Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis

Pérez-Muñoz, María Elisa; Bergstrom, Kirk; Peng, Vincent; Schmaltz, Robert; Jimenez-Cardona, Roberto; Marsteller, Nathan L.; McGee, Sam; Clavel, Thomas; Ley, Ruth E.; Fu, Jianxin; Xia, Lijun; Peterson, Daniel A.

doi:10.4161/gmic.28622

Cited by 45 publications

(37 citation statements)

References 33 publications

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“…34,35 Similar findings were reported with mice deficient in fucosyltransferase 2 (Fut2) responsible for terminal fucosylaton of glycans, and the galactosyltransferase β4GalnT2 that forms the terminal Cad carbohydrate antigen. 36,37 The basis for this selection and whether glycan-mediated influences on microbiota composition reflect a dysbiotic community that potentiates colitis is unclear, although Fut2-deficiency has recently been linked to Crohn’s disease.…”

Section: Discussionsupporting

confidence: 64%

Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice

et al. 2017

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Core 1- and core 3-derived mucin-type O-glycans are primary components of the mucus layer in the colon. Reduced mucus thickness and impaired O-glycosylation are observed in human ulcerative colitis. However, how both types of O-glycans maintain mucus barrier function in the colon is unclear. We found that C1galt1 expression, which synthesizes core 1 O-glycans, was detected throughout the colon, whereas C3GnT, which controls core 3 O-glycan formation, was most highly expressed in the proximal colon. Consistent with this, mice lacking intestinal core 1-derived O-glycans (IEC C1galt1−/−) developed spontaneous colitis primarily in the distal colon, whereas mice lacking both intestinal core 1- and core 3-derived O-glycans (DKO) developed spontaneous colitis in both distal and proximal colon. DKO mice showed an early onset and more severe colitis than IEC C1galt1−/− mice. Antibiotic treatment restored the mucus layer and attenuated colitis in DKO mice. Mucins from DKO mice were more susceptible to proteolysis than WT mucins. This study indicates that core 1- and 3-derived O-glycans collectively contribute to the mucus barrier by protecting it from bacterial protease degradation and suggests new therapeutic targets to promote mucus barrier function in colitis patients.

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Section: Discussionsupporting

confidence: 64%

Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice

et al. 2017

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“…Even in the absence of pathogens, loss of O -linked glycans on mucin can lead to colitis associated with myeloid cell infiltration of the colonic lamina propria and increased TNF production (35). Colitis in mice lacking core 1-derived O -glycans was associated with increases in the frequency of Lactobacillus and Clostridium species and a decrease in bacteria belonging to the Ruminococcaceae and Lachnospiraceae families (177) (Figure 2). The development of colitis is associated with mucous layer penetration by luminal bacteria that are normally kept at a distance from epithelial cells and presumably also dendritic cells and mononuclear phagocytes inhabiting the underlying lamina propria (178).…”

Section: Autoimmunity Inflammatory Diseases and The Microbiotamentioning

confidence: 99%

Microbiota-Mediated Inflammation and Antimicrobial Defense in the Intestine

Caballero

Pamer²

2015

Annu. Rev. Immunol.

228

160

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The diverse microbial populations constituting the intestinal microbiota promote immune development and differentiation, but because of their complex metabolic requirements and the consequent difficulty culturing them, they remained, until recently, largely uncharacterized and mysterious. In the last decade, deep nucleic acid sequencing platforms, new computational and bioinformatics tools, and full-genome characterization of several hundred commensal bacterial species facilitated studies of the microbiota and revealed that differences in microbiota composition can be associated with inflammatory, metabolic, and infectious diseases, that each human is colonized by a distinct bacterial flora, and that the microbiota can be manipulated to reduce and even cure some diseases. Different bacterial species induce distinct immune cell populations that can play pro- and anti-inflammatory roles, and thus the composition of the microbiota determines, in part, the level of resistance to infection and susceptibility to inflammatory diseases. This review summarizes recent work characterizing commensal microbes that contribute to the antimicrobial defense/inflammation axis.

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“…Detrimental host effects associated with disrupted mucin glycosylation and bacterial degradation of host glycan structures are beginning to emerge as well. Studies using mouse models that lack normal mucin expression or glycosylation have observed spontaneous colonic inflammation or increased susceptibility to inflammatory agents, including individual bacteria ( 18 – 21 ), raising the possibility that microbe-catalyzed alterations to mucus could also be harmful. This notion is supported by findings in humans with ulcerative colitis, which show that O -glycosylation patterns are simpler in people with active disease versus the same patients during remission ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Symbiotic Human Gut Bacteria with Variable Metabolic Priorities for Host Mucosal Glycans

Pudlo

Urs

Kumar

et al. 2015

mBio

162

154

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Many symbiotic gut bacteria possess the ability to degrade multiple polysaccharides, thereby providing nutritional advantages to their hosts. Like microorganisms adapted to other complex nutrient environments, gut symbionts give different metabolic priorities to substrates present in mixtures. We investigated the responses of Bacteroides thetaiotaomicron, a common human intestinal bacterium that metabolizes more than a dozen different polysaccharides, including the O-linked glycans that are abundant in secreted mucin. Experiments in which mucin glycans were presented simultaneously with other carbohydrates show that degradation of these host carbohydrates is consistently repressed in the presence of alternative substrates, even by B. thetaiotaomicron previously acclimated to growth in pure mucin glycans. Experiments with media containing systematically varied carbohydrate cues and genetic mutants reveal that transcriptional repression of genes involved in mucin glycan metabolism is imposed by simple sugars and, in one example that was tested, is mediated through a small intergenic region in a transcript-autonomous fashion. Repression of mucin glycan-responsive gene clusters in two other human gut bacteria, Bacteroides massiliensis and Bacteroides fragilis, exhibited variable and sometimes reciprocal responses compared to those of B. thetaiotaomicron, revealing that these symbionts vary in their preference for mucin glycans and that these differences occur at the level of controlling individual gene clusters. Our results reveal that sensing and metabolic triaging of glycans are complex processes that vary among species, underscoring the idea that these phenomena are likely to be hidden drivers of microbiota community dynamics and may dictate which microorganisms preferentially commit to various niches in a constantly changing nutritional environment.

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Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis

Cited by 45 publications

References 33 publications

Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice

Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice

Microbiota-Mediated Inflammation and Antimicrobial Defense in the Intestine

Symbiotic Human Gut Bacteria with Variable Metabolic Priorities for Host Mucosal Glycans

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