Sep 13, 2017 - Matthieu Million, Julie Tomas, Camille Wagner, Hugues Lelouard, ...... Lee SM, Donaldson GP, Mikulski Z, Boyajian S, Ley K, Mazmanian SK.
Accepted Manuscript New Insights in Gut Microbiota and Mucosal Immunity of the Small Intestine Matthieu Million, Julie Tomas, Camille Wagner, Hugues Lelouard, Didier Raoult, Jean-Pierre Gorvel PII: DOI: Reference:
S2452-2317(17)30019-2 https://doi.org/10.1016/j.humic.2018.01.004 HUMIC 34
To appear in:
Human Microbiome Journal
Received Date: Accepted Date:
13 September 2017 8 January 2018
Please cite this article as: M. Million, J. Tomas, C. Wagner, H. Lelouard, D. Raoult, J-P. Gorvel, New Insights in Gut Microbiota and Mucosal Immunity of the Small Intestine, Human Microbiome Journal (2018), doi: https:// doi.org/10.1016/j.humic.2018.01.004
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New Insights in Gut Microbiota and Mucosal Immunity of the Small Intestine Matthieu MILLION1,2, Julie TOMAS2, Camille WAGNER2, Hugues LELOUARD2, Didier RAOULT1, Jean-Pierre GORVEL2 1
URMITE, Aix Marseille Université, UM63, Centre National de la Recherche Scientifique
7278, IRD 198, Institut National de la Santé Et de la Recherche Médicale 1095, IHU— Méditerranée Infection, Marseille, France 2
Centre d’Immunologie de Marseille-Luminy, CIML, Aix Marseille Univ, CNRS, INSERM,
Marseille, France. Keywords: mucosal immunity, gut microbiota, oxidative stress, nutrition, Peyer’s patches Abstract word count: 199 Body text count: 4,744 Running head: Oxidative stress, gut microbiota and immunity
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Abstract Beyond host genetics, the environment determines microbiota-immunity interactions. Most recent studies have focused on the interconnections between micronutrients, microbial and immune populations. However, the control of the gut oxidative stress and redox status has been neglected. Oxidative stress sensitive (Ox-S) prokaryotes include butyrate producers and minority mucosa-associated immunogenic symbionts, such as specific Lactobacillus strains, Bifidobacterium adolescentis, and segmented filamentous bacteria which exemplify the mucosal “minority report” paradigm. Butyrate, produced by Lachnospiraceae, Ruminococcaceae and Bacteroidetes, is the main microbiota-derived gut mucosal immunity regulator and the best functional marker of the healthy mature anaerobic gut microbiota (HMAGM). Oxidative stress during the “window of opportunity” around weaning is observed in severe acute malnutrition and results in Ox-S prokaryote depletion, HMAGM disruption, collapse of butyrate production and durable gut mucosal immunity alteration. High saturatedfat diet leads to oxidative stress, selection of oxidative stress-resistant (Ox-R) Lactobacillus reuteri strains in Peyer’s patches, secretion of pro-inflammatory cytokines, disruption of mucosal immune compartmentalization (leaky gut) and obesity. Beyond dietary micronutrient diversity and pathogen control, future research should focus on antioxidants, control of oxidative stress and Ox-S gut prokaryote preservation as new instrumental targets for maintenance of the gut microbiota-immunity symbiotic loop and prevention of malnutrition and obesity.
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Abbreviations CCF: commensal colonization factor DC: dendritic cells EOS: extremely oxygen sensitive prokaryotes GF: germ free HF: high saturated-fat diet HMAGM: healthy mature anaerobic gut microbiota IFR: interfollicular region ILC: innate lymphoid cells IgA: immunoglobulin A LRC: lymphoid tissue-resident commensal bacteria NOD: nucleotide oligomerization domain receptor Ox-R: oxidative stress resistance Ox-S: oxidative stress sensitivity PP: Peyer’s patches PRRs: pattern recognition receptors SFB: segmented filamentous bacteria (Candidatus Arthromitus) Th cells: T-helper cells TLR: toll-like receptor Treg: regulatory T cells
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Introduction: The immune system: from pathogen recognition and killing to the microbiota-immunity symbiotic loop Microbes and humans are not indifferent neighbors, but have cohabited and coevolved for a few million years in a well-balanced mutualism (1). Host genetics influences the microbiota via host immunity regulation and barrier defense (2, 3). Compartmentalization is the main process of “immunity” in maintaining the host’s integrity, organized with walls, interfaces, firewalls, and several cell populations specialized in microorganism interactions (4). This stringent immune compartmentalization results in an absence of systemic response, called systemic immune ignorance, which is beneficial for the host (4). The fact that the gut is a closed compartment allows the active maintenance of anoxic areas (strongly reduced environment) (5) and this has a dramatic impact on its microbial content (6). The succession of aerobic, facultative anaerobes, anaerobes and extremely oxygen sensitive (EOS) bacteria, along with gut maturation, is associated with a decreasing, from positive to negative, redox potential (Eh, in mV) in the gut (7). In this review, we call all prokaryotes destroyed or inhibited by oxidative stress as oxidative stress-sensitive (Ox-S), including anaerobes and EOS. Prokaryotes with effective systems to deal with oxidative stress (notably catalase, superoxide dismutase) were called oxidative stress-resistant (Ox-R). Indeed, our previous work suggests a critical link between oxidative stress and gut microbiota alteration, according to the oxidative stress resistance of each gut microbe (6, 8). In animals, a diet containing antioxidants lowers gut redox potential, controls oxidative stress and increases Bifidobacterium (strict anaerobe), while decreasing Escherichia coli (facultative anaerobe) in the jejunum, ileum and colon (9-11). This suggests that gut maturation includes a decrease in redox potential, oxygen pressure, and free radical concentration, allowing the rise and emergence of Ox-S prokaryote populations that may be critical in immune development, maintenance and regulation.
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The gut includes very different anatomical segments, and germ-free models suggest that the gut microbiota shapes both the gut mucosal immune system and the systemic immune system. However, we have focused this review on the recent findings on the gut microbiota and mucosal immunity in the small intestine, because this organ is particularly relevant for health and disease (12) and for microbiota-immunity interactions. Indeed, Peyer’s patches (PP), the main gut mucosal immune system inductor sites, are specifically found in the small intestine, and immunoglobulin A (IgA), the main gut mucosal immune effector, predominantly targets commensal bacteria that reside in the small intestine (13).
1.
Gut mucosal immunity
1.1. Immunoglobulin A is mainly induced by microbes of the small intestine To date, physicians have no marker to diagnose trouble in the gut microbiota – mucosal immunity interaction. IgA-producing B cells and IgA itself are markers of the intensity of the mucosal immunity – gut microbiota interaction. The IgA index, which can be evaluated by the ratio of bacteria coated with IgA compared to bacteria not coated by IgA (IgA+/IgA- ratio or proportion of IgA+/all bacteria), is therefore a measurable marker representing the intensity of the gut microbiota – mucosal immunity interaction. For instance, the fecal IgA index is particularly increased in inflammatory bowel disease associated with gut dysbiosis, such as in Crohn's disease or ulcerative colitis (14). The IgA index is high in the small intestine (4060%), but low in the colon (
