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Miki T, Ito M, Haneda T, Kim YG. Crohn's Disease‒Associated Escherichia coli BasRS Is Involved in Fimbriae Expression, Contributing to Epithelial Cell Invasion. Microbiol Immunol 2025. [PMID: 40221934 DOI: 10.1111/1348-0421.13221] [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: 03/16/2025] [Accepted: 04/02/2025] [Indexed: 04/15/2025]
Abstract
Crohn's disease‒associated adherent-invasive Escherichia coli (AIEC) colonizes the gut lumen through Type 1 fimbriae. We demonstrated that the two-component signal transduction system BasRS is involved in the expression of fimbriae in the AIEC strain LF82, as evidenced by the reduced transcriptional activity of fimA in an LF82 mutant lacking BasRS. Consequently, the basRS mutant showed decreased invasiveness to HeLa cells, which was restored by introducing a plasmid expressing fimbriae in a BasRS-independent manner. These findings may provide new prospects for developing therapeutic interventions for AIEC-related Crohn's disease.
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Affiliation(s)
- Tsuyoshi Miki
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Masahiro Ito
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Takeshi Haneda
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Yun-Gi Kim
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, Japan
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2
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Doghish AS, Elazazy O, Mohamed HH, Mansour RM, Ghanem A, Faraag AHI, Elballal MS, Elrebehy MA, Elesawy AE, Abdel Mageed SS, Saber S, Nassar YA, Abulsoud AI, Abdel-Reheim MA, Elawady AS, Ali MA, Basiouny MS, Hemdan M, Lutfy RH, Awad FA, El-Sayed SA, Ashour MM, El-Sayyad GS, Mohammed OA. A Review on miRNAs in Enteric Bacteria-mediated Host Pathophysiology: Mechanisms and Implications. J Biochem Mol Toxicol 2025; 39:e70160. [PMID: 39907181 DOI: 10.1002/jbt.70160] [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: 09/15/2024] [Revised: 12/22/2024] [Accepted: 01/16/2025] [Indexed: 02/06/2025]
Abstract
Recently, many studies focused on the billions of native bacteria found inside and all over the human body, commonly known as the microbiota, and its interactions with the eukaryotic host. One of the niches for such microbiota is the gastrointestinal tract (GIT), which harbors hundreds to thousands of bacterial species commonly known as enteric bacteria. Changes in the enteric bacterial populations were linked to various pathologies such as irritable bowel syndrome and obesity. The gut microbiome could affect the health status of individuals. MicroRNAs (miRNAs) are one of the extensively studied small-sized noncoding RNAs (ncRNAs) over the past decade to explore their multiple roles in health and disease. It was proven that miRNAs circulate in almost all body fluids and tissues, showing signature patterns of dysregulation associated with pathologies. Both cellular and circulating miRNAs participate in the posttranscriptional regulation of genes and are considered the potential key regulators of genes and participate in cellular communication. This manuscript explores the unique interplay between miRNAs and enteric bacteria in the gastrointestinal tract, emphasizing their dual role in shaping host-microbiota dynamics. It delves into the molecular mechanisms by which miRNAs influence bacterial colonization and host immune responses, linking these findings to gut-related diseases. The review highlights innovative therapeutic and diagnostic opportunities, offering insights for targeted treatments of dysbiosis-associated pathologies.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
| | - Hend H Mohamed
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, Egypt
- Molecular Biology and Biotechnology Department, School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Aml Ghanem
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Ahmed H I Faraag
- Botany and Microbiology Department, Faculty of Science, Helwan University, Helwan, Egypt
- Medical Department, School of Biotechnology, Badr University in Cairo, Badr City, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Galala University, New Galala City, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Yara A Nassar
- Department of Botany, Faculty of Science, Biotechnology and Its Application Program, Mansoura University, Mansoura, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
- Department of Biochemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Egypt
| | | | - Alaa S Elawady
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mohamed A Ali
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | | | - Mohamed Hemdan
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Salma A El-Sayed
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Mohamed M Ashour
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, Egypt
| | - Gharieb S El-Sayyad
- Medical Laboratory Technology Department, Faculty of Applied Health Sciences Technology, Badr University in Cairo (BUC), Cairo, Egypt
- Microbiology and Immunology Department, Faculty of Pharmacy, Galala University, New Galala city, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, Saudi Arabia
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Damianos J, Abdelnaem N, Camilleri M. Gut Goo: Physiology, Diet, and Therapy of Intestinal Mucus and Biofilms in Gastrointestinal Health and Disease. Clin Gastroenterol Hepatol 2025; 23:205-215. [PMID: 39426645 PMCID: PMC11761393 DOI: 10.1016/j.cgh.2024.09.007] [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: 07/24/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/21/2024]
Abstract
The gastrointestinal tract has remarkable capacity to withstand considerable insults from exposure to abrasive food particles, chemicals, allergens, and pathogenic microbes. Maintaining a robust epithelial barrier sequesters these potentially harmful substances in the lumen, preventing absorption into the systemic circulation. Normal functioning of this barrier is central in diverse physiological processes including digestion, immunity, inflammation, and gut-brain signaling. One crucial component of the barrier is the mucus layer covering the epithelium. There is increased appreciation of the importance of mucus in maintenance of the gut barrier, and how dysregulation of the mucus layer contributes to several common gastrointestinal pathologies. This manuscript reviews the physical and chemical properties of mucus, its maintenance and turnover, and its role in maintaining gut barrier integrity. The dynamic interactions of the mucus layer within the gut ecosystem are illustrated by highlighting how a weakened mucus layer or defective mucus production facilitate pathogenic microbial colonization and mucosal biofilm formation. These may potentially contribute to the pathogenesis of gastrointestinal diseases such as inflammatory bowel diseases or result in secretion and mucosal damage and inflammation in bile acid diarrhea. A final goal is to review how certain dietary factors, especially low-fiber diets and emulsifiers common in Western diets, can harm the mucus layer. This report summarizes evidence from preclinical and human studies that document damage to the mucus layer, and reviews approaches, including diets and probiotics, that promote a healthy mucus layer and break down pathogenic biofilms, thereby potentially preventing and/or treating gastrointestinal diseases that impact mucosal integrity.
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Affiliation(s)
- John Damianos
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nada Abdelnaem
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Ahn JH, da Silva Pedrosa M, Lopez LR, Tibbs TN, Jeyachandran JN, Vignieri EE, Rothemich A, Cumming I, Irmscher AD, Haswell CJ, Zamboni WC, Yu YRA, Ellermann M, Denson LA, Arthur JC. Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host Microbe 2025; 33:71-88.e9. [PMID: 39701098 DOI: 10.1016/j.chom.2024.11.012] [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: 05/09/2024] [Revised: 11/11/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
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Affiliation(s)
- Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marlus da Silva Pedrosa
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lacey R Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor N Tibbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joanna N Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Emily E Vignieri
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Aaron Rothemich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ian Cumming
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
| | - Alexander D Irmscher
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Corey J Haswell
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yen-Rei A Yu
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Melissa Ellermann
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Lee A Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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5
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Caruso R, Lo BC, Chen GY, Núñez G. Host-pathobiont interactions in Crohn's disease. Nat Rev Gastroenterol Hepatol 2024:10.1038/s41575-024-00997-y. [PMID: 39448837 DOI: 10.1038/s41575-024-00997-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/26/2024]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Grace Y Chen
- Department of Internal Medicine and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Muñiz Pedrogo DA, Sears CL, Melia JMP. Colorectal Cancer in Inflammatory Bowel Disease: A Review of the Role of Gut Microbiota and Bacterial Biofilms in Disease Pathogenesis. J Crohns Colitis 2024; 18:1713-1725. [PMID: 38703073 DOI: 10.1093/ecco-jcc/jjae061] [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: 11/17/2023] [Revised: 01/31/2024] [Accepted: 05/03/2024] [Indexed: 05/06/2024]
Abstract
The risk of colorectal cancer [CRC] is increased in patients with inflammatory bowel disease [IBD], particularly in extensive ulcerative colitis [UC] and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation, as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and proinflammatory properties by organising into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumour-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histological inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. Commonly used in the treatment of UC, 5-aminosalicylates have antimicrobial and anticarcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially of biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC, via mechanisms independent of inflammation, is still unknown. Further research is warranted to identify potential new microbial targets in therapy for chemoprevention of dysplasia and CRC in IBD.
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Affiliation(s)
- David A Muñiz Pedrogo
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cynthia L Sears
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joanna M P Melia
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Miki T, Ito M, Haneda T, Kim YG. Outer membrane barrier impairment by envC deletion reduces gut colonization of Crohn's disease pathobiont Escherichia coli. MICROBIOLOGY (READING, ENGLAND) 2024; 170:001509. [PMID: 39405098 PMCID: PMC11570989 DOI: 10.1099/mic.0.001509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 10/02/2024] [Indexed: 11/07/2024]
Abstract
Adherent-invasive Escherichia coli (AIEC) has been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract. The presence of Enterobacteriaceae, including AIEC, is heightened in the intestines of CD patients. Therefore, inhibiting AIEC colonization in the gastrointestinal tract could be a promising therapeutic intervention for CD. This study aims to assess the potential of EnvC as a novel therapeutic target, examining how disrupting EnvC activity through the deletion of the envC gene decreases AIEC gut colonization levels. EnvC serves as a catalyst for peptidoglycan (also called murein) amidases, facilitating bacterial cell division. An AIEC mutant lacking the envC gene exhibited impaired cell division. Furthermore, envC deletion led to a diminished outer membrane barrier, as seen in our finding that the envC mutant became susceptible to vancomycin. Finally, we found that the envC mutant is impaired in competitive gut colonization in a dysbiotic mouse model. The colonization defects might be attributable to reduced resistance to colonic bile acids, as evidenced by our finding that increased colonic levels of bile acids inhibited the colonization of the gastrointestinal tract by AIEC strains. The present findings suggest that targeting bacterial cell division through the inhibition of EnvC activity could represent a promising intervention for CD.
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Affiliation(s)
- Tsuyoshi Miki
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, 108-8641, Japan
| | - Masahiro Ito
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, 108-8641, Japan
| | - Takeshi Haneda
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, 108-8641, Japan
| | - Yun-Gi Kim
- Department of Microbiology, School of Pharmacy, Kitasato University, Tokyo, 108-8641, Japan
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Chatterjee P, Canale V, King SJ, Shawki A, Lei H, Haddad M, Gries CM, McGovern DP, Borneman J, McCole DF. The JAK inhibitor, Tofacitinib, Corrects the Overexpression of CEACAM6 and Limits Susceptibility to AIEC Caused by Reduced Activity of the IBD Associated Gene, PTPN2. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.26.24314341. [PMID: 39399045 PMCID: PMC11469354 DOI: 10.1101/2024.09.26.24314341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Background and Aims A cohort of patients with inflammatory bowel disease (IBD) exhibit expansion of the gut pathobiont, adherent-invasive E. coli (AIEC). Loss of activity of the IBD susceptibility gene, protein tyrosine phosphatase type 2 (PTPN2), results in dysbiosis of the gut microbiota both in human subjects and mice. Further, constitutive Ptpn2 knock-out (Ptpn2-KO) mice display expansion of AIEC compared to wildtype littermates. CEACAM6, a host cell surface glycoprotein, is exploited by AIEC to attach to and enter intestinal epithelial cells (IECs). Here, we investigate the role of IEC-specific PTPN2 in restricting AIEC invasion. Methods Biopsies from IBD patients heterozygous (CT) or homozygous (CC) for the PTPN2 SNP (single nucleotide polymorphism) rs1893217 were processed for immunohistochemistry. HT-29 intestinal epithelial cells (IEC) were transfected with control shRNA (PTPN2-CTL), or a shRNA targeted towards PTPN2 (PTPN2-KD). The rs1893217 SNP was inserted (PTPN2-KI), or a complete knock-out of PTPN2 (PTPN2-KO) was generated, with CRISPR-Cas9 gene editing of Caco-2BBe IEC lines. Adherence and invasion assays were performed with either the human IBD AIEC isolate, LF82, or a novel fluorescent-tagged mouse adherent-invasive E. coli (mAIECred) at multiplicity of infection (MOI) of 10. IL-6 and the pan-JAK inhibitor tofacitinib were administered to interrogate JAK-STAT signaling. Protein expression was determined by western blotting and densitometry. Results CEACAM6 expression was elevated (colon and ileum) in IBD patients carrying the PTPN2 rs1893217 SNP (CT, CC) compared to wildtype (TT) IBD patients. HT-29 and Caco-2BBe cell lines deficient in PTPN2 expressed significantly higher levels of CEACAM6. Further, PTPN2-KI and PTPN2-KO cell lines also displayed greater adherence and invasion by AIEC LF82 and higher mAIECred invasion. CEACAM6 expression was further elevated after administration of IL-6 in PTPN2-deficient cell lines compared to untreated controls. Silencing of STAT1 and 3 partially reduced CEACAM6 protein expression. Tofacitinib significantly reduced the elevated CEACAM6 protein expression and the higher AIEC adherence and invasion in PTPN2-KI and PTPN2-KO cell lines compared to DMSO controls. Conclusion Our findings highlight a crucial role for PTPN2 in restricting pathobiont entry into host cells. Our study also describes a role for the FDA-approved drug, tofacitinib (Xeljanz) in correcting the JAK-STAT-mediated over-expression of CEACAM6, used by pathobionts as an entry portal into host cells. These findings suggest a role for JAK-inhibitors in mitigating AIEC colonization in IBD-susceptible hosts.
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Affiliation(s)
- Pritha Chatterjee
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Vinicius Canale
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Stephanie J. King
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Ali Shawki
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Hillmin Lei
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Michael Haddad
- Department of Biology, University of California, Riverside, Riverside, California
| | - Casey M. Gries
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Dermot P.B. McGovern
- Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California
| | - James Borneman
- Department of Microbiology and Plant Pathology, University of California, Riverside, California
| | - Declan F. McCole
- Division of Biomedical Sciences, University of California, Riverside, Riverside, California
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9
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Bosselaar S, Dhelin L, Dautel E, Titecat M, Duthoy S, Stelmaszczyk M, Delory N, De Sousa Violante M, Machuron F, Ait-Abderrahim H, Desreumaux P, Foligné B, Monnet C. Taxonomic and phenotypic analysis of bifidobacteria isolated from IBD patients as potential probiotic strains. BMC Microbiol 2024; 24:233. [PMID: 38951788 PMCID: PMC11218132 DOI: 10.1186/s12866-024-03368-4] [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: 02/14/2024] [Accepted: 06/12/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Inflammatory Bowel Diseases (IBD) are a major public health issue with unclear aetiology. Changes in the composition and functionality of the intestinal microbiota are associated with these pathologies, including the depletion of strict anaerobes such as Feacalibacterium prausnitzii. Less evidence is observed for depletion in other anaerobes, among which bifidobacteria. This study characterized the taxonomic and functional diversity of bifidobacteria isolated from the human intestinal microbiota in active and non-active IBD patients by a culturomics approach and evaluated if these bifidobacteria might be used as probiotics for gut health. RESULTS A total of 341 bifidobacteria were isolated from the intestinal microbiota of IBD patients (52 Crohn's disease and 26 ulcerative colitis patients), with a high proportion of Bifidobacterium dentium strains (28% of isolated bifidobacteria). In ulcerative colitis, the major species identified was B. dentium (39% of isolated bifidobacteria), in active and non-active ulcerative colitis. In Crohn's disease, B. adolescentis was the major species isolated from non-active patients (40%), while similar amounts of B. dentium and B. adolescentis were found in active Crohn's disease patients. The relative abundance of B. dentium was increased with age, both in Crohn's disease and ulcerative colitis and active and non-active IBD patients. Antibacterial capacities of bifidobacteria isolated from non-active ulcerative colitis against Escherichia coli LF82 and Salmonella enterica ATCC 14028 were observed more often compared to strains isolated from active ulcerative colitis. Finally, B. longum were retained as strains with the highest probiotic potential as they were the major strains presenting exopolysaccharide synthesis, antibacterial activity, and anti-inflammatory capacities. Antimicrobial activity and EPS synthesis were further correlated to the presence of antimicrobial and EPS gene clusters by in silico analysis. CONCLUSIONS Different bifidobacterial taxonomic profiles were identified in the microbiota of IBD patients. The most abundant species were B. dentium, mainly associated to the microbiota of ulcerative colitis patients and B. adolescentis, in the intestinal microbiota of Crohn's disease patients. Additionally, the relative abundance of B. dentium significantly increased with age. Furthermore, this study evidenced that bifidobacteria with probiotic potential (antipathogenic activity, exopolysaccharide production and anti-inflammatory activity), especially B. longum strains, can be isolated from the intestinal microbiota of both active and non-active Crohn's disease and ulcerative colitis patients.
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Affiliation(s)
- Sabine Bosselaar
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France.
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, 59000, Lille, France.
| | - Lucile Dhelin
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Ellena Dautel
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Marie Titecat
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, 59000, Lille, France
| | - Stéphanie Duthoy
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Marie Stelmaszczyk
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Nathan Delory
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Madeleine De Sousa Violante
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - François Machuron
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Hassina Ait-Abderrahim
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
| | - Pierre Desreumaux
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, 59000, Lille, France
- Department of Hepato-Gastroenterology, Lille University Hospital, 59037, Lille, France
| | - Benoit Foligné
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, 59000, Lille, France
| | - Céline Monnet
- Lesaffre International - Lesaffre Institute of Science and Technology, 101 Rue de Menin, 59706, Marcq-en-Barœul, France
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10
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Paksoy A, Meller S, Schwotzer F, Moroder P, Trampuz A, Imiolczyk JP, Perka C, Hackl M, Plachel F, Akgün D. MicroRNA expression analysis in peripheral blood and soft-tissue of patients with periprosthetic hip infection. Bone Jt Open 2024; 5:479-488. [PMID: 38839054 PMCID: PMC11152758 DOI: 10.1302/2633-1462.56.bjo-2023-0172.r2] [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] [Indexed: 06/07/2024] Open
Abstract
Aims Current diagnostic tools are not always able to effectively identify periprosthetic joint infections (PJIs). Recent studies suggest that circulating microRNAs (miRNAs) undergo changes under pathological conditions such as infection. The aim of this study was to analyze miRNA expression in hip arthroplasty PJI patients. Methods This was a prospective pilot study, including 24 patients divided into three groups, with eight patients each undergoing revision of their hip arthroplasty due to aseptic reasons, and low- and high-grade PJI, respectively. The number of intraoperative samples and the incidence of positive cultures were recorded for each patient. Additionally, venous blood samples and periarticular tissue samples were collected from each patient to determine miRNA expressions between the groups. MiRNA screening was performed by small RNA-sequencing using the miRNA next generation sequencing (NGS) discovery (miND) pipeline. Results Overall, several miRNAs in plasma and tissue were identified to be progressively deregulated according to ongoing PJI. When comparing the plasma samples, patients with a high-grade infection showed significantly higher expression levels for hsa-miR-21-3p, hsa-miR-1290, and hsa-miR-4488, and lower expression levels for hsa-miR-130a-3p and hsa-miR-451a compared to the aseptic group. Furthermore, the high-grade group showed a significantly higher regulated expression level of hsa-miR-1260a and lower expression levels for hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-148b-5p, hsa-miR-301a-3p, hsa-miR-451a, and hsa-miR-454-3p compared to the low-grade group. No significant differences were found between the low-grade and aseptic groups. When comparing the tissue samples, the high-grade group showed significantly higher expression levels for 23 different miRNAs and lower expression levels for hsa-miR-2110 and hsa-miR-3200-3p compared to the aseptic group. No significant differences were found in miRNA expression between the high- and low-grade groups, as well as between the low-grade and aseptic groups. Conclusion With this prospective pilot study, we were able to identify a circulating miRNA signature correlating with high-grade PJI compared to aseptic patients undergoing hip arthroplasty revision. Our data contribute to establishing miRNA signatures as potential novel diagnostic and prognostic biomarkers for PJI.
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Affiliation(s)
- Alp Paksoy
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
| | - Sebastian Meller
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
| | - Florian Schwotzer
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
| | | | - Andrej Trampuz
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
| | | | - Carsten Perka
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
| | | | | | - Doruk Akgün
- Charité University Hospital, Center for Musculoskeletal Surgery, Berlin, Germany
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11
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Nieva C, Pryor J, Williams GM, Hoedt EC, Burns GL, Eslick GD, Talley NJ, Duncanson K, Keely S. The Impact of Dietary Interventions on the Microbiota in Inflammatory Bowel Disease: A Systematic Review. J Crohns Colitis 2024; 18:920-942. [PMID: 38102104 PMCID: PMC11147801 DOI: 10.1093/ecco-jcc/jjad204] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/12/2023] [Accepted: 12/09/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND AND AIMS Diet plays an integral role in the modulation of the intestinal environment, with the potential to be modified for management of individuals with inflammatory bowel disease [IBD]. It has been hypothesised that poor 'Western-style' dietary patterns select for a microbiota that drives IBD inflammation and, that through dietary intervention, a healthy microbiota may be restored. This study aimed to systematically review the literature and assess current available evidence regarding the influence of diet on the intestinal microbiota composition in IBD patients, and how this may affect disease activity. METHODS MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library were searched from January 2013 to June 2023, to identify studies investigating diet and microbiota in IBD. RESULTS Thirteen primary studies met the inclusion criteria and were selected for narrative synthesis. Reported associations between diet and microbiota in IBD were conflicting due to the considerable degree of heterogeneity between studies. Nine intervention studies trialled specific diets and did not demonstrate significant shifts in the diversity and abundance of intestinal microbial communities or improvement in disease outcomes. The remaining four cross-sectional studies did not find a specific microbial signature associated with habitual dietary patterns in IBD patients. CONCLUSIONS Diet modulates the gut microbiota, and this may have implications for IBD; however, the body of evidence does not currently support clear dietary patterns or food constituents that are associated with a specific microbiota profile or disease marker in IBD patients. Further research is required with a focus on robust and consistent methodology to achieve improved identification of associations.
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Affiliation(s)
- Cheenie Nieva
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jennifer Pryor
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Georgina M Williams
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Emily C Hoedt
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Grace L Burns
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Guy D Eslick
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J Talley
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Kerith Duncanson
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Simon Keely
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
- National Health and Medical Research Council [NHMRC], Centre of Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia
- Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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12
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Zhang Y, Wang B, Bai J, Wei L, Chen X, Song J, Liu Y, Suo H, Wang C. Food intervention strategy for oral microbiome: A review. Trends Food Sci Technol 2024; 148:104514. [DOI: 10.1016/j.tifs.2024.104514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Li X, Cole J, Vaughan D, Xiao Y, Walker D, Wall DM. Stratifying macrophages based on their infectious burden identifies novel host targets for intervention during Crohn's disease associated adherent-invasive Escherichia coli infection. MICROBIOLOGY (READING, ENGLAND) 2024; 170:001470. [PMID: 38916198 PMCID: PMC11261827 DOI: 10.1099/mic.0.001470] [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: 01/23/2024] [Accepted: 05/24/2024] [Indexed: 06/26/2024]
Abstract
Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their bacterial load and duration of infection. In the case of infection of macrophages with Crohn's disease (CD) associated adherent-invasive Escherichia coli (AIEC), understanding the drivers of pathogen success may allow targeting of cells where AIEC replicate to high levels. Here we show that stratifying immune cells based on their bacterial load identifies novel pathways and therapeutic targets not previously associated with AIEC when using a traditional homogeneous infected population approach. Using flow cytometry-based cell sorting we stratified cells into those with low or high intracellular pathogen loads, or those which were bystanders to infection. Immune cells transcriptomics revealed a diverse response to the varying levels of infection while pathway analysis identified novel intervention targets that were directly related to increasing intracellular AIEC numbers. Chemical inhibition of identified targets reduced AIEC intracellular replication or inhibited secretion of tumour necrosis factor alpha (TNFα), a key cytokine associated with AIEC infection. Our results have identified new avenues of intervention in AIEC infection that may also be applicable to CD through the repurposing of already available inhibitors. Additionally, they highlight the applicability of immune cell stratification post-infection as an effective approach for the study of microbial pathogens.
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Affiliation(s)
- Xiang Li
- School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - John Cole
- School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Diane Vaughan
- School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Yinbo Xiao
- Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Daniel Walker
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK
| | - Daniel M. Wall
- School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, Glasgow, G12 8QQ, UK
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14
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Nanlohy NM, Johannesson N, Wijnands L, Arroyo L, de Wit J, den Hartog G, Wolthers KC, Sridhar A, Fuentes S. Exploring host-commensal-pathogen dynamics in cell line and organotypic human intestinal epithelial models. iScience 2024; 27:109771. [PMID: 38711444 PMCID: PMC11070716 DOI: 10.1016/j.isci.2024.109771] [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: 11/28/2023] [Revised: 02/26/2024] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
Host and microbiome intricately interact in the ecosystem of the human digestive tract, playing a crucial role in our health. These interactions can initiate immune responses in the epithelial cells, which, in turn, activate downstream responses in other immune cells. Here, we used a CaCo-2 and a human intestinal enteroid (HIE) model to explore epithelial responses to both commensal and pathogenic bacteria, individually and combined. CaCo-2 cells were co-cultured with peripheral blood mononuclear cells, revealing downstream activation of immune cells. While both systems showed comparable cytokine profiles, they differed in their responses to the different bacteria, with the organoid system being more representative of responses observed in humans. We provide evidence of the pro-inflammatory responses associated with these bacteria. These models contribute to a deeper understanding of the interactions between the microbiota, intestinal epithelium, and immune cells in the gut, promoting advances in the field of host-microbe interactions.
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Affiliation(s)
- Nening M. Nanlohy
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Nina Johannesson
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands
| | - Lucas Wijnands
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Laura Arroyo
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Jelle de Wit
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Gerco den Hartog
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
- Laboratory of Medical Immunology, Radboudumc, Nijmegen, the Netherlands
| | - Katja C. Wolthers
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands
| | - Adithya Sridhar
- OrganoVIR Labs, Department of Medical Microbiology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands
- OrganoVIR Labs, Department of Pediatric Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands
- Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands
| | - Susana Fuentes
- Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
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15
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Jia K, Shen J. Transcriptome-wide association studies associated with Crohn's disease: challenges and perspectives. Cell Biosci 2024; 14:29. [PMID: 38403629 PMCID: PMC10895848 DOI: 10.1186/s13578-024-01204-w] [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: 09/27/2023] [Accepted: 02/04/2024] [Indexed: 02/27/2024] Open
Abstract
Crohn's disease (CD) is regarded as a lifelong progressive disease affecting all segments of the intestinal tract and multiple organs. Based on genome-wide association studies (GWAS) and gene expression data, transcriptome-wide association studies (TWAS) can help identify susceptibility genes associated with pathogenesis and disease behavior. In this review, we overview seven reported TWASs of CD, summarize their study designs, and discuss the key methods and steps used in TWAS, which affect the prioritization of susceptibility genes. This article summarized the screening of tissue-specific susceptibility genes for CD, and discussed the reported potential pathological mechanisms of overlapping susceptibility genes related to CD in a certain tissue type. We observed that ileal lipid-related metabolism and colonic extracellular vesicles may be involved in the pathogenesis of CD by performing GO pathway enrichment analysis for susceptibility genes. We further pointed the low reproducibility of TWAS associated with CD and discussed the reasons for these issues, strategies for solving them. In the future, more TWAS are needed to be designed into large-scale, unified cohorts, unified analysis pipelines, and fully classified databases of expression trait loci.
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Affiliation(s)
- Keyu Jia
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China
| | - Jun Shen
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Nephrology department, Shanghai Jiao Tong University, 1058 Huanzhen Northroad, Shanghai, 200444, China.
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
- NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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16
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Khaledi M, Poureslamfar B, Alsaab HO, Tafaghodi S, Hjazi A, Singh R, Alawadi AH, Alsaalamy A, Qasim QA, Sameni F. The role of gut microbiota in human metabolism and inflammatory diseases: a focus on elderly individuals. ANN MICROBIOL 2024; 74:1. [DOI: 10.1186/s13213-023-01744-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Background
The gut microbiota plays a crucial role in regulating the host’s immune responses during aging, which was characterized by a different abundance of bacteria in several age groups.
Main body
Gut microbiota dysbiosis is associated with aging, antibiotic exposure, underlying diseases, infections, hormonal variations, circadian rhythm, and malnutrition, either singularly or in combination. The appropriate use of prebiotics and probiotics may be able to prevent or reduce this disruption.
Conclusion
The current review focuses on the gut microbiota composition across the life cycle, factors affecting gut microbiota changes with aging, and interventions to modulate gut microbiota.
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17
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Leccese G, Chiara M, Dusetti I, Noviello D, Billard E, Bibi A, Conte G, Consolandi C, Vecchi M, Conte MP, Barnich N, Caprioli F, Facciotti F, Paroni M. AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn's disease is suppressed by rfaP and ybaT deletion. Gut Microbes 2024; 16:2380064. [PMID: 39069911 PMCID: PMC11290758 DOI: 10.1080/19490976.2024.2380064] [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: 05/14/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/30/2024] Open
Abstract
Mucosal enrichment of the Adherent-Invasive E. coli (AIEC) pathotype and the expansion of pathogenic IFNγ-producing Th17 (pTh17) cells have been linked to Crohn's Disease (CD) pathogenesis. However, the molecular pathways underlying the AIEC-dependent pTh17 cell transdifferentiation in CD patients remain elusive. To this aim, we created and functionally screened a transposon AIEC mutant library of 10.058 mutants to identify the virulence determinants directly implicated in triggering IL-23 production and pTh17 cell generation. pTh17 cell transdifferentiation was assessed in functional assays by co-culturing AIEC-infected human dendritic cells (DCs) with autologous conventional Th17 (cTh17) cells isolated from blood of Healthy Donors (HD) or CD patients. AIEC triggered IL-23 hypersecretion and transdifferentiation of cTh17 into pTh17 cells selectively through the interaction with CD-derived DCs. Moreover, the chronic release of IL-23 by AIEC-colonized DCs required a continuous IL-23 neutralization to significantly reduce the AIEC-dependent pTh17 cell differentiation. The multi-step screenings of the AIEC mutant's library revealed that deletion of ybaT or rfaP efficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFNγ-producing pTh17 cells. Overall, our findings indicate that ybaT (inner membrane transport protein) and rfaP (LPS-core heptose kinase) represent novel and attractive candidate targets to prevent chronic intestinal inflammation in CD.
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Affiliation(s)
- G. Leccese
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - M. Chiara
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - I. Dusetti
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - D. Noviello
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - E. Billard
- M2iSH, UMR 1071 Inserm, INRAe USC 1382, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - A. Bibi
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - G. Conte
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - C. Consolandi
- Institute of Biomedical Technologies, National Research Council (ITB-CNR), Segrate, Milan, Italy
| | - M. Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - MP Conte
- Department of Public Health and Infectious Diseases, ‘Sapienza’ University of Rome, Rome, Italy
| | - N. Barnich
- M2iSH, UMR 1071 Inserm, INRAe USC 1382, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - F. Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - F. Facciotti
- Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy
| | - M. Paroni
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
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18
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Zangara MT, Darwish L, Coombes BK. Characterizing the Pathogenic Potential of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. EcoSal Plus 2023; 11:eesp00182022. [PMID: 37220071 PMCID: PMC10729932 DOI: 10.1128/ecosalplus.esp-0018-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/04/2023] [Indexed: 01/28/2024]
Abstract
The microbiome of Crohn's disease (CD) patients is composed of a microbial community that is considered dysbiotic and proinflammatory in nature. The overrepresentation of Enterobacteriaceae species is a common feature of the CD microbiome, and much attention has been given to understanding the pathogenic role this feature plays in disease activity. Over 2 decades ago, a new Escherichia coli subtype called adherent-invasive E. coli (AIEC) was isolated and linked to ileal Crohn's disease. Since the isolation of the first AIEC strain, additional AIEC strains have been isolated from both inflammatory bowel disease (IBD) patients and non-IBD individuals using the original in vitro phenotypic characterization methods. Identification of a definitive molecular marker of the AIEC pathotype has been elusive; however, significant advancements have been made in understanding the genetic, metabolic, and virulence determinants of AIEC infection biology. Here, we review the current knowledge of AIEC pathogenesis to provide additional, objective measures that could be considered in defining AIEC and their pathogenic potential.
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Affiliation(s)
- Megan T. Zangara
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Lena Darwish
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Brian K. Coombes
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
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19
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Fetter K, Weigel M, Ott B, Fritzenwanker M, Stricker S, de Laffolie J, Hain T. The microbiome landscape in pediatric Crohn's disease and therapeutic implications. Gut Microbes 2023; 15:2247019. [PMID: 37614093 PMCID: PMC10453987 DOI: 10.1080/19490976.2023.2247019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/29/2023] [Accepted: 08/08/2023] [Indexed: 08/25/2023] Open
Abstract
Dysbiosis of the gut microbiome and a pathological immune response in intestinal tissues form the basis of Crohn's disease (CD), which is a debilitating disease with relevant morbidity and mortality. It is increasing in childhood and adolescents, due to western life-style and nutrition and a large set of predisposing genetic factors. Crohn's disease-associated genetic mutations play an essential role in killing pathogens, altering mucosal barrier function, and protecting the host microbiome, suggesting an important pathogenic link. The intestinal microbiome is highly variable and can be influenced by environmental factors. Changes in microbial composition and a reduction in species diversity have been shown to be central features of disease progression and are therefore the target of therapeutic approaches. In this review, we summarize the current literature on the role of the gut microbiome in childhood, adolescent, and adult CD, current therapeutic options, and their impact on the microbiome.
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Affiliation(s)
- Karin Fetter
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Justus Liebig University Giessen, Giessen, Germany
| | - Markus Weigel
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
| | - Benjamin Ott
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
| | - Moritz Fritzenwanker
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
| | - Sebastian Stricker
- Department of Pediatrics, Justus Liebig University Giessen, Giessen, Germany
| | - Jan de Laffolie
- Department of Pediatrics, Justus Liebig University Giessen, Giessen, Germany
| | - Torsten Hain
- Institute of Medical Microbiology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Justus Liebig University Giessen, Giessen, Germany
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20
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Krawczyk A, Gosiewski T, Zapała B, Kowalska-Duplaga K, Salamon D. Alterations in intestinal Archaea composition in pediatric patients with Crohn's disease based on next-generation sequencing - a pilot study. Gut Microbes 2023; 15:2276806. [PMID: 37955638 PMCID: PMC10653639 DOI: 10.1080/19490976.2023.2276806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
Intestinal dysbiosis can lead to the induction of systemic immune-mediated inflammatory diseases, such as Crohn's disease Although archaea are part of the commensal microbiota, they are still one of the least studied microorganisms. The aim of our study was the standardization of the optimal conditions and primers for sequencing of the gut archaeome using Next Generation Sequencing, and evaluation of the differences between the composition of archaea in patients and healthy volunteers, as well as analysis of the changes that occur in the archaeome of patients depending on disease activity. Newly diagnosed patients were characterized by similar archeal profiles at every taxonomic level as in healthy individuals (the dominance of Methanobacteria at the class level, and Methanobrevibacter at the genus level). In turn, in patients previously diagnosed with Crohn's disease (both in active and remission phase), an increased prevalence of Thermoplasmata, Thermoprotei, Halobacteria (at the class level), and Halococcus, Methanospaera or Picrophilus (at the genus level) were observed. Furthermore, we have found a significant correlation between the patient's parameters and the individual class or species of Archaea. Our study confirms changes in archaeal composition in pediatric patients with Crohn's disease, however, only in long-standing disease. At the beginning of the disease, the archeal profile is similar to that of healthy people. However, in the chronic form of the disease, significant differences in the composition of archaeome begin to appear. It seems that some archaea may be a good indicator of the chronicity and activity of Crohn's disease.
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Affiliation(s)
- A. Krawczyk
- Department of Molecular Medical Microbiology, Division of Microbiology, Jagiellonian University Medical College, Krakow, Poland
| | - T. Gosiewski
- Department of Molecular Medical Microbiology, Division of Microbiology, Jagiellonian University Medical College, Krakow, Poland
| | - B. Zapała
- Department of Pharmaceutical Microbiology, Jagiellonian University Medical College, Krakow, Poland
- Jagiellonian University Hospital in Krakow, Krakow, Poland
| | - K. Kowalska-Duplaga
- Department of Pediatrics, Gastroenterology and Nutrition,Jagiellonian University Medical College, Krakow, Poland
| | - D. Salamon
- Department of Molecular Medical Microbiology, Division of Microbiology, Jagiellonian University Medical College, Krakow, Poland
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Ma X, Zhao C, Xu Y, Zhang H. Roles of host SUMOylation in bacterial pathogenesis. Infect Immun 2023; 91:e0028323. [PMID: 37725062 PMCID: PMC10580907 DOI: 10.1128/iai.00283-23] [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] [Indexed: 09/21/2023] Open
Abstract
Bacteria frequently interfere with the post-translational modifications of host cells to facilitate their survival and growth after invasion. SUMOylation, a reversible post-translational modification process, plays an important role in biological life activities. In addition to being critical to host cell metabolism and survival, SUMOylation also regulates gene expression and cell signal transmission. Moreover, SUMOylation in eukaryotic cells can be used by a variety of bacterial pathogens to advance bacterial invasion. In this minireview, we focused on the role and mechanism of host SUMOylation in the pathogenesis of six important clinical bacterial pathogens (Listeria monocytogenes, Shigella flexneri, Salmonella Typhimurium, Klebsiella pneumoniae, Staphylococcus aureus, and Escherichia coli). Taken together, this review provided new insights for understanding the unique pathogen-host interaction based on host SUMOylation and provided a novel perspective on the development of new strategies to combat bacterial infections in the future.
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Affiliation(s)
- Xin Ma
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Chenhao Zhao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yuyao Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Clinical Laboratory, Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, China
| | - Haifang Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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22
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Bonet-Rossinyol Q, Camprubí-Font C, López-Siles M, Martinez-Medina M. Identification of differences in gene expression implicated in the Adherent-Invasive Escherichia coli phenotype during in vitro infection of intestinal epithelial cells. Front Cell Infect Microbiol 2023; 13:1228159. [PMID: 37767199 PMCID: PMC10519790 DOI: 10.3389/fcimb.2023.1228159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/21/2023] [Indexed: 09/29/2023] Open
Abstract
Introduction Adherent-invasive Escherichia coli (AIEC) is strongly associated with the pathogenesis of Crohn's disease (CD). However, no molecular markers currently exist for AIEC identification. This study aimed to identify differentially expressed genes (DEGs) between AIEC and non-AIEC strains that may contribute to AIEC pathogenicity and to evaluate their utility as molecular markers. Methods Comparative transcriptomics was performed on two closely related AIEC/non-AIEC strain pairs during Intestine-407 cell infection. DEGs were quantified by RT-qPCR in the same RNA extracts, as well as in 14 AIEC and 23 non-AIEC strains to validate the results across a diverse strain collection. Binary logistical regression was performed to identify DEGs whose quantification could be used as AIEC biomarkers. Results Comparative transcriptomics revealed 67 differences in expression between the two phenotypes in the strain pairs, 50 of which (81.97%) were corroborated by RT-qPCR. When explored in the whole strain collection, 29 DEGs were differentially expressed between AIEC and non-AIEC phenotypes (p-value < 0.042), and 42 genes between the supernatant fraction of infected cell cultures and the cellular fraction containing adhered and intracellular bacteria (p-value < 0.049). Notably, six DEGs detected in the strain collection were implicated in arginine biosynthesis and five in colanic acid synthesis. Furthermore, two biomarkers based on wzb and cueR gene expression were proposed with an accuracy of ≥ 85% in our strain collection. Discussion This is the first transcriptomic study conducted using AIEC-infected cell cultures. We have identified several genes that may be involved in AIEC pathogenicity, two of which are putative biomarkers for identification.
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Kamal S, Parkash N, Beattie W, Christensen B, Segal JP. Are We Ready to Reclassify Crohn's Disease Using Molecular Classification? J Clin Med 2023; 12:5786. [PMID: 37762727 PMCID: PMC10532006 DOI: 10.3390/jcm12185786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/21/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Crohn's disease (CD) is a type of inflammatory bowel disease. The number of IBD cases worldwide was estimated to be 4.9 million in 2019. CD exhibits heterogeneity in clinical presentation, anatomical involvement, disease behaviour, clinical course and response to treatment. The classical description of CD involves transmural inflammation with skip lesions anywhere along the entire gastrointestinal tract. The complexity and heterogeneity of Crohn's disease is not currently reflected in the conventional classification system. Though the knowledge of Crohn's pathophysiology remains far from understood, the established complex interplay of the omics-genomics, transcriptomics, proteomics, epigenomics, metagenomics, metabolomics, lipidomics and immunophenomics-provides numerous targets for potential molecular markers of disease. Advancing technology has enabled identification of small molecules within these omics, which can be extrapolated to differentiate types of Crohn's disease. The multi-omic future of Crohn's disease is promising, with potential for advancements in understanding of its pathogenesis and implementation of personalised medicine.
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Affiliation(s)
- Shahed Kamal
- Department of Gastroenterology, Northern Hospital, Epping, Melbourne VIC 3076, Australia
| | - Nikita Parkash
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - William Beattie
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - Britt Christensen
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
| | - Jonathan P. Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
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24
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Tian Y, Zhang T, Li J, Tao Y. Advances in development of exosomes for ophthalmic therapeutics. Adv Drug Deliv Rev 2023; 199:114899. [PMID: 37236425 DOI: 10.1016/j.addr.2023.114899] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/18/2023] [Accepted: 05/21/2023] [Indexed: 05/28/2023]
Abstract
Exosomes contain multiple bioactive molecules and maintain the connection between cells. Recent advances in exosome-based therapeutics have witnessed unprecedented opportunities in treating ophthalmic diseases, including traumatic diseases, autoimmune diseases, chorioretinal diseases and others. Utilization of exosomes as delivery vectors to encapsulate both drugs and therapeutic genes could yield higher efficacy and avoid the unnecessary immune responses. However, exosome-based therapies also come with some potential ocular risks. In this review, we first present a general introduction to exosomes. Then we provide an overview of available applications and discuss their potential risks. Moreover, we review recently reported exosomes as delivery vectors for ophthalmic diseases. Finally, we put forward future perspectives to grapple with its translation and underlying issues.
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Affiliation(s)
- Ying Tian
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Tao Zhang
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Jing Li
- Beijing Key Laboratory of DNA Damage Response, College of Life Sciences, Capital Normal University, Beijing 100048, PR China
| | - Yong Tao
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China.
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25
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Krawczyk A, Salamon D, Kowalska-Duplaga K, Zapała B, Książek T, Drażniuk-Warchoł M, Gosiewski T. Changes in the gut mycobiome in pediatric patients in relation to the clinical activity of Crohn's disease. World J Gastroenterol 2023; 29:2172-2187. [PMID: 37122605 PMCID: PMC10130967 DOI: 10.3748/wjg.v29.i14.2172] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/13/2023] [Accepted: 03/13/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Numerous studies have shown that in Crohn’s disease (CD), the gut microbiota is of great importance in the induction and maintenance of inflammation in the gastrointestinal tract. Until recently, studies have focused almost exclusively on bacteria in the gut. Lately, more attention has been paid to the role of intestinal fungi.
AIM To study the gut mycobiome analysis of pediatric patients with CD (in different stages of disease activity) compared to healthy children.
METHODS Fecal samples were collected from patients: With active, newly diagnosed CD (n = 50); active but previously diagnosed and treated CD (n = 16); non-active CD and who were in clinical remission (n = 39) and from healthy volunteers (n = 40). Fungal DNA was isolated from the samples. Next, next generation sequencing (MiSeq, Illumina) was performed. The composition of mycobiota was correlated with clinical and blood parameters.
RESULTS Candida spp. were overrepresented in CD patients, while in the control group, the most abundant genus was Saccharomyces. In CD patients, the percentage of Malassezia was almost twice that of the control (P < 0.05). In active CD patients, we documented a higher abundance of Debaryomyces hansenii (D. hansenii) compared to the non-active CD and control (P < 0.05) groups. Moreover, statistically significant changes in the abundance of Mycosphaerella, Rhodotorula, and Microidium were observed. The analyses at the species level and linear discriminant analysis showed that in each group it was possible to distinguish a specific species characteristic of a given patient population. Moreover, we have documented statistically significant correlations between: D. hansenii and patient age (negative); C. zeylanoides and patient age (positive); C. dubliniensis and calprotectin (positive); C. sake and calprotectin (positive); and C. tropicalis and pediatric CD activity index (PCDAI) (positive).
CONCLUSION Mycobiome changes in CD patients, and the positive correlation of some species with calprotectin or PCDAI, give strong evidence that fungi may be of key importance in the development of CD.
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Affiliation(s)
- Agnieszka Krawczyk
- Department of Microbiology, Division of Molecular Medical Microbiology, Jagiellonian University Medical College, Cracow 31-121, Poland
| | - Dominika Salamon
- Department of Microbiology, Division of Molecular Medical Microbiology, Jagiellonian University Medical College, Cracow 31-121, Poland
| | - Kinga Kowalska-Duplaga
- Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow 30-663, Poland
| | - Barbara Zapała
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Cracow 31-066, Poland
| | - Teofila Książek
- Department of Medical Genetics, Jagiellonian University Medical College, Cracow 30-663, Poland
| | - Marta Drażniuk-Warchoł
- Department of Pediatrics, Gastroenterology and Nutrition, University Children's Hospital, Cracow 30-663, Poland
| | - Tomasz Gosiewski
- Department of Microbiology, Division of Molecular Medical Microbiology, Jagiellonian University Medical College, Cracow 31-121, Poland
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Evidence for a Causal Role for Escherichia coli Strains Identified as Adherent-Invasive (AIEC) in Intestinal Inflammation. mSphere 2023; 8:e0047822. [PMID: 36883813 PMCID: PMC10117065 DOI: 10.1128/msphere.00478-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Enrichment of adherent-invasive Escherichia coli (AIEC) has been consistently detected in subsets of inflammatory bowel disease (IBD) patients. Although some AIEC strains cause colitis in animal models, these studies did not systematically compare AIEC with non-AIEC strains, and causal links between AIEC and disease are still disputed. Specifically, it remains unclear whether AIEC shows enhanced pathogenicity compared to that of commensal E. coli found in the same ecological microhabitat and if the in vitro phenotypes used to classify strains as AIEC are pathologically relevant. Here, we utilized in vitro phenotyping and a murine model of intestinal inflammation to systematically compare strains identified as AIEC with those identified as non-AIEC and relate AIEC phenotypes to pathogenicity. Strains identified as AIEC caused, on average, more severe intestinal inflammation. Intracellular survival/replication phenotypes routinely used to classify AIEC positively correlated with disease, while adherence to epithelial cells and tumor necrosis factor alpha production by macrophages did not. This knowledge was then applied to design and test a strategy to prevent inflammation by selecting E. coli strains that adhered to epithelial cells but poorly survived/replicated intracellularly. Two E. coli strains that ameliorated AIEC-mediated disease were subsequently identified. In summary, our results show a relationship between intracellular survival/replication in E. coli and pathology in murine colitis, suggesting that strains possessing these phenotypes might not only become enriched in human IBD but also contribute to disease. We provide new evidence that specific AIEC phenotypes are pathologically relevant and proof of principle that such mechanistic information can be therapeutically exploited to alleviate intestinal inflammation. IMPORTANCE Inflammatory bowel disease (IBD) is associated with an altered gut microbiota composition, including expansion of Proteobacteria. Many species in this phylum are thought to contribute to disease under certain conditions, including adherent-invasive Escherichia coli (AIEC) strains, which are enriched in some patients. However, whether this bloom contributes to disease or is just a response to IBD-associated physiological changes is unknown. Although assigning causality is challenging, appropriate animal models can test the hypothesis that AIEC strains have an enhanced ability to cause colitis in comparison to other gut commensal E. coli strains and to identify bacterial traits contributing to virulence. We observed that AIEC strains are generally more pathogenic than commensal E. coli and that bacterial intracellular survival/replication phenotypes contributed to disease. We also found that E. coli strains lacking primary virulence traits can prevent inflammation. Our findings provide critical information on E. coli pathogenicity that may inform development of IBD diagnostic tools and therapies.
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Aggeletopoulou I, Marangos M, Assimakopoulos SF, Mouzaki A, Thomopoulos K, Triantos C. Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2023:S0002-9440(23)00055-X. [PMID: 36868465 DOI: 10.1016/j.ajpath.2023.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 03/05/2023]
Abstract
Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. In this review, we examine the role of the gut microbiome in IBD and discuss how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece; Division of Hematology, Department of Internal Medicine, Laboratory of Immunohematology, Medical School, University Hospital of Patras, Patras, Greece.
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Laboratory of Immunohematology, Medical School, University Hospital of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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Anti- E. coli Immunoglobulin Yolk (IgY): Reduction of pathogen receptors and inflammation factors could be caused by decrease in E. coli load. Heliyon 2023; 9:e13876. [PMID: 36873547 PMCID: PMC9982617 DOI: 10.1016/j.heliyon.2023.e13876] [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: 05/10/2022] [Revised: 02/14/2023] [Accepted: 02/14/2023] [Indexed: 02/24/2023] Open
Abstract
Graft versus host disease (GVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation, especially for intestinal GVHD, as steroid resistant GVHD results in high mortality. For this reason, new treatments of GVHD are needed. One approach is the reduction of pathogenic bacteria using anti-E. coli Immunoglobulin Yolk (IgY). In a haploidentical murine model, B6D2F1 mice conditioned with total body irradiation (TBI), received bone marrow cells (BM) and splenocytes (SC) from either syngeneic (Syn = B6D2F1) or allogeneic (Allo = C57BL/6) donors. Following this, animals received from day -2 until day +28 chow contained IgY or control chow. Thereafter the incidence and severity of aGVHD, the cytokines, chemokines, IDO1 and different pathogen-recognition receptors (PRR) were analyzed and compared to control animals (received chow without IgY). We found that animals receiving chow with IgY antibody showed reduced GVHD severity compared to control animals. On day28 after alloBMT, IDO, NOD2, TLR2, TLR4 and the inflammatory chemokine CCL3, were reduced in the colon and correlated with a significant decrease in E. coli bacteria. In summary chow containing chicken antibodies (IgY) improved GVHD via decrease in bacterial load of E coli conducting to reduction of pathogen receptors (NOD2, TLR2 and 4), IDO, chemokines and cytokines.
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29
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Arroyo-Mendoza M, Proctor A, Correa-Medina A, Brand MW, Rosas V, Wannemuehler MJ, Phillips GJ, Hinton DM. The E. coli pathobiont LF82 encodes a unique variant of σ 70 that results in specific gene expression changes and altered phenotypes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.08.523653. [PMID: 36798310 PMCID: PMC9934711 DOI: 10.1101/2023.02.08.523653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
LF82, an adherent invasive Escherichia coli pathobiont, is associated with ileal Crohn's disease, an inflammatory bowel disease of unknown etiology. Although LF82 contains no virulence genes, it carries several genetic differences, including single nucleotide polymorphisms (SNPs), that distinguish it from nonpathogenic E. coli. We have identified and investigated an extremely rare SNP that is within the highly conserved rpoD gene, encoding σ70, the primary sigma factor for RNA polymerase. We demonstrate that this single residue change (D445V) results in specific transcriptome and phenotypic changes that are consistent with multiple phenotypes observed in LF82, including increased antibiotic resistance and biofilm formation, modulation of motility, and increased capacity for methionine biosynthesis. Our work demonstrates that a single residue change within the bacterial primary sigma factor can lead to multiple alterations in gene expression and phenotypic changes, suggesting an underrecognized mechanism by which pathobionts and other strain variants with new phenotypes can emerge.
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Affiliation(s)
- Melissa Arroyo-Mendoza
- Gene Expression and Regulation Section, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Dr., Bethesda, MD, United States, 20892
- Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States, 50011
| | - Alexandra Proctor
- Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States, 50011
| | - Abraham Correa-Medina
- Gene Expression and Regulation Section, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Dr., Bethesda, MD, United States, 20892
| | - Meghan Wymore Brand
- Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States, 50011
| | - Virginia Rosas
- Gene Expression and Regulation Section, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Dr., Bethesda, MD, United States, 20892
| | - Michael J Wannemuehler
- Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States, 50011
| | - Gregory J Phillips
- Department of Veterinary Microbiology and Preventative Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States, 50011
| | - Deborah M Hinton
- Gene Expression and Regulation Section, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Dr., Bethesda, MD, United States, 20892
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30
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Valibouze C, Speca S, Dubuquoy C, Mourey F, M'Ba L, Schneider L, Titecat M, Foligné B, Genin M, Neut C, Zerbib P, Desreumaux P. Saccharomyces cerevisiae prevents postoperative recurrence of Crohn's disease modeled by ileocecal resection in HLA-B27 transgenic rats. World J Gastroenterol 2023; 29:851-866. [PMID: 36816618 PMCID: PMC9932430 DOI: 10.3748/wjg.v29.i5.851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/16/2022] [Accepted: 12/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Postoperative recurrence (POR) after ileocecal resection (ICR) affects most Crohn's disease patients within 3-5 years after surgery. Adherent-invasive Escherichia coli (AIEC) typified by the LF82 strain are pathobionts that are frequently detected in POR of Crohn's disease and have a potential role in the early stages of the disease pathogenesis. Saccharomyces cerevisiae CNCM I-3856 is a probiotic yeast reported to inhibit AIEC adhesion to intestinal epithelial cells and to favor their elimination from the gut.
AIM To evaluate the efficacy of CNCM I-3856 in preventing POR induced by LF82 in an HLA-B27 transgenic (TgB27) rat model.
METHODS Sixty-four rats [strain F344, 38 TgB27, 26 control non-Tg (nTg)] underwent an ICR at the 12th wk (W12) of life and were sacrificed at the 18th wk (W18) of life. TgB27 rats were challenged daily with oral administration of LF82 (109 colony forming units (CFUs)/day (d), n = 8), PBS (n = 5), CNCM I-3856 (109 CFUs/d, n = 7) or a combination of LF82 and CNCM I-3856 (n = 18). nTg rats receiving LF82 (n = 5), PBS (n = 5), CNCM I-3856 (n = 7) or CNCM I-3856 and LF82 (n = 9) under the same conditions were used as controls. POR was analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal LF82 quantifications were performed weekly for each animal. Adherent LF82 and inflammatory/regulatory cytokines were quantified in biopsies at W12 and W18. Data are expressed as the median with the interquartile range.
RESULTS nTg animals did not develop POR. A total of 7/8 (87%) of the TgB27 rats receiving LF82 alone had POR (macroscopic score ≥ 2), which was significantly prevented by CNCM I-3856 administration [6/18 (33%) TgB27 rats, P = 0.01]. Macroscopic lesions were located 2 cm above the anastomosis in the TgB27 rats receiving LF82 alone and consisted of ulcerations with a score of 3.5 (2 - 4). Seven out of 18 TgB27 rats (39%) receiving CNCM I-3856 and LF82 had no macroscopic lesions. Compared to untreated TgB27 animals receiving LF82 alone, coadministration of CNCM I-3856 and LF82 significantly reduced the macroscopic [3.5 (2 - 4) vs 1 (0 - 3), P = 0.002] and histological lesions by more than 50% [4.5 (3.3 - 5.8) vs 2 (1.3 - 3), P = 0.003]. The levels of adherent LF82 were correlated with anastomotic macroscopic scores in TgB27 rats (r = 0.49, P = 0.006), with a higher risk of POR in animals having high levels of luminal LF82 (71.4% vs 25%, P = 0.02). Administration of CNCM I-3856 significantly reduced the levels of luminal and adherent LF82, increased the production of interleukin (IL)-10 and decreased the production of IL-23 and IL-17 in TgB27 rats.
CONCLUSION In a reliable model of POR induced by LF82 in TgB27 rats, CNCM I-3856 prevents macroscopic POR by decreasing LF82 infection and gut inflammation.
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Affiliation(s)
- Caroline Valibouze
- Department of Digestive Surgery and Transplantation, Lille University Hospital, Lille 59037, France
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | - Silvia Speca
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | | | - Florian Mourey
- Department of Research and Applications, Gnosis by Lesaffre, Lesaffre Group, Marcq-en-Baroeul 59700, France
| | - Lena M'Ba
- Department of Digestive Surgery and Transplantation, Lille University Hospital, Lille 59037, France
| | - Lucil Schneider
- Department of Digestive Surgery and Transplantation, Lille University Hospital, Lille 59037, France
| | - Marie Titecat
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | - Benoît Foligné
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | - Michaël Genin
- ULR 2694 - METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, University of Lille, Lille University Hospital, Lille 59000, France
| | - Christel Neut
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | - Philippe Zerbib
- Department of Digestive Surgery and Transplantation, Lille University Hospital, Lille 59037, France
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
| | - Pierre Desreumaux
- U1286 - INFINITE - Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille 59000, France
- Department of Hepato-Gastroenterology, Lille University Hospital, Lille 59037, France
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31
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Pokharel P, Dhakal S, Dozois CM. The Diversity of Escherichia coli Pathotypes and Vaccination Strategies against This Versatile Bacterial Pathogen. Microorganisms 2023; 11:344. [PMID: 36838308 PMCID: PMC9965155 DOI: 10.3390/microorganisms11020344] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
Escherichia coli (E. coli) is a gram-negative bacillus and resident of the normal intestinal microbiota. However, some E. coli strains can cause diseases in humans, other mammals and birds ranging from intestinal infections, for example, diarrhea and dysentery, to extraintestinal infections, such as urinary tract infections, respiratory tract infections, meningitis, and sepsis. In terms of morbidity and mortality, pathogenic E. coli has a great impact on public health, with an economic cost of several billion dollars annually worldwide. Antibiotics are not usually used as first-line treatment for diarrheal illness caused by E. coli and in the case of bloody diarrhea, antibiotics are avoided due to the increased risk of hemolytic uremic syndrome. On the other hand, extraintestinal infections are treated with various antibiotics depending on the site of infection and susceptibility testing. Several alarming papers concerning the rising antibiotic resistance rates in E. coli strains have been published. The silent pandemic of multidrug-resistant bacteria including pathogenic E. coli that have become more difficult to treat favored prophylactic approaches such as E. coli vaccines. This review provides an overview of the pathogenesis of different pathotypes of E. coli, the virulence factors involved and updates on the major aspects of vaccine development against different E. coli pathotypes.
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Affiliation(s)
- Pravil Pokharel
- Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), 531 Boul des Prairies, Laval, QC H7V 1B7, Canada
- Centre de Recherche en Infectiologie Porcine et Avicole (CRIPA), Faculté de Médecine Vétérinaire, Université de Montréal Saint-Hyacinthe, Saint-Hyacinthe, QC J2S 2M2, Canada
| | - Sabin Dhakal
- Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), 531 Boul des Prairies, Laval, QC H7V 1B7, Canada
- Centre de Recherche en Infectiologie Porcine et Avicole (CRIPA), Faculté de Médecine Vétérinaire, Université de Montréal Saint-Hyacinthe, Saint-Hyacinthe, QC J2S 2M2, Canada
| | - Charles M. Dozois
- Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique (INRS), 531 Boul des Prairies, Laval, QC H7V 1B7, Canada
- Centre de Recherche en Infectiologie Porcine et Avicole (CRIPA), Faculté de Médecine Vétérinaire, Université de Montréal Saint-Hyacinthe, Saint-Hyacinthe, QC J2S 2M2, Canada
- Pasteur Network, Laval, QC H7V 1B7, Canada
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Mansour S, Asrar T, Elhenawy W. The multifaceted virulence of adherent-invasive Escherichia coli. Gut Microbes 2023; 15:2172669. [PMID: 36740845 PMCID: PMC9904308 DOI: 10.1080/19490976.2023.2172669] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/16/2023] [Indexed: 02/07/2023] Open
Abstract
The surge in inflammatory bowel diseases, like Crohn's disease (CD), is alarming. While the role of the gut microbiome in CD development is unresolved, the frequent isolation of adherent-invasive Escherichia coli (AIEC) strains from patient biopsies, together with their propensity to trigger gut inflammation, underpin the potential role of these bacteria as disease modifiers. In this review, we explore the spectrum of AIEC pathogenesis, including their metabolic versatility in the gut. We describe how AIEC strains hijack the host defense mechanisms to evade immune attrition and promote inflammation. Furthermore, we highlight the key traits that differentiate AIEC from commensal E. coli. Deciphering the main components of AIEC virulence is cardinal to the discovery of the next generation of antimicrobials that can selectively eradicate CD-associated bacteria.
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Affiliation(s)
- Sarah Mansour
- Department of Medical Microbiology & Immunology, Faculty of Medicine & Dentistry, University of Alberta, Canada
| | - Tahreem Asrar
- Department of Medical Microbiology & Immunology, Faculty of Medicine & Dentistry, University of Alberta, Canada
| | - Wael Elhenawy
- Department of Medical Microbiology & Immunology, Faculty of Medicine & Dentistry, University of Alberta, Canada
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada
- Li Ka Shing Institute of Virology, Canada
- Women and Children’s Health Research Institute, Edmonton, Alberta, Canada
- Antimicrobial Resistance, One Health Consortium - Edmonton, AB, Canada
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Wang EJ, Wu MY, Ren ZY, Zheng Y, Ye RD, TAN CSH, Wang Y, Lu JH. Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease. BURNS & TRAUMA 2023; 11:tkad004. [PMID: 37152076 PMCID: PMC10157272 DOI: 10.1093/burnst/tkad004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/22/2022] [Accepted: 01/16/2023] [Indexed: 05/09/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.
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Affiliation(s)
- Er-jin Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Ming-Yue Wu
- Center for Metabolic Liver Diseases and Center for Cholestatic Liver Diseases, Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Zheng-yu Ren
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
| | - Richard D Ye
- Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, 518172, China
| | - Chris Soon Heng TAN
- Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China
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Biofilms and Benign Colonic Diseases. Int J Mol Sci 2022; 23:ijms232214259. [PMID: 36430737 PMCID: PMC9698058 DOI: 10.3390/ijms232214259] [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: 09/30/2022] [Revised: 11/06/2022] [Accepted: 11/10/2022] [Indexed: 11/19/2022] Open
Abstract
The colon has a very large surface area that is covered by a dense mucus layer. The biomass in the colon includes 500-1000 bacterial species at concentrations of ~1012 colony-forming units per gram of feces. The intestinal epithelial cells and the commensal bacteria in the colon have a symbiotic relationship that results in nutritional support for the epithelial cells by the bacteria and maintenance of the optimal commensal bacterial population by colonic host defenses. Bacteria can form biofilms in the colon, but the exact frequency is uncertain because routine methods to undertake colonoscopy (i.e., bowel preparation) may dislodge these biofilms. Bacteria in biofilms represent a complex community that includes living and dead bacteria and an extracellular matrix composed of polysaccharides, proteins, DNA, and exogenous debris in the colon. The formation of biofilms occurs in benign colonic diseases, such as inflammatory bowel disease and irritable bowel syndrome. The development of a biofilm might serve as a marker for ongoing colonic inflammation. Alternatively, the development of biofilms could contribute to the pathogenesis of these disorders by providing sanctuaries for pathogenic bacteria and reducing the commensal bacterial population. Therapeutic approaches to patients with benign colonic diseases could include the elimination of biofilms and restoration of normal commensal bacteria populations. However, these studies will be extremely difficult unless investigators can develop noninvasive methods for measuring and identifying biofilms. These methods that might include the measurement of quorum sensing molecules, measurement of bile acids, and identification of bacteria uniquely associated with biofilms in the colon.
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Dubinsky V, Reshef L, Rabinowitz K, Wasserberg N, Dotan I, Gophna U. Escherichia coli Strains from Patients with Inflammatory Bowel Diseases have Disease-specific Genomic Adaptations. J Crohns Colitis 2022; 16:1584-1597. [PMID: 35560165 DOI: 10.1093/ecco-jcc/jjac071] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Escherichia coli is over-abundant in the gut microbiome of patients with inflammatory bowel disease [IBD]. Here, we aimed to identify IBD-specific genomic functions of diverse E. coli lineages. METHODS We investigated E. coli genomes from patients with ulcerative colitis [UC], Crohn's disease [CD] or a pouch, and healthy subjects. The majority of genomes were reconstructed from metagenomic samples, including newly sequenced faecal metagenomes. Clinical metadata were collected. Functional analysis at the gene and mutation level were performed and integrated with IBD phenotypes and biomarkers. RESULTS Overall, 530 E. coli genomes were analysed. The E. coli B2 lineage was more prevalent in UC compared with other IBD phenotypes. Genomic metabolic capacities varied across E. coli lineages and IBD phenotypes. Host mucin utilisation enzymes were present in a single lineage and depleted in patients with a pouch, whereas those involved in inulin hydrolysis were enriched in patients with a pouch. E. coli strains from patients with UC were twice as likely to encode the genotoxic molecule colibactin than strains from patients with CD or a pouch. Strikingly, patients with a pouch showed the highest inferred E. coli growth rates, even in the presence of antibiotics. Faecal calprotectin did not correlate with the relative abundance of E. coli. Finally, we identified multiple IBD-specific non-synonymous mutations in E. coli genes encoding for bacterial cell envelope components. CONCLUSIONS Comparative genomics indicates that E. coli is a commensal species adapted to the overactive mucosal immune milieu in IBD, rather than causing it. Our results reveal mutations that may lead to attenuated antigenicity in some E. coli strains.
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Affiliation(s)
- Vadim Dubinsky
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel
| | - Leah Reshef
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel
| | - Keren Rabinowitz
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Nir Wasserberg
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.,Colorectal Unit, Division of Surgery, Rabin Medical Center, Petah-Tikva, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Uri Gophna
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel
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Titécat M, Rousseaux C, Dubuquoy C, Foligné B, Rahmouni O, Mahieux S, Desreumaux P, Woolston J, Sulakvelidze A, Wannerberger K, Neut C. Safety and Efficacy of an AIEC-targeted Bacteriophage Cocktail in a Mice Colitis Model. J Crohns Colitis 2022; 16:1617-1627. [PMID: 35997152 DOI: 10.1093/ecco-jcc/jjac064] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Adherent invasive Escherichia coli [AIEC] are recovered with a high frequency from the gut mucosa of Crohn's disease patients and are believed to contribute to the dysbiosis and pathogenesis of this inflammatory bowel disease. In this context, bacteriophage therapy has been proposed for specifically targeting AIEC in the human gut with no deleterious impact on the commensal microbiota. METHODS The in vitro efficacy and specificity of a seven lytic phage cocktail [EcoActive™] was assessed against [i] 210 clinical AIEC strains, and [ii] 43 non-E. coli strains belonging to the top 12 most common bacterial genera typically associated with a healthy human microbiome. These data were supported by in vivo safety and efficacy assays conducted on healthy and AIEC-colonized mice, respectively. RESULTS The EcoActive cocktail was effective in vitro against 95% of the AIEC strains and did not lyse any of the 43 non-E. coli commensal strains, in contrast to conventional antibiotics. Long-term administration of the EcoActive cocktail to healthy mice was safe and did not induce dysbiosis according to metagenomic data. Using a murine model of induced colitis of animals infected with the AIEC strain LF82, we found that a single administration of the cocktail failed to alleviate inflammatory symptoms, while mice receiving the cocktail twice a day for 15 days were protected from clinical and microscopical manifestations of inflammation. CONCLUSIONS Collectively, the data support the approach of AIEC-targeted phage therapy as safe and effective treatment for reducing AIEC levels in the gut of IBD patients.
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Affiliation(s)
- Marie Titécat
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France
| | | | | | - Benoît Foligné
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France
| | - Oumaïra Rahmouni
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France
| | - Séverine Mahieux
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France
| | - Pierre Desreumaux
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France.,Intestinal Biotech Development, 59045 Lille, France
| | | | | | | | - Christel Neut
- Univ. Lille, INSERM, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille, France
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Chervy M, Sivignon A, Dambrine F, Buisson A, Sauvanet P, Godfraind C, Allez M, Le Bourhis L, The Remind Group, Barnich N, Denizot J. Epigenetic master regulators HDAC1 and HDAC5 control pathobiont Enterobacteria colonization in ileal mucosa of Crohn's disease patients. Gut Microbes 2022; 14:2127444. [PMID: 36175163 PMCID: PMC9542275 DOI: 10.1080/19490976.2022.2127444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
AIEC Adherent-Invasive Escherichia coli; BSA Bovine serum albumin; CD Crohn's disease; CEABAC10 Carcinoembryonic antigen bacterial artificial chromosome 10; CEACAM Carcinoembryonic antigen-related cell adhesion molecule; FBS Fetal bovine serum; IBD Inflammatory Bowel Disease; HAT Histone acetyltransferase; HDAC Histone deacetylase; kDa KiloDalton; SAHA Suberoylanilide Hydroxamic Acid; Scr Scramble.
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Affiliation(s)
- Mélissa Chervy
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France
| | - Adeline Sivignon
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Institut Universitaire de Technologie, Génie Biologique, Aubière, France
| | - Flavie Dambrine
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France
| | - Anthony Buisson
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Pierre Sauvanet
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Surgery and Oncology Digestive Department, CHU Estaing, Clermont-Ferrand, France
| | - Catherine Godfraind
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Neuropathology Unit, CHU Gabriel Montpied, Clermont-Ferrand, France
| | - Matthieu Allez
- Gastroenterology Department, Hôpital Saint-Louis - APHP, Paris, France,Université De Paris, Institut de Recherche Saint-Louis, EMily, INSERM U1160, Paris, France,Hôpital Saint-Louis, Paris, France
| | - Lionel Le Bourhis
- Université De Paris, Institut de Recherche Saint-Louis, EMily, INSERM U1160, Paris, France
| | | | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Institut Universitaire de Technologie, Génie Biologique, Aubière, France
| | - Jérémy Denizot
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Clermont-Ferrand, France,Institut Universitaire de Technologie, Génie Biologique, Aubière, France,CONTACT Jérémy Denizot M2iSH, UMR 1071 Inserm/Université Clermont Auvergne, CBRV, 28 place Henri Dunant, Clermont-Ferrand63001, France
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Efficacy of Selected Live Biotherapeutic Candidates to Inhibit the Interaction of an Adhesive-Invasive Escherichia coli Strain with Caco-2, HT29-MTX Cells and Their Co-Culture. Biomedicines 2022; 10:biomedicines10092245. [PMID: 36140346 PMCID: PMC9496071 DOI: 10.3390/biomedicines10092245] [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: 07/26/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) has been implicated as a microbiological factor in the pathogenesis of inflammatory bowel disease (IBD). We evaluated the ability of six live biotherapeutic products (LBPs) to inhibit the interaction of an AIEC strain to three cell lines representing human gut epithelium. Co-inoculation of LBPs with AIEC showed a reduction in adhesion (up to 73%) and invasion of AIEC (up to 89%). Pre-inoculation of LBPs in HT-29-MTX and Caco-2 cells before challenging with AIEC further reduced the adhesion and invasion of the AIEC, with three LBPs showing significantly (p < 0.0001) higher efficiency in reducing the adhesion of AIEC. In co-inoculation experiments, the highest reduction in adhesion (73%) of AIEC was observed in HT-29-MTX cells, whereas the highest reduction in invasion (89%) was seen in HT-29-MTX and the co-culture of cells. Pre-inoculation of LBPs further reduced the invasion of AIEC with highest reduction (97%) observed in co-culture of cells. Our results indicated that whilst there were differences in the efficacy of LBPs, they all reduced interaction of AIEC with cell lines representing gut epithelium. Their efficiency was higher when they were pre-inoculated onto the cells, suggesting their potential as candidates for alleviating pathogenesis of AIEC in patients with IBD.
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Nadalian B, Nadalian B, Houri H, Shahrokh S, Abdehagh M, Yadegar A, Ebrahimipour G. Phylogrouping and characterization of Escherichia coli isolated from colonic biopsies and fecal samples of patients with flare of inflammatory bowel disease in Iran. Front Med (Lausanne) 2022; 9:985300. [PMID: 36106322 PMCID: PMC9464868 DOI: 10.3389/fmed.2022.985300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/05/2022] [Indexed: 12/02/2022] Open
Abstract
Background Although the etiopathogenesis of inflammatory bowel disease (IBD) is still poorly understood, Escherichia coli has been described as a potential causative microorganism in IBD pathogenesis and also disease progression, offering a potential therapeutic target for disease management. Therefore, we conducted this study to investigate the pathotypes, phylogenetic groups, and antimicrobial resistance of E. coli isolates from patients with IBD in Iran. Methods Fecal and biopsy colonic samples were collected from IBD patients experiencing flare-up episodes referred to Taleghani hospital in Tehran, Iran, between August 2020 and January 2021. Identification of E. coli strains was performed based on biochemical and molecular methods. Antibiotic susceptibility testing was performed as recommended by the Clinical and Laboratory Standards Institute. Phylogrouping and pathotyping of each isolate were carried out using polymerase chain reaction (PCR) and multilocus sequence typing (MLST) assays. Results A total of 132 non-duplicate E. coli strains were isolated from 113 IBD patients, including 96 ulcerative colitis (UC), and 17 Crohn’s disease (CD) patients. In our study, 55% of CD-related E. coli and 70.5% of UC-related isolates were non-susceptible to at least three or more unique antimicrobial classes, and were considered as multidrug-resistant (MDR) strains. E. coli strains exhibited a high level of resistance to cefazolin, ampicillin, tetracycline, ceftazidime, ciprofloxacin, and cefotaxime. Enterotoxigenic E. coli (ETEC) and diffusely adherent E. coli (DAEC) were the most prevalent pathotypes, and groups B2 and D were the predominant phylogroups. Conclusion In the present study, we found that E. coli strains that colonize the gut of Iranian patients with IBD most frequently belonged to phylogenetic groups B2 and D. We also conclude that E. coli isolates from IBD patients have been revealed to be resistant to commonly used antibiotics, in which most of them harbored strains that would be categorized as MDR.
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Affiliation(s)
- Banafsheh Nadalian
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Bahareh Nadalian
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Houri
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdehagh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Abbas Yadegar, ;
| | - Gholamhossein Ebrahimipour
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
- Gholamhossein Ebrahimipour,
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40
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Chang R, Chen J, Zhong Z, Li Y, Wu K, Zheng H, Yang Y. Inflammatory bowel disease-associated Escherichia coli strain LF82 in the damage of gut and cognition of honeybees. Front Cell Infect Microbiol 2022; 12:983169. [PMID: 36093189 PMCID: PMC9453226 DOI: 10.3389/fcimb.2022.983169] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/01/2022] [Indexed: 12/13/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) are often accompanied with some cognitive impairment, but the mechanism is unclear. By orally exposing honeybees (Apis mellifera) to IBD-associated Escherichia coli LF82 (LF82), and non-pathogenic Escherichia coli MG1655 (MG1655) as the normal strain, we investigated whether and how LF82 induces enteritis-like manifestations and cognitive behavioral modifications in honeybees using multiparametric analysis. LF82 significantly increased gut permeability, impaired learning and memory ability in olfactory proboscis extension response conditioning, and shortened the lifespan of honeybees. Compared to MG1655, LF82 reduced the levels of tryptophan metabolism pathway substances in the honeybee gut. LF82 also upregulated genes involved in immune and apoptosis-related pathways and downregulated genes involved in G protein-coupled receptors in the honeybee brain. In conclusion, LF82 can induce enteritis-like manifestations and cognition impairment through gut metabolites and brain transcriptome alteration in honeybees. Honeybees can serve as a novel potential model to study the microbiota-gut-brain interaction in IBD condition.
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Affiliation(s)
- Ruqi Chang
- Medical College of Nankai University, Tianjin, China
| | - Jieteng Chen
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Zhaopeng Zhong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yiyuan Li
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | | | - Hao Zheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yunsheng Yang
- Medical College of Nankai University, Tianjin, China
- Microbiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Saitz W, Montero DA, Pardo M, Araya D, De la Fuente M, Hermoso MA, Farfán MJ, Ginard D, Rosselló-Móra R, Rasko DA, Del Canto F, Vidal RM. Characterization of Adherent-Invasive Escherichia coli (AIEC) Outer Membrane Proteins Provides Potential Molecular Markers to Screen Putative AIEC Strains. Int J Mol Sci 2022; 23:ijms23169005. [PMID: 36012279 PMCID: PMC9409007 DOI: 10.3390/ijms23169005] [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: 07/14/2022] [Revised: 08/07/2022] [Accepted: 08/09/2022] [Indexed: 01/28/2023] Open
Abstract
Adherent-invasive E. coli (AIEC) is a pathotype associated with the etiopathogenesis of Crohn's disease (CD), albeit with an as-yet unclear role. The main pathogenic mechanisms described for AIEC are adherence to epithelial cells, invasion of epithelial cells, and survival and replication within macrophages. A few virulence factors have been described as participating directly in these phenotypes, most of which have been evaluated only in AIEC reference strains. To date, no molecular markers have been identified that can differentiate AIEC from other E. coli pathotypes, so these strains are currently identified based on the phenotypic characterization of their pathogenic mechanisms. The identification of putative AIEC molecular markers could be beneficial not only from the diagnostic point of view but could also help in better understanding the determinants of AIEC pathogenicity. The objective of this study was to identify molecular markers that contribute to the screening of AIEC strains. For this, we characterized outer membrane protein (OMP) profiles in a group of AIEC strains and compared them with the commensal E. coli HS strain. Notably, we found a set of OMPs that were present in the AIEC strains but absent in the HS strain. Moreover, we developed a PCR assay and performed phylogenomic analyses to determine the frequency and distribution of the genes coding for these OMPs in a larger collection of AIEC and other E. coli strains. As result, it was found that three genes (chuA, eefC, and fitA) are widely distributed and significantly correlated with AIEC strains, whereas they are infrequent in commensal and diarrheagenic E. coli strains (DEC). Additional studies are needed to validate these markers in diverse strain collections from different geographical regions, as well as investigate their possible role in AIEC pathogenicity.
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Affiliation(s)
- Waleska Saitz
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - David A. Montero
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago 8370993, Chile
| | - Mirka Pardo
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Daniela Araya
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Marjorie De la Fuente
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Marcela A. Hermoso
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Department of Gastroenterology and Hepatology, University Medical Center Groningen (UMCG), University of Groningen, 9712 Groningen, The Netherlands
| | - Mauricio J. Farfán
- Departamento de Pediatría y Cirugía Infantil Oriente, Hospital Dr. Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago 7500539, Chile
| | - Daniel Ginard
- Department of Gastroenterology and Palma Health Research Institute, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
| | - Ramon Rosselló-Móra
- Grupo de Microbiología Marina, Instituto Mediterráneo de Estudios Avanzados (IMEDEA; CSIC-UIB), 07190 Esporles, Illes Balears, Spain
| | - Dave A. Rasko
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Felipe Del Canto
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Correspondence: (F.D.C.); (R.M.V.)
| | - Roberto M. Vidal
- Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Instituto Milenio de Inmunología e Inmunoterapia, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Correspondence: (F.D.C.); (R.M.V.)
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Lopez LR, Ahn JH, Alves T, Arthur JC. Microenvironmental Factors that Shape Bacterial Metabolites in Inflammatory Bowel Disease. Front Cell Infect Microbiol 2022; 12:934619. [PMID: 35959366 PMCID: PMC9362432 DOI: 10.3389/fcimb.2022.934619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/21/2022] [Indexed: 11/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a significant global health problem that involves chronic intestinal inflammation and can involve severe comorbidities, including intestinal fibrosis and inflammation-associated colorectal cancer (CRC). Disease-associated alterations to the intestinal microbiota often include fecal enrichment of Enterobacteriaceae, which are strongly implicated in IBD development. This dysbiosis of intestinal flora accompanies changes in microbial metabolites, shaping host:microbe interactions and disease risk. While there have been numerous studies linking specific bacterial taxa with IBD development, our understanding of microbial function in the context of IBD is limited. Several classes of microbial metabolites have been directly implicated in IBD disease progression, including bacterial siderophores and genotoxins. Yet, our microbiota still harbors thousands of uncharacterized microbial products. In-depth discovery and characterization of disease-associated microbial metabolites is necessary to target these products in IBD treatment strategies. Towards improving our understanding of microbiota metabolites in IBD, it is important to recognize how host relevant factors influence microbiota function. For example, changes in host inflammation status, metal availability, interbacterial community structure, and xenobiotics all play an important role in shaping gut microbial ecology. In this minireview, we outline how each of these factors influences gut microbial function, with a specific focus on IBD-associated Enterobacteriaceae metabolites. Importantly, we discuss how altering the intestinal microenvironment could improve the treatment of intestinal inflammation and associated disorders, like intestinal fibrosis and CRC.
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Affiliation(s)
- Lacey R. Lopez
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ju-Hyun Ahn
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Tomaz Alves
- Division of Comprehensive Oral Health, Adams School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Janelle C. Arthur
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Center for Gastrointestinal Biology and Disease, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- *Correspondence: Janelle C. Arthur,
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Wei J, Zhang C, Gao Y, Li Y, Zhang Q, Qi H, Jin M, Yang X, Su X, Zhang Y, Yang R. Gut Epithelial-derived CXCL9 Maintains Gut Homeostasis Through Preventing Overgrown E. coli. J Crohns Colitis 2022; 16:963-977. [PMID: 34964882 DOI: 10.1093/ecco-jcc/jjab234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/25/2021] [Accepted: 12/25/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Increased E. coli in the colon are related to the occurrence and development of multiple diseases. Chemokines are shown to possess potential antimicrobial activity, including against Gram-positive and -negative bacterial pathogens. We here investigated function[s] of chemokine CXCL9 expressed in the gut epithelial cells, and mechanism[s] of CXCL9 by which to kill E. coli. METHODS We generated CXCL9fl/flpvillin-creT mice [pvillin-cre positive mice] and their control CXCL9fl/flpvillin-crewmice [pvillin-cre negative mice], and then employed a dextran sulphate sodium [DSS]-mediated colitis model to determine the sensitivity of CXCL9fl/flpvillin-creT mice. We analysed the composition of the gut microbiota by using 16S ribosomal RNA [V3-V4 variable region] sequencing and shotgun metagenomic analyses. We generated E. coli ΔFtsX [FtsX-depleted E. coli] and E. coli ΔaceE [aceE-depleted E. coli] by using a bacterium red recombining system to investigate the mechanism[s] of CXCL9 by which to kill E. coli. RESULTS CXCL9 fl/flpvillin-creTmice were more sensitive to chemically induced colitis than their control littermates, CXCL9fl/flpvillin-crewmice. After DSS treatment, there were markedly increased gut E. coli [Escherichia-Shigella] in the colonic contents of CXCL9fl/flpvillin-creT mice as compared with control CXCL9fl/flpvillin-crew mice. The increased E. coli could promote colitis through NLRC4 and caspase 1/11-mediated IL-18, which was derived from gut epithelial cells. We finally demonstrated that CXCL9 expressed in gut epithelial cells could kill the overgrown E. coli. E. coli expressed Ftsx and PDHc subunits aceE. E.coliΔaceE but not E. coliΔFtsX were resistant to CXCL9-mediated killing. CONCLUSIONS Gut epithelial cells-derived CXCL9 can kill the expanded E. coli through aceE, to remain gut homeostasis.
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Affiliation(s)
- Jianmei Wei
- Translational Medicine Institute, Tianjin Union Medical Center of Nankai University, Tianjin,China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Chunze Zhang
- Translational Medicine Institute, Tianjin Union Medical Center of Nankai University, Tianjin,China.,Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin,China
| | - Yunhuan Gao
- Translational Medicine Institute, Tianjin Union Medical Center of Nankai University, Tianjin,China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yuanyuan Li
- Translational Medicine Institute, Tianjin Union Medical Center of Nankai University, Tianjin,China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Qianjing Zhang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Houbao Qi
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Mengli Jin
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xiaorong Yang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xiaomin Su
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yuan Zhang
- Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Rongcun Yang
- Translational Medicine Institute, Tianjin Union Medical Center of Nankai University, Tianjin,China.,Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.,Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China
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López-Siles M, Camprubí-Font C, Gómez Del Pulgar EM, Sabat Mir M, Busquets D, Sanz Y, Martinez-Medina M. Prevalence, Abundance, and Virulence of Adherent-Invasive Escherichia coli in Ulcerative Colitis, Colorectal Cancer, and Coeliac Disease. Front Immunol 2022; 13:748839. [PMID: 35359974 PMCID: PMC8960851 DOI: 10.3389/fimmu.2022.748839] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/31/2022] [Indexed: 01/08/2023] Open
Abstract
Background & Aims Adherent-invasive E. coli (AIEC) has largely been implicated in the pathogenesis of Crohn’s disease (CD). E. coli strains with similar genetic backgrounds and virulence genes profiles have been associated with other intestinal disorders, such as ulcerative colitis (UC), colorectal cancer (CRC), and coeliac disease (CeD), but the role of AIEC in these diseases remains unexplored. We aimed to assess the distribution, abundance, and pathogenic features of AIEC in UC, CRC, and CeD. Methods The AIEC phenotype was investigated in 4,233 E. coli isolated from the ileum and colon of 14 UC and 15 CRC patients and in 38 fecal E. coli strains obtained from 17 CeD and 10 healthy (H) children. AIEC prevalence and abundance were compared with previous data from CD patients and H controls. Clonality, virulence gene carriage, and phylogenetic origin were determined for the AIEC identified. Results In UC, AIEC prevalence was intermediate between CD and H subjects (UC: 35.7%, CD: 55.0%, H: 21.4%), and similar to CD patients with colonic disease (C-CD: 40.0%). In CRC, the prevalence was lower (6.7%) than these groups. In patients with AIEC, the estimated abundance was similar across all intestinal conditions. All AIEC strains isolated from UC and CRC belonged to the B1 phylogroup, except for a strain of the A phylogroup, and the majority (75% of clonally distinct AIEC) harbored the Afa/Dr operon and the cdt gene. None of the E. coli isolated from the CeD cohort were AIEC. Nonetheless, E. coli strains isolated from active CeD patients showed higher invasion indices than those isolated from H and inactive CeD pediatric patients. Conclusion We support the hypothesis that AIEC-like strains can be involved not only in CD but also in UC. Further works are needed to study the virulence particularities of these groups of strains and to determine if there is a causative link between AIEC and UC. In contrast, we rule out the possible association of AIEC with CRC. In addition, to further study the E. coli strains in CeD for their possible pathogenic role would be of interest.
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Affiliation(s)
- Mireia López-Siles
- Microbiology of Intestinal Diseases, Biology Department, Universitat de Girona, Girona, Spain
| | - Carla Camprubí-Font
- Microbiology of Intestinal Diseases, Biology Department, Universitat de Girona, Girona, Spain
| | - Eva M Gómez Del Pulgar
- Instituto de Agroquímica y Tecnología de Alimentos, Spanish National Research Council (CSIC), Paterna, Spain
| | - Miriam Sabat Mir
- Department of Gastroenterology, Hospital Santa Caterina, Salt, Spain
| | - David Busquets
- Department of Gastroenterology, Hospital Universitari Doctor Josep Trueta, Girona, Spain
| | - Yolanda Sanz
- Instituto de Agroquímica y Tecnología de Alimentos, Spanish National Research Council (CSIC), Paterna, Spain
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Wymore Brand M, Proctor AL, Hostetter JM, Zhou N, Friedberg I, Jergens AE, Phillips GJ, Wannemuehler MJ. Vertical transmission of attaching and invasive E. coli from the dam to neonatal mice predisposes to more severe colitis following exposure to a colitic insult later in life. PLoS One 2022; 17:e0266005. [PMID: 35381031 PMCID: PMC8982877 DOI: 10.1371/journal.pone.0266005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/14/2022] [Indexed: 11/18/2022] Open
Abstract
The gastrointestinal microbiota begins to be acquired at birth and continually matures through early adolescence. Despite the relevance for gut health, few studies have evaluated the impact of pathobiont colonization of neonates on the severity of colitis later in life. LF82 is an adherent invasive E. coli strain associated with ileal Crohn’s disease. The aim of this study was to evaluate the severity of dextran sodium sulfate (DSS)-induced colitis in mice following E. coli LF82 colonization. Gnotobiotic mice harboring the altered Schaedler flora (ASF) were used as the model. While E. coli LF82 is neither adherent nor invasive, it was been demonstrated that adult ASF mice colonized with E. coli LF82 develop more severe DSS-induced colitis compared to control ASF mice treated with DSS. Therefore, we hypothesized that E. coli LF82 colonization of neonatal ASF mice would reduce the severity of DSS-induced inflammation compared to adult ASF mice colonized with E. coli LF82. To test this hypothesis, adult ASF mice were colonized with E. coli LF82 and bred to produce offspring (LF82N) that were vertically colonized with LF82. LF82N and adult-colonized (LF82A) mice were given 2.0% DSS in drinking water for seven days to trigger colitis. More severe inflammatory lesions were observed in the LF82N + DSS mice when compared to LF82A + DSS mice, and were characterized as transmural in most of the LF82N + DSS mice. Colitis was accompanied by secretion of proinflammatory cytokines (IFNγ, IL-17) and specific mRNA transcripts within the colonic mucosa. Using 16S rRNA gene amplicon sequencing, LF82 colonization did not induce significant changes in the ASF community; however, minimal changes in spatial redistribution by fluorescent in situ hybridization were observed. These results suggest that the age at which mice were colonized with E. coli LF82 pathobiont differentially impacted severity of subsequent colitic events.
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Affiliation(s)
- Meghan Wymore Brand
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Alexandra L. Proctor
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Jesse M. Hostetter
- Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Naihui Zhou
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Iddo Friedberg
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Albert E. Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Gregory J. Phillips
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
| | - Michael J. Wannemuehler
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, United States of America
- * E-mail:
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Verstockt B, Bressler B, Martinez-Lozano H, McGovern D, Silverberg MS. Time to Revisit Disease Classification in Inflammatory Bowel Disease: Is the Current Classification of Inflammatory Bowel Disease Good Enough for Optimal Clinical Management? Gastroenterology 2022; 162:1370-1382. [PMID: 34995534 DOI: 10.1053/j.gastro.2021.12.246] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), historically subdivided into Crohn's disease and ulcerative colitis, is a very heterogeneous condition. While the tendency in medicine is to try to reduce complexity, IBD is a disease that cannot justify a one-size-fits-all principle. Our current clinical classification tools are suboptimal and need further refinement to capture, at least in part, the variety of phenotypes encountered in daily clinical practice. Although these revised classification tools alone will not be sufficient and should be complemented by more detailed molecular subclassifications, optimized clinical phenotypes can contribute to improved trial designs, future translational research approaches, and better treatment outcomes. In the current review, we discuss key clinical features important in IBD disease heterogeneity, tackle limitations of the current classification systems, propose some potential improvements, and raise priorities for future research in this domain.
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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Brian Bressler
- Division of Gastroenterology, Department of Medicine, St. Paul's Hopsital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Helena Martinez-Lozano
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Dermot McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark S Silverberg
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
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Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease. Can J Gastroenterol Hepatol 2022; 2022:8416578. [PMID: 35360442 PMCID: PMC8964223 DOI: 10.1155/2022/8416578] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 03/05/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies. AIMS This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options. METHODS We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease. RESULTS Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease. CONCLUSIONS Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.
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Sheh A, Artim SC, Burns MA, Molina-Mora JA, Lee MA, Dzink-Fox J, Muthupalani S, Fox JG. Analysis of gut microbiome profiles in common marmosets (Callithrix jacchus) in health and intestinal disease. Sci Rep 2022; 12:4430. [PMID: 35292670 PMCID: PMC8924212 DOI: 10.1038/s41598-022-08255-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/01/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic gastrointestinal (GI) diseases are the most common diseases in captive common marmosets. To understand the role of the microbiome in GI diseases, we characterized the gut microbiome of 91 healthy marmosets (303 samples) and 59 marmosets diagnosed with inflammatory bowel disease (IBD) (200 samples). Healthy marmosets exhibited "humanized," Bacteroidetes-dominant microbiomes. After up to 2 years of standardized diet, housing and husbandry, marmoset microbiomes could be classified into four distinct marmoset sources based on Prevotella and Bacteroides levels. Using a random forest (RF) model, marmosets were classified by source with an accuracy of 93% with 100% sensitivity and 95% specificity using abundance data from 4 Prevotellaceae amplicon sequence variants (ASVs), as well as single ASVs from Coprobacter, Parabacteroides, Paraprevotella, Phascolarctobacterium, Oribacterium and Fusobacterium. A single dysbiotic IBD state was not found across all marmoset sources, but IBD was associated with lower alpha diversity and a lower Bacteroides:Prevotella copri ratio within each source. IBD was highest in a Prevotella-dominant cohort, and consistent with Prevotella-linked diseases, pro-inflammatory genes in the jejunum were upregulated. RF analysis of serum biomarkers identified serum calcium, hemoglobin and red blood cell (RBC) counts as potential biomarkers for marmoset IBD. This study characterizes the microbiome of healthy captive common marmosets and demonstrates that source-specific microbiomes can be retained despite standardized diets and husbandry practices. Marmosets with IBD had decreased alpha diversity and a shift in the ratio of Bacteroides:Prevotella copri compared to healthy marmosets.
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Affiliation(s)
- Alexander Sheh
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Stephen C Artim
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
- Merck Research Laboratories, Merck, South San Francisco, CA, USA
| | - Monika A Burns
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jose Arturo Molina-Mora
- Centro de Investigación en Enfermedades Tropicales (CIET), Universidad de Costa Rica, San José, Costa Rica
| | - Mary Anne Lee
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Sciences, Wellesley College, Wellesley, MA, USA
| | - JoAnn Dzink-Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Mourenza Á, Lorente-Torres B, Durante E, Llano-Verdeja J, Aparicio JF, Fernández-López A, Gil JA, Mateos LM, Letek M. Understanding microRNAs in the Context of Infection to Find New Treatments against Human Bacterial Pathogens. Antibiotics (Basel) 2022; 11:356. [PMID: 35326819 PMCID: PMC8944844 DOI: 10.3390/antibiotics11030356] [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: 02/03/2022] [Revised: 02/25/2022] [Accepted: 03/04/2022] [Indexed: 02/04/2023] Open
Abstract
The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), or microRNAs (miRNAs). Notably, the role of miRNAs on the post-transcriptional regulation of gene expression has been studied in detail in the context of cancer and many other genetic diseases. However, it is also becoming apparent that some human miRNAs possess important antimicrobial roles by silencing host genes essential for the progress of bacterial or viral infections. Therefore, their potential use as novel antimicrobial therapies has gained interest during the last decade. The challenges of the transport and delivery of miRNAs to target cells are important, but recent research with exosomes is overcoming the limitations in RNA-cellular uptake, avoiding their degradation. Therefore, in this review, we have summarised the latest developments in the exosomal delivery of miRNA-based therapies, which may soon be another complementary treatment to pathogen-targeted antibiotics that could help solve the problem caused by multidrug-resistant bacteria.
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Affiliation(s)
- Álvaro Mourenza
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
| | - Blanca Lorente-Torres
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
| | - Elena Durante
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
- L’Università di Urbino Carlo Bo, Via Aurelio Saffi, 2, 61029 Urbino, Italy
| | - Jesús Llano-Verdeja
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
| | - Jesús F. Aparicio
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
| | - Arsenio Fernández-López
- Departamento de Biología Molecular, Área de Biología Celular, Universidad de León, 24071 León, Spain;
- Instituto de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain
- Neural Therapies SL, Campus de Vegazana s/n, 24071 León, Spain
| | - José A. Gil
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
- Instituto de Biología Molecular, Genómica y Proteómica (INBIOMIC), Universidad de León, 24071 León, Spain
| | - Luis M. Mateos
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
- Instituto de Biología Molecular, Genómica y Proteómica (INBIOMIC), Universidad de León, 24071 León, Spain
| | - Michal Letek
- Departamento de Biología Molecular, Área de Microbiología, Universidad de León, 24071 León, Spain; (Á.M.); (B.L.-T.); (E.D.); (J.L.-V.); (J.F.A.); (J.A.G.)
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, 24071 León, Spain
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Battat R, Qatomah A, Kopylov U, Wyse J, Cohen A, Afif W, Lakatos PL, Seidman E, Bitton A, Bessissow T. Fucosyltransferase 2 Mutations Are Associated With a Favorable Clinical Course in Crohn's Disease. J Clin Gastroenterol 2022; 56:e166-e170. [PMID: 34739405 DOI: 10.1097/mcg.0000000000001626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 09/07/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND Fucosyltransferase 2 (FUT2) participates in intestinal antigen secretion and bacterial adherence. FUT2 homozygous nonsense mutations (FUT2M) and subsequent nonsecretor status is associated with Crohn's disease (CD). The common null allele is rs601338. We assessed the relationship between FUT2M and disease course. METHODS In consecutive adult CD outpatients, clinical, biochemical, and genetic data were collected at baseline visits. Patients were longitudinally followed over 5 years. The primary outcome analyzed the relationship between FUT2M and rates of CD patients in persistent steroid-free clinical remission requiring neither surgery, biologics, nor immunomodulators. RESULTS Sixty-two CD patients were recruited. FUT2M homozygotes (rs601338 or any mutation in linkage disequilibrium) were detected in 27% of CD (17/62). Patients with rs601338 mutations had higher rates of the primary outcome (homozygous: 46.6%, heterozygous: 28.0%, wild-type: 5.3%, P=0.02). Similar findings existed for CD patients with homozygous mutations in any single-nucleotide polymorphism for FUT2 (homozygous: 41.2%, heterozygous: 25.9%, wild-type: 5.6%, P=0.04). On multivariable analysis, rs601338 mutation was associated with the primary outcome (odds ratio=3.4, 95% confidence interval: 1.3-8.7, P=0.01), while other parameters were not. Mutation of rs601338 was associated with lower rates of penetrating disease (homozygous: 13.3%, heterozygous: 28.0%, wild-type: 52.6%, P=0.05) and particularly in high-risk patients (homozygous: 0%, heterozygous: 37.5%, wild-type: 83.3%, P=0.01). CONCLUSIONS FUT2 mutation status is associated with a favorable clinical course in CD. Further confirmatory studies are needed.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology and Hepatology, Department of Medicine, Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medical College, New York, NY
- Division of Gastroenterology and Hepatology, McGill University Health Centre
| | - Abdulrahman Qatomah
- Division of Gastroenterology and Hepatology, McGill University Health Centre
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer
- Sackler Medical School, Tel Aviv, Israel
| | - Jonathan Wyse
- Division of Gastroenterology, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Albert Cohen
- Division of Gastroenterology, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Waqqas Afif
- Division of Gastroenterology and Hepatology, McGill University Health Centre
| | - Peter L Lakatos
- Division of Gastroenterology and Hepatology, McGill University Health Centre
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Ernest Seidman
- Division of Gastroenterology and Hepatology, McGill University Health Centre
| | - Alain Bitton
- Division of Gastroenterology and Hepatology, McGill University Health Centre
| | - Talat Bessissow
- Division of Gastroenterology and Hepatology, McGill University Health Centre
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