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1
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Rose AE, Fansler RT, Zhu W. Commensal resilience: ancient ecological lessons for the modern microbiota. Infect Immun 2025:e0050224. [PMID: 40387449 DOI: 10.1128/iai.00502-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025] Open
Abstract
The gut microbiota constitutes a complex ecosystem essential for host health, offering metabolic support, modulating the immune system, and protecting against pathogens. However, this community faces constant destabilizing challenges, including dietary changes, antibiotics, and enteric infection. Prolonged microbiota imbalance or dysbiosis can exacerbate intestinal disease states, including inflammatory bowel disease and colorectal cancer. Understanding the mechanisms that sustain microbiota resilience in the face of these imbalances is crucial for maintaining host health and developing effective therapeutics. This review explores microbiota resilience through the lens of an ecological model, emphasizing the interplay between microbial communities and host-driven environmental controls. We highlight two critical factors shaping microbiota resilience: oxygen tension and iron availability-challenges encountered by ancient anaerobic organisms during early evolutionary history, from which the predominant members of the microbiota have descended. Disruptions in intestinal anaerobiosis during inflammation increase luminal oxygen levels, favoring pro-inflammatory facultative anaerobes and depleting obligately anaerobic commensals. Simultaneously, host nutritional immunity restricts iron availability, further challenging commensal survival. This dual environmental challenge of rising oxygen tension and reduced iron availability is a convergent outcome of a diverse array of perturbations, from pathogen invasion to antibiotic treatment. By highlighting these conserved downstream environmental challenges rather than the specific upstream perturbations, this ecological view offers a focused framework for understanding microbiota resilience. This perspective not only enhances our understanding of host-microbiota interactions but also informs therapeutic strategies to foster resilience and support host health.
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Affiliation(s)
- Abigail E Rose
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ryan T Fansler
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wenhan Zhu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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2
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Chavez-Arroyo A, Radlinski LC, Bäumler AJ. Principles of gut microbiota assembly. Trends Microbiol 2025:S0966-842X(25)00071-X. [PMID: 40089422 DOI: 10.1016/j.tim.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/17/2025]
Abstract
The gut microbiota plays a critical role in human health, yet its taxonomic complexity, interpersonal variability, and resistance to change in adulthood present challenges for understanding the factors driving shifts in its composition and function. Here, we propose a hierarchy of ecological factors governing gut microbiota assembly, stability, and resilience. At the apex of this hierarchy is habitat filtering by host-derived electron acceptors, which dictates the ecological guilds that dominate distinct gut regions. Host dietary behavior shapes niche availability within these ecological guilds by regulating nutrient availability. Priority effects preserve taxonomic stability whereas microbial antagonism governs competition for open ecological positions. This framework highlights how host control over microbial energy metabolism directs microbiota self-assembly and maintains gut homeostasis.
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Affiliation(s)
- Alfredo Chavez-Arroyo
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Lauren C Radlinski
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Andreas J Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA.
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3
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Wasney M, Briscoe L, Wolff R, Ghezzi H, Tropini C, Garud N. Uniform bacterial genetic diversity along the guts of mice inoculated with human stool. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.28.635365. [PMID: 39974986 PMCID: PMC11838389 DOI: 10.1101/2025.01.28.635365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Environmental gradients exist throughout the digestive tract, driving spatial variation in the membership and abundance of bacterial species along the gut. However, less is known about the distribution of genetic diversity within bacterial species along the gut. Understanding this distribution is important because bacterial genetic variants confer traits important for the functioning of the microbiome and are also known to impart phenotypes to the hosts, including local inflammation along the gut and the ability to digest food. Thus, to be able to understand how the microbiome functions at a mechanistic level, it is essential to understand how genetic diversity is organized along the gut and the ecological and evolutionary processes that give rise to this organization. In this study, we analyzed bacterial genetic diversity of approximately 30 common gut commensals in five regions along the gut lumen in germ-free mice colonized with the same healthy human stool sample. While species membership and abundances varied considerably along the gut, genetic diversity within species was substantially more uniform. Driving this uniformity were similar strain frequencies along the gut, implying that multiple, genetically divergent strains of the same species can coexist within a host without spatially segregating. Additionally, the approximately 60 unique evolutionary adaptations arising within mice tended to sweep throughout the gut, showing little specificity for particular gut regions. Together, our findings show that genetic diversity may be more uniform along the gut than species diversity, which implies that species presence-absence may play a larger role than genetic variation in responding to varied environments along the gut.
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Affiliation(s)
- Michael Wasney
- University of California, Los Angeles, Human Genetics, Los Angeles, CA
| | - Leah Briscoe
- University of California, Los Angeles, Interdepartmental Program in Bioinformatics, Los Angeles, CA
| | - Richard Wolff
- University of California, Los Angeles, Ecology and Evolutionary Biology, Los Angeles, CA
| | - Hans Ghezzi
- University of British Columbia, Department of Bioinformatics, Vancouver, Canada
| | - Carolina Tropini
- University of British Columbia, Department of Microbiology and Immunology, Vancouver, Canada
- University of British Columbia, School of Biomedical Engineering, Vancouver, Canada
- Canadian Institute for Advanced Research, Humans and the Microbiome Program, Toronto, Canada
| | - Nandita Garud
- University of California, Los Angeles, Human Genetics, Los Angeles, CA
- University of California, Los Angeles, Interdepartmental Program in Bioinformatics, Los Angeles, CA
- University of California, Los Angeles, Ecology and Evolutionary Biology, Los Angeles, CA
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4
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Ma ZS. Species specificity and specificity diversity (SSD) framework: a novel method for detecting the unique and enriched species associated with disease by leveraging the microbiome heterogeneity. BMC Biol 2024; 22:283. [PMID: 39639304 PMCID: PMC11619696 DOI: 10.1186/s12915-024-02024-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 09/30/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Differentiating the microbiome changes associated with diseases is challenging but critically important. Majority of existing efforts have been focused on a community level, but the discerning power of community or holistic metrics such as diversity analysis seems limited. This prompts many researchers to believe that the promise should be downward to species or even strain level-effectively and efficiently identifying unique or enriched species in diseased microbiomes with statistical rigor. Nevertheless, virtually, all species-level approaches such as differential abundance and differential network analysis methods exclusively rely on species abundances without considering species distribution information, while it can be said that distribution is equally, if not more, important than abundance in shaping the spatiotemporal heterogeneity of community compositions. RESULTS Here, we fill the gap by developing a novel framework-species specificity and specificity diversity (SSD)-that synthesizes both abundance and distribution information to differentiate microbiomes, at both species and community scales, under different environmental gradients such as the healthy and diseased treatments. The proposed SSD framework consists of three essential elements. The first is species specificity (SS), a concept that reincarnates the traditional specialist-generalist continuum and is defined by Mariadassou et al. (Ecol Lett 18:974-82, 2015). The SS synthesizes a species' local prevalence (distribution) and global abundance information and attaches specificity measure to each species in a specific habitat (e.g., healthy or diseased treatment). The second element is a new concept to introduce here, the (species) specificity diversity (SD), which is inspired by traditional species (abundance) diversity in community ecology and measures the diversity of specificity (a proxy for metacommunity heterogeneity, essentially) with Renyi's entropy. The third element is a pair of statistical tests based on the principle of permutation tests. CONCLUSIONS The SSD framework can (i) identify and catalogue lists of unique species (US), significantly enriched species (ES) in each treatment based on SS and specificity permutation (SP) test and (ii) measure the holistic differences between assemblages (or treatments) based on SD and specificity diversity permutation (SDP) test. Both capacities can be enabling technologies for general comparative microbiome research including risk assessment, diagnosis, and treatment of microbiome-associated diseases.
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Affiliation(s)
- Zhanshan Sam Ma
- Computational Biology and Medical Ecology Lab, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
- Department of Entomology, College of Plant Protection, Hebei Agricultural University, Baoding, China.
- Microbiome Medicine and Advanced AI Lab, Cambridge, MA, 02138, USA.
- Faculty of Arts and Science, Harvard University, Cambridge, MA, 02138, USA.
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5
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Oh VKS, Li RW. Wise Roles and Future Visionary Endeavors of Current Emperor: Advancing Dynamic Methods for Longitudinal Microbiome Meta-Omics Data in Personalized and Precision Medicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400458. [PMID: 39535493 DOI: 10.1002/advs.202400458] [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: 01/12/2024] [Revised: 09/16/2024] [Indexed: 11/16/2024]
Abstract
Understanding the etiological complexity of diseases requires identifying biomarkers longitudinally associated with specific phenotypes. Advanced sequencing tools generate dynamic microbiome data, providing insights into microbial community functions and their impact on health. This review aims to explore the current roles and future visionary endeavors of dynamic methods for integrating longitudinal microbiome multi-omics data in personalized and precision medicine. This work seeks to synthesize existing research, propose best practices, and highlight innovative techniques. The development and application of advanced dynamic methods, including the unified analytical frameworks and deep learning tools in artificial intelligence, are critically examined. Aggregating data on microbes, metabolites, genes, and other entities offers profound insights into the interactions among microorganisms, host physiology, and external stimuli. Despite progress, the absence of gold standards for validating analytical protocols and data resources of various longitudinal multi-omics studies remains a significant challenge. The interdependence of workflow steps critically affects overall outcomes. This work provides a comprehensive roadmap for best practices, addressing current challenges with advanced dynamic methods. The review underscores the biological effects of clinical, experimental, and analytical protocol settings on outcomes. Establishing consensus on dynamic microbiome inter-studies and advancing reliable analytical protocols are pivotal for the future of personalized and precision medicine.
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Affiliation(s)
- Vera-Khlara S Oh
- Big Biomedical Data Integration and Statistical Analysis (DIANA) Research Center, Department of Data Science, College of Natural Sciences, Jeju National University, Jeju City, Jeju Do, 63243, South Korea
| | - Robert W Li
- United States Department of Agriculture, Agricultural Research Service, Animal Genomics and Improvement Laboratory, Beltsville, MD, 20705, USA
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6
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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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7
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Hachfi S, Brun-Barale A, Fichant A, Munro P, Nawrot-Esposito MP, Michel G, Ruimy R, Rousset R, Bonis M, Boyer L, Gallet A. Ingestion of Bacillus cereus spores dampens the immune response to favor bacterial persistence. Nat Commun 2024; 15:7733. [PMID: 39231950 PMCID: PMC11375157 DOI: 10.1038/s41467-024-51689-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024] Open
Abstract
Strains of the Bacillus cereus (Bc) group are sporulating bacteria commonly associated with foodborne outbreaks. Spores are dormant cells highly resistant to extreme conditions. Nevertheless, the pathological processes associated with the ingestion of either vegetative cells or spores remain poorly understood. Here, we demonstrate that while ingestion of vegetative bacteria leads to their rapid elimination from the intestine of Drosophila melanogaster, a single ingestion of spores leads to the persistence of bacteria for at least 10 days. We show that spores do not germinate in the anterior part of the intestine which bears the innate immune defenses. Consequently, spores reach the posterior intestine where they germinate and activate both the Imd and Toll immune pathways. Unexpectedly, this leads to the induction of amidases, which are negative regulators of the immune response, but not to antimicrobial peptides. Thereby, the local germination of spores in the posterior intestine dampens the immune signaling that in turn fosters the persistence of Bc bacteria. This study provides evidence for how Bc spores hijack the intestinal immune defenses allowing the localized birth of vegetative bacteria responsible for the digestive symptoms associated with foodborne illness outbreaks.
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Affiliation(s)
- Salma Hachfi
- Université Côte d'Azur, CNRS, INRAE, ISA, Sophia Antipolis, France
- Université Côte d'Azur, Inserm, C3M, Nice, France
| | | | - Arnaud Fichant
- Université Côte d'Azur, CNRS, INRAE, ISA, Sophia Antipolis, France
- Anses (Laboratoire de Sécurité des Aliments), Université Paris-Est, Maisons-Alfort, France
| | | | | | | | - Raymond Ruimy
- Université Côte d'Azur, Inserm, C3M, Nice, France
- Bacteriology Laboratory, Archet 2 Hospital, CHU, Université Côte d'Azur, Nice, France
| | - Raphaël Rousset
- Université Côte d'Azur, CNRS, INRAE, ISA, Sophia Antipolis, France
| | - Mathilde Bonis
- Anses (Laboratoire de Sécurité des Aliments), Université Paris-Est, Maisons-Alfort, France
| | | | - Armel Gallet
- Université Côte d'Azur, CNRS, INRAE, ISA, Sophia Antipolis, France.
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8
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Kumar A, Vaiphei KK, Singh N, Datta Chigurupati SP, Paliwal SR, Paliwal R, Gulbake A. Nanomedicine for colon-targeted drug delivery: strategies focusing on inflammatory bowel disease and colon cancer. Nanomedicine (Lond) 2024; 19:1347-1368. [PMID: 39105753 PMCID: PMC11318742 DOI: 10.1080/17435889.2024.2350356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/29/2024] [Indexed: 08/07/2024] Open
Abstract
The nanostructured drug-delivery systems for colon-targeted drug delivery are a promising field of research for localized diseases particularly influencing the colonic region, in other words, ulcerative colitis, Crohn's disease, and colorectal cancer. There are various drug-delivery approaches designed for effective colonic disease treatment, including stimulus-based formulations (enzyme-triggered systems, pH-sensitive systems) and magnetically driven drug-delivery systems. In addition, targeted drug delivery by means of overexpressed receptors also offers site specificity and reduces drug resistance. It also covers GI tract-triggered emulsifying systems, nontoxic plant-derived nanoformulations as advanced drug-delivery techniques as well as nanotechnology-based clinical trials toward colonic diseases. This review gives insight into advancements in colon-targeted drug delivery to meet site specificity or targeted drug-delivery requirements.
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Affiliation(s)
- Ankaj Kumar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Klaudi K Vaiphei
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Naveen Singh
- Nanomedicine & Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, 484887, India
| | - Sri Pada Datta Chigurupati
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
| | - Shivani Rai Paliwal
- Department of Pharmacy, Guru Ghasidas Vishwavidhyalaya (A Central University), Koni Bilaspur, Chhattisgarh, 495009, India
| | - Rishi Paliwal
- Nanomedicine & Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, 484887, India
| | - Arvind Gulbake
- Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research, Guwahati, Assam, 781101, India
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9
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Liang SH, Sircaik S, Dainis J, Kakade P, Penumutchu S, McDonough LD, Chen YH, Frazer C, Schille TB, Allert S, Elshafee O, Hänel M, Mogavero S, Vaishnava S, Cadwell K, Belenky P, Perez JC, Hube B, Ene IV, Bennett RJ. The hyphal-specific toxin candidalysin promotes fungal gut commensalism. Nature 2024; 627:620-627. [PMID: 38448595 PMCID: PMC11230112 DOI: 10.1038/s41586-024-07142-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/31/2024] [Indexed: 03/08/2024]
Abstract
The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence1-3. Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin4,5, which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells1,6. Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche.
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Affiliation(s)
- Shen-Huan Liang
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Shabnam Sircaik
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Joseph Dainis
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Pallavi Kakade
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Swathi Penumutchu
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Liam D McDonough
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Ying-Han Chen
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Corey Frazer
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Tim B Schille
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
- Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany
| | - Stefanie Allert
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
| | - Osama Elshafee
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
| | - Maria Hänel
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
| | - Selene Mogavero
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany
| | - Shipra Vaishnava
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Ken Cadwell
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Peter Belenky
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - J Christian Perez
- Department of Microbiology and Molecular Genetics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany.
- Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Jena, Germany.
- Institute of Microbiology, Friedrich Schiller University Jena, Jena, Germany.
| | - Iuliana V Ene
- Institut Pasteur, Université Paris Cité, Fungal Heterogeneity Group, Paris, France
| | - Richard J Bennett
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
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10
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Lee JY, Tiffany CR, Mahan SP, Kellom M, Rogers AWL, Nguyen H, Stevens ET, Masson HLP, Yamazaki K, Marco ML, Eloe-Fadrosh EA, Turnbaugh PJ, Bäumler AJ. High fat intake sustains sorbitol intolerance after antibiotic-mediated Clostridia depletion from the gut microbiota. Cell 2024; 187:1191-1205.e15. [PMID: 38366592 PMCID: PMC11023689 DOI: 10.1016/j.cell.2024.01.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 09/27/2023] [Accepted: 01/18/2024] [Indexed: 02/18/2024]
Abstract
Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism. The restoration of sorbitol catabolism by inoculation with probiotic Escherichia coli protected mice against sorbitol intolerance but did not restore Clostridia abundance. Inoculation with the butyrate producer Anaerostipes caccae restored a normal Clostridia abundance, which protected mice against sorbitol-induced diarrhea even when the probiotic was cleared. Butyrate restored Clostridia abundance by stimulating epithelial peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling to restore epithelial hypoxia in the colon. Collectively, these mechanistic insights identify microbial sorbitol catabolism as a potential target for approaches for the diagnosis, treatment, and prevention of sorbitol intolerance.
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Affiliation(s)
- Jee-Yon Lee
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Connor R Tiffany
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Scott P Mahan
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Matthew Kellom
- Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Andrew W L Rogers
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Henry Nguyen
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Eric T Stevens
- Department of Food Science and Technology, University of California at Davis, Davis, CA 95616, USA
| | - Hugo L P Masson
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA
| | - Kohei Yamazaki
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA; Laboratory of Veterinary Public Health, School of Veterinary Medicine, Kitasato University, Towada, Japan
| | - Maria L Marco
- Department of Food Science and Technology, University of California at Davis, Davis, CA 95616, USA
| | - Emiley A Eloe-Fadrosh
- Environmental Genomics & Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Peter J Turnbaugh
- Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub-San Francisco, San Francisco, CA 94158, USA
| | - Andreas J Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, CA 95616, USA.
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11
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Zentek J, Vahjen W, Grześkowiak Ł, Martínez-Vallespín B, Holthausen JS, Saliu EM. The Gut Microbiome in Pigs and Its Impact on Animal Health. PRODUCTION DISEASES IN FARM ANIMALS 2024:157-177. [DOI: 10.1007/978-3-031-51788-4_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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12
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Winter SE, Bäumler AJ. Gut dysbiosis: Ecological causes and causative effects on human disease. Proc Natl Acad Sci U S A 2023; 120:e2316579120. [PMID: 38048456 PMCID: PMC10722970 DOI: 10.1073/pnas.2316579120] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/02/2023] [Indexed: 12/06/2023] Open
Abstract
The gut microbiota plays a role in many human diseases, but high-throughput sequence analysis does not provide a straightforward path for defining healthy microbial communities. Therefore, understanding mechanisms that drive compositional changes during disease (gut dysbiosis) continues to be a central goal in microbiome research. Insights from the microbial pathogenesis field show that an ecological cause for gut dysbiosis is an increased availability of host-derived respiratory electron acceptors, which are dominant drivers of microbial community composition. Similar changes in the host environment also drive gut dysbiosis in several chronic human illnesses, and a better understanding of the underlying mechanisms informs approaches to causatively link compositional changes in the gut microbiota to an exacerbation of symptoms. The emerging picture suggests that homeostasis is maintained by host functions that control the availability of resources governing microbial growth. Defining dysbiosis as a weakening of these host functions directs attention to the underlying cause and identifies potential targets for therapeutic intervention.
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Affiliation(s)
- Sebastian E. Winter
- Department of Medicine, Division of Infectious Diseases, University of California, Davis, CA95616
- Department of Medical Microbiology and Immunology, University of California, Davis, CA95616
| | - Andreas J. Bäumler
- Department of Medical Microbiology and Immunology, University of California, Davis, CA95616
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13
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Hernández M, Ancona S, Hereira-Pacheco S, Díaz DE LA Vega-Pérez AH, Navarro-Noya YE. Comparative analysis of two nonlethal methods for the study of the gut bacterial communities in wild lizards. Integr Zool 2023; 18:1056-1071. [PMID: 36881373 DOI: 10.1111/1749-4877.12711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Fecal samples or cloacal swabs are preferred over lethal dissections to study vertebrate gut microbiota for ethical reasons, but it remains unclear which nonlethal methods provide more accurate information about gut microbiota. We compared the bacterial communities of three gastrointestinal tract (GIT) segments, that is, stomach, small intestine (midgut), and rectum (hindgut) with the bacterial communities of the cloaca and feces in the mesquite lizard Sceloporus grammicus. The hindgut had the highest taxonomic and functional alpha diversity, followed by midgut and feces, whereas the stomach and cloaca showed the lowest diversities. The taxonomic assemblages of the GIT segments at the phylum level were strongly correlated with those retrieved from feces and cloacal swabs (rs > 0.84 in all cases). The turnover ratio of Amplicon Sequence Variants (ASVs) between midgut and hindgut and the feces was lower than the ratio between these segments and the cloaca. More than half of the core-ASVs in the midgut (24 of 32) and hindgut (58 of 97) were also found in feces, while less than 5 were found in the cloaca. At the ASVs level, however, the structure of the bacterial communities of the midgut and hindgut were similar to those detected in feces and cloaca. Our findings suggest that fecal samples and cloacal swabs of spiny lizards provide a good approximation of the taxonomic assemblages and beta diversity of midgut and hindgut microbiota, while feces better represent the bacterial communities of the intestinal segments at a single nucleotide variation level than cloacal swabs.
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Affiliation(s)
- Mauricio Hernández
- Doctorado en Ciencias Biológicas, Centro de Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
| | - Sergio Ancona
- Departamento de Ecología Evolutiva, Instituto de Ecología, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Stephanie Hereira-Pacheco
- Estación Científica la Malinche, Centro de Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
| | - Aníbal H Díaz DE LA Vega-Pérez
- Consejo Nacional de Ciencia y Tecnología-Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
| | - Yendi E Navarro-Noya
- Laboratorio de Interacciones Bióticas, Centro de Investigación en Ciencias Biológicas, Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
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14
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Spiga L, Fansler RT, Perera YR, Shealy NG, Munneke MJ, David HE, Torres TP, Lemoff A, Ran X, Richardson KL, Pudlo N, Martens EC, Folta-Stogniew E, Yang ZJ, Skaar EP, Byndloss MX, Chazin WJ, Zhu W. Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection. Cell Host Microbe 2023; 31:1639-1654.e10. [PMID: 37776864 PMCID: PMC10599249 DOI: 10.1016/j.chom.2023.08.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 07/06/2023] [Accepted: 08/29/2023] [Indexed: 10/02/2023]
Abstract
During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients, such as iron. Pathogens scavenge iron using siderophores, including enterobactin; however, this strategy is counteracted by host protein lipocalin-2, which sequesters iron-laden enterobactin. Although this iron competition occurs in the presence of gut bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron and sustains its resilience in the inflamed gut by utilizing siderophores produced by other bacteria, including Salmonella, via a secreted siderophore-binding lipoprotein XusB. Notably, XusB-bound enterobactin is less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. Because the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the host-pathogen interactions and nutritional immunity.
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Affiliation(s)
- Luisella Spiga
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Ryan T Fansler
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yasiru R Perera
- Departments of Biochemistry and Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Nicolas G Shealy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Matthew J Munneke
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Holly E David
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Teresa P Torres
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Andrew Lemoff
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xinchun Ran
- Departments of Chemistry, Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37232, USA
| | - Katrina L Richardson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Nicholas Pudlo
- Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Eric C Martens
- Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Ewa Folta-Stogniew
- Keck Foundation Biotechnology Resource Laboratory, Yale University, 300 George Street, New Haven, CT 06511, USA
| | - Zhongyue J Yang
- Departments of Chemistry, Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37232, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mariana X Byndloss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Walter J Chazin
- Departments of Biochemistry and Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA.
| | - Wenhan Zhu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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15
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Madhu B, Miller BM, Levy M. Single-cell analysis and spatial resolution of the gut microbiome. Front Cell Infect Microbiol 2023; 13:1271092. [PMID: 37860069 PMCID: PMC10582963 DOI: 10.3389/fcimb.2023.1271092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/11/2023] [Indexed: 10/21/2023] Open
Abstract
Over the past decade it has become clear that various aspects of host physiology, metabolism, and immunity are intimately associated with the microbiome and its interactions with the host. Specifically, the gut microbiome composition and function has been shown to play a critical role in the etiology of different intestinal and extra-intestinal diseases. While attempts to identify a common pattern of microbial dysbiosis linked with these diseases have failed, multiple studies show that bacterial communities in the gut are spatially organized and that disrupted spatial organization of the gut microbiome is often a common underlying feature of disease pathogenesis. As a result, focus over the last few years has shifted from analyzing the diversity of gut microbiome by sequencing of the entire microbial community, towards understanding the gut microbiome in spatial context. Defining the composition and spatial heterogeneity of the microbiome is critical to facilitate further understanding of the gut microbiome ecology. Development in single cell genomics approach has advanced our understanding of microbial community structure, however, limitations in approaches exist. Single cell genomics is a very powerful and rapidly growing field, primarily used to identify the genetic composition of microbes. A major challenge is to isolate single cells for genomic analyses. This review summarizes the different approaches to study microbial genomes at single-cell resolution. We will review new techniques for microbial single cell sequencing and summarize how these techniques can be applied broadly to answer many questions related to the microbiome composition and spatial heterogeneity. These methods can be used to fill the gaps in our understanding of microbial communities.
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Affiliation(s)
| | | | - Maayan Levy
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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16
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Penumutchu S, Korry BJ, Hewlett K, Belenky P. Fiber supplementation protects from antibiotic-induced gut microbiome dysbiosis by modulating gut redox potential. Nat Commun 2023; 14:5161. [PMID: 37620319 PMCID: PMC10449846 DOI: 10.1038/s41467-023-40553-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Antibiotic-induced gut dysbiosis (AID) is a frequent and serious side effect of antibiotic use and mitigating this dysbiosis is a critical therapeutic target. We propose that the host diet can modulate the chemical environment of the gut resulting in changes to the structure and function of the microbiome during antibiotic treatment. Gut dysbiosis is typically characterized by increases in aerobic respiratory bacterial metabolism, redox potential, and abundance of Proteobacteria. In this study, we explore dietary fiber supplements as potential modulators of the chemical environment in the gut to reduce this pattern of dysbiosis. Using defined-diets and whole-genome sequencing of female murine microbiomes during diet modulation and antibiotic treatment, we find that fiber prebiotics significantly reduced the impact of antibiotic treatment on microbiome composition and function. We observe reduced abundance of aerobic bacteria as well as metabolic pathways associated with oxidative metabolism. These metatranscriptomic results are corroborated by chemical measurements of eH and pH suggesting that fiber dampens the dysbiotic effects of antibiotics. This work indicates that fiber may act as a potential therapeutic for AID by modulating bacterial metabolism in the gut to prevent an increase in redox potential and protect commensal microbes during antibiotic treatment.
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Affiliation(s)
- Swathi Penumutchu
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, 02912, USA
| | - Benjamin J Korry
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, 02912, USA
| | - Katharine Hewlett
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Peter Belenky
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, 02912, USA.
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17
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Spiga L, Fansler RT, Perera YR, Shealy NG, Munneke MJ, Torres TP, David HE, Lemoff A, Ran X, Richardson KL, Pudlo N, Martens EC, Yang ZJ, Skaar EP, Byndloss MX, Chazin WJ, Zhu W. Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.25.546471. [PMID: 37425782 PMCID: PMC10326984 DOI: 10.1101/2023.06.25.546471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella , allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.
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18
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Kuhn T, Junier P, Bshary R, Terrettaz C, Gonzalez D, Richter XYL. Nutrients and flow shape the cyclic dominance games between Escherichia coli strains. Philos Trans R Soc Lond B Biol Sci 2023; 378:20210503. [PMID: 36934746 PMCID: PMC10024984 DOI: 10.1098/rstb.2021.0503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/08/2022] [Indexed: 03/20/2023] Open
Abstract
Evolutionary game theory has provided various models to explain the coexistence of competing strategies, one of which is the rock-paper-scissors (RPS) game. A system of three Escherichia coli strains-a toxin-producer, a resistant and a sensitive-has become a classic experimental model for studying RPS games. Previous experimental and theoretical studies, however, often ignored the influence of ecological factors such as nutrients and toxin dynamics on the evolutionary game dynamics. In this work, we combine experiments and modelling to study how these factors affect competition dynamics. Using three-dimensional printed mini-bioreactors, we tracked the frequency of the three strains in different culturing media and under different flow regimes. Although our experimental system fulfilled the requirements of cyclic dominance, we did not observe clear cycles or long-term coexistence between strains. We found that both nutrients and flow rates strongly impacted population dynamics. In our simulations, we explicitly modelled the release, removal and diffusion of toxin. We showed that the amount of toxin that is retained in the system is a simple indicator that can predict competition outcomes across broad parameter space. Moreover, our simulation results suggest that high rates of toxin diffusion might have prevented cyclic patterns from emerging in our experimental system. This article is part of the theme issue 'Half a century of evolutionary games: a synthesis of theory, application and future directions'.
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Affiliation(s)
- Thierry Kuhn
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
| | - Pilar Junier
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
| | - Redouan Bshary
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
| | - Céline Terrettaz
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
| | - Diego Gonzalez
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
| | - Xiang-Yi Li Richter
- Institute of Biology, University of Neuchâtel, Rue Emile-Argand 11, 2000 Neuchâtel, Switzerland
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19
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Pabst O, Hornef MW, Schaap FG, Cerovic V, Clavel T, Bruns T. Gut-liver axis: barriers and functional circuits. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00771-6. [PMID: 37085614 DOI: 10.1038/s41575-023-00771-6] [Citation(s) in RCA: 137] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2023] [Indexed: 04/23/2023]
Abstract
The gut and the liver are characterized by mutual interactions between both organs, the microbiome, diet and other environmental factors. The sum of these interactions is conceptualized as the gut-liver axis. In this Review we discuss the gut-liver axis, concentrating on the barriers formed by the enterohepatic tissues to restrict gut-derived microorganisms, microbial stimuli and dietary constituents. In addition, we discuss the establishment of barriers in the gut and liver during development and their cooperative function in the adult host. We detail the interplay between microbial and dietary metabolites, the intestinal epithelium, vascular endothelium, the immune system and the various host soluble factors, and how this interplay establishes a homeostatic balance in the healthy gut and liver. Finally, we highlight how this balance is disrupted in diseases of the gut and liver, outline the existing therapeutics and describe the cutting-edge discoveries that could lead to the development of novel treatment approaches.
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Affiliation(s)
- Oliver Pabst
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
| | - Mathias W Hornef
- Institute of Medical Microbiology, RWTH Aachen University, Aachen, Germany
| | - Frank G Schaap
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University, Aachen, Germany
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, RWTH Aachen University, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, RWTH Aachen University, Aachen, Germany
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20
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Cui Y, Wang H, Guo F, Cao X, Wang X, Zeng X, Cui G, Lin J, Xu F. Monoclonal antibody-based indirect competitive ELISA for quantitative detection of Enterobacteriaceae siderophore enterobactin. Food Chem 2022; 391:133241. [PMID: 35598389 DOI: 10.1016/j.foodchem.2022.133241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/18/2022] [Accepted: 05/15/2022] [Indexed: 12/16/2022]
Abstract
Enterobactin (Ent) is a promising indicator to monitor intestinal level of Enterobacteriaceae for assessment of gut inflammation. In this study, we developed a monoclonal antibody (mAb)-based ELISA for Ent quantification. We immunized mice with an Ent conjugate vaccine. An mAb named 2E4, with the highest anti-Ent antibody titer, was selected for developing indirect competitive ELISA (ic-ELISA). The purified mAb 2E4 showed high affinity (3.1 × 10-10 M) and specificity to Ent. The limit of detection of ic-ELISA was 0.39 μg/mL. The intra- and inter-assay recovery rates of standard curve were up to 94.6% with the coefficients of variation between 4.0% and 12.3%, indicating high accuracy, repeatability, and reproducibility of the ic-ELISA. In addition, the ic-ELISA was able to quantitatively detect Ent produced in different bacterial cultures. Collectively, this study developed an ic-ELISA with excellent performance in Ent quantification, laying a solid foundation for Ent-based diagnostics of gut health.
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Affiliation(s)
- Yifang Cui
- Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
| | - Huiwen Wang
- Department of Animal Science, The University of Tennessee, Knoxville, TN 37996, USA
| | - Fangfang Guo
- Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
| | - Xiaoya Cao
- Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
| | - Xue Wang
- Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China
| | - Ximin Zeng
- Department of Animal Science, The University of Tennessee, Knoxville, TN 37996, USA
| | - Guolin Cui
- College of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
| | - Jun Lin
- Department of Animal Science, The University of Tennessee, Knoxville, TN 37996, USA.
| | - Fuzhou Xu
- Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China.
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21
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Robinson CM, Short NE, Riglar DT. Achieving spatially precise diagnosis and therapy in the mammalian gut using synthetic microbial gene circuits. Front Bioeng Biotechnol 2022; 10:959441. [PMID: 36118573 PMCID: PMC9478464 DOI: 10.3389/fbioe.2022.959441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
The mammalian gut and its microbiome form a temporally dynamic and spatially heterogeneous environment. The inaccessibility of the gut and the spatially restricted nature of many gut diseases translate into difficulties in diagnosis and therapy for which novel tools are needed. Engineered bacterial whole-cell biosensors and therapeutics have shown early promise at addressing these challenges. Natural and engineered sensing systems can be repurposed in synthetic genetic circuits to detect spatially specific biomarkers during health and disease. Heat, light, and magnetic signals can also activate gene circuit function with externally directed spatial precision. The resulting engineered bacteria can report on conditions in situ within the complex gut environment or produce biotherapeutics that specifically target host or microbiome activity. Here, we review the current approaches to engineering spatial precision for in vivo bacterial diagnostics and therapeutics using synthetic circuits, and the challenges and opportunities this technology presents.
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Affiliation(s)
| | | | - David T. Riglar
- Section of Structural and Synthetic Biology, Department of Infectious Disease, Imperial College London, London, United Kingdom
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22
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Peña-Ocaña BA, Hoshiko Y, Silva-Flores M, Maeda T, Pérez-Torres I, García-Contreras R, Gutiérrez-Sarmiento W, Hernández-Esquivel L, Marín-Hernández Á, Sánchez-Thomas R, Saavedra E, Rodríguez-Zavala JS, Jasso-Chávez R. Cultivation of gastrointestinal microbiota in a new growth system revealed dysbiosis and metabolic disruptions in carcinoma-bearing rats. Front Microbiol 2022; 13:949272. [PMID: 36118191 PMCID: PMC9479207 DOI: 10.3389/fmicb.2022.949272] [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: 05/20/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
A challenge in the study of gastrointestinal microbiota (GITm) is the validation of the genomic data with metabolic studies of the microbial communities to understand how the microbial networks work during health and sickness. To gain insights into the metabolism of the GITm, feces from healthy and sick rats with cancer were inoculated in a defined synthetic medium directed for anaerobic prokaryote growth (INC-07 medium). Significant differences between cultures of healthy and sick individuals were found: 1) the consumption of the carbon source and the enzyme activity involved in their catabolism (e.g., sucrase, lactase, lipases, aminotransferases, and dehydrogenases); 2) higher excretion of acetic, propionic, isobutyric, butyric, valeric, and isovaleric acids; 3) methane production; 4) ability to form biofilms; and 5) up to 500 amplicon sequencing variants (ASVs) identified showed different diversity and abundance. Moreover, the bowel inflammation induced by cancer triggered oxidative stress, which correlated with deficient antioxidant machinery (e.g., NADPH-producing enzymes) determined in the GITm cultures from sick individuals in comparison with those from control individuals. Altogether, the data suggested that to preserve the microbial network between bacteria and methanogenic archaea, a complete oxidation of the carbon source may be essential for healthy microbiota. The correlation of 16S rRNA gene metabarcoding between cultures and feces, as well as metabolomic data found in cultures, suggest that INC-07 medium may be a useful tool to understand the metabolism of microbiota under gut conditions.
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Affiliation(s)
- Betsy Anaid Peña-Ocaña
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Yuki Hoshiko
- Division of Environment-Conscious Chemistry and Bioengineering, Department of Biological Functions Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | - Mayel Silva-Flores
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Toshinari Maeda
- Division of Environment-Conscious Chemistry and Bioengineering, Department of Biological Functions Engineering, Kyushu Institute of Technology, Kitakyushu, Japan
| | - Israel Pérez-Torres
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Rodolfo García-Contreras
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Wilbert Gutiérrez-Sarmiento
- Instituto Tecnológico Nacional de México/Instituto Tecnológico de Tuxtla Gutiérrez, Tuxtla Gutiérrez, Chiapas, Mexico
| | - Luz Hernández-Esquivel
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Álvaro Marín-Hernández
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Rosina Sánchez-Thomas
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Emma Saavedra
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | - Ricardo Jasso-Chávez
- Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- *Correspondence: Ricardo Jasso-Chávez
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Polyphenols–Gut–Heart: An Impactful Relationship to Improve Cardiovascular Diseases. Antioxidants (Basel) 2022; 11:antiox11091700. [PMID: 36139775 PMCID: PMC9495581 DOI: 10.3390/antiox11091700] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/30/2022] Open
Abstract
A healthy gut provides the perfect habitat for trillions of bacteria, called the intestinal microbiota, which is greatly responsive to the long-term diet; it exists in a symbiotic relationship with the host and provides circulating metabolites, hormones, and cytokines necessary for human metabolism. The gut–heart axis is a novel emerging concept based on the accumulating evidence that a perturbed gut microbiota, called dysbiosis, plays a role as a risk factor in the pathogenesis of cardiovascular disease. Consequently, recovery of the gut microbiota composition and function could represent a potential new avenue for improving patient outcomes. Despite their low absorption, preclinical evidence indicates that polyphenols and their metabolites are transformed by intestinal bacteria and halt detrimental microbes’ colonization in the host. Moreover, their metabolites are potentially effective in human health due to antioxidant, anti-inflammatory, and anti-cancer effects. The aim of this review is to provide an overview of the causal role of gut dysbiosis in the pathogenesis of atherosclerosis, hypertension, and heart failure; to discuss the beneficial effects of polyphenols on the intestinal microbiota, and to hypothesize polyphenols or their derivatives as an opportunity to prevent and treat cardiovascular diseases by shaping gut eubiosis.
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Loktionov A. Colon mucus in colorectal neoplasia and beyond. World J Gastroenterol 2022; 28:4475-4492. [PMID: 36157924 PMCID: PMC9476883 DOI: 10.3748/wjg.v28.i32.4475] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/23/2022] [Accepted: 08/06/2022] [Indexed: 02/06/2023] Open
Abstract
Little was known about mammalian colon mucus (CM) until the beginning of the 21st century. Since that time considerable progress has been made in basic research addressing CM structure and functions. Human CM is formed by two distinct layers composed of gel-forming glycosylated mucins that are permanently secreted by goblet cells of the colonic epithelium. The inner layer is dense and impenetrable for bacteria, whereas the loose outer layer provides a habitat for abundant commensal microbiota. Mucus barrier integrity is essential for preventing bacterial contact with the mucosal epithelium and maintaining homeostasis in the gut, but it can be impaired by a variety of factors, including CM-damaging switch of commensal bacteria to mucin glycan consumption due to dietary fiber deficiency. It is proven that impairments in CM structure and function can lead to colonic barrier deterioration that opens direct bacterial access to the epithelium. Bacteria-induced damage dysregulates epithelial proliferation and causes mucosal inflammatory responses that may expand to the loosened CM and eventually result in severe disorders, including colitis and neoplastic growth. Recently described formation of bacterial biofilms within the inner CM layer was shown to be associated with both inflammation and cancer. Although obvious gaps in our knowledge of human CM remain, its importance for the pathogenesis of major colorectal diseases, comprising inflammatory bowel disease and colorectal cancer, is already recognized. Continuing progress in CM exploration is likely to result in the development of a range of new useful clinical applications addressing colorectal disease diagnosis, prevention and therapy.
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A single respiratory tract infection early in life reroutes healthy microbiome development and affects adult metabolism in a preclinical animal model. NPJ Biofilms Microbiomes 2022; 8:51. [PMID: 35780244 PMCID: PMC9250495 DOI: 10.1038/s41522-022-00315-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 06/15/2022] [Indexed: 11/18/2022] Open
Abstract
In adult animals, acute viral infections only temporarily alter the composition of both respiratory and intestinal commensal microbiota, potentially due to the intrinsic stability of this microbial ecosystem. In stark contrast, commensal bacterial communities are rather vulnerable to perturbation in infancy. Animal models proved that disruption of a balanced microbiota development e.g., by antibiotics treatment early in life, increases the probability for metabolic disorders in adults. Importantly, infancy is also a phase in life with high incidence of acute infections. We postulated that acute viral infections in early life might pose a similarly severe perturbation and permanently shape microbiota composition with long-term physiological consequences for the adult host. As a proof of concept, we infected infant mice with a sub-lethal dose of influenza A virus. We determined microbiota composition up to early adulthood (63 days) from small intestine by 16S rRNA gene-specific next-generation sequencing. Infected mice underwent long-lasting changes in microbiota composition, associated with increase in fat mass. High-fat-high-glucose diet promoted this effect while co-housing with mock-treated animals overwrote the weight gain. Our data suggest that in the critical phase of infancy even a single silent viral infection could cast a long shadow and cause long-term microbiota perturbations, affecting adult host physiology.
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Sibinelli-Sousa S, de Araújo-Silva AL, Hespanhol JT, Bayer-Santos E. Revisiting the steps of Salmonella gut infection with a focus on antagonistic interbacterial interactions. FEBS J 2021; 289:4192-4211. [PMID: 34546626 DOI: 10.1111/febs.16211] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/12/2021] [Accepted: 09/20/2021] [Indexed: 12/20/2022]
Abstract
A commensal microbial community is established in the mammalian gut during its development, and these organisms protect the host against pathogenic invaders. The hallmark of noninvasive Salmonella gut infection is the induction of inflammation via effector proteins secreted by the type III secretion system, which modulate host responses to create a new niche in which the pathogen can overcome the colonization resistance imposed by the microbiota. Several studies have shown that endogenous microbes are important to control Salmonella infection by competing for resources. However, there is limited information about antimicrobial mechanisms used by commensals and pathogens during these in vivo disputes for niche control. This review aims to revisit the steps that Salmonella needs to overcome during gut colonization-before and after the induction of inflammation-to achieve an effective infection. We focus on a series of reported and hypothetical antagonistic interbacterial interactions in which both contact-independent and contact-dependent mechanisms might define the outcome of the infection.
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Affiliation(s)
| | | | - Julia Takuno Hespanhol
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil
| | - Ethel Bayer-Santos
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil
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