredo
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Elizabeth Pradel
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-Center for Infection and Immunity of Lille, F-59000 Lille, France;
| | - Fanny George
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Séverine Mahieux
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Isabelle Houcke
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Muriel Pottier
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Chantal Fradin
- Univ. Lille, Inserm, Institut Pasteur de Lille, U1167-RID-AGE, F-59000 Lille, France;
| | - Christel Neut
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
| | - Catherine Daniel
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-Center for Infection and Immunity of Lille, F-59000 Lille, France;
| | - Antonino Bongiovanni
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41-UMS 2014-PLBS, F-59000 Lille, France;
| | - Benoît Foligné
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
- Correspondence: (B.F.); (M.T.)
| | - Marie Titécat
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France; (M.B.d.S.F.); (E.P.); (F.G.); (S.M.); (I.H.); (M.P.); (C.N.)
- Correspondence: (B.F.); (M.T.)
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14
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Diversity and Adaptations of Escherichia coli Strains: Exploring the Intestinal Community in Crohn's Disease Patients and Healthy Individuals. Microorganisms 2021; 9:microorganisms9061299. [PMID: 34203637 PMCID: PMC8232093 DOI: 10.3390/microorganisms9061299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/17/2022] Open
Abstract
Crohn's disease (CD) is characterized by a chronic, progressive inflammation across the gastrointestinal tract with a series of exacerbations and remissions. A significant factor in the CD pathogenesis is an imbalance in gut microbiota composition, particularly the prevalence of Escherichia coli. In the present study, the genomes of sixty-three E. coli strains from the gut of patients with CD and healthy subjects were sequenced. In addition, eighteen E. coli-like metagenome-assembled genomes (MAGs) were reconstructed from the shotgun-metagenome sequencing data of fecal samples. The comparative analysis revealed the similarity of E. coli genomes regardless of the origin of the strain. The strains exhibited similar genetic patterns of virulence, antibiotic resistance, and bacteriocin-producing systems. The study showed antagonistic activity of E. coli strains and the metabolic features needed for their successful competition in the human gut environment. These observations suggest complex bacterial interactions within the gut which may affect the host and cause intestinal damage.
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