A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility

Desai, Mahesh S.; Seekatz, Anna M.; Koropatkin, Nicole M.; Kamada, Nobuhiko; Hickey, Christina; Wolter, Mathis; Pudlo, Nicholas A.; Kitamoto, Sho; Terrapon, Nicolas; Muller, Arnaud; Young, Vincent B.; Henrissat, Bernard; Wilmes, Paul; Stappenbeck, Thaddeus S.; Núñez, Gabriel; Martens, Eric C.

doi:10.1016/j.cell.2016.10.043

Cited by 2,148 publications

(2,242 citation statements)

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“…27,28 Exogenous perturbations may upset this balance further to induce acute disease pathogenesis. Such perturbations include withdrawal of dietary fiber (e.g.…”

Section: Resultsmentioning

confidence: 99%

TheBacteroides fragilispathogenicity island links virulence and strain competition

et al. 2017

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The mature microbiome is a stable ecosystem that resists perturbation despite constant host exposure to exogenous microbes. However, the microbial mechanisms determining microbiome development and composition are poorly understood. We recently demonstrated that a nontoxigenic B. fragilis (NTBF) strain restricts enteric colonization by an enterotoxigenic (ETBF) strain dependent on a type VI secretion system (T6SS). We show here that a second enterotoxigenic strain is competent to colonize, dependent on the Bacteroides fragilis pathogenicity island (BFPAI). Additional data showing complex environmental regulation of the Bacteroides fragilis toxin (BFT) suggest that virulence factors may be adapted to modify the colonic niche to provide a strainspecific colonization advantage. We conclude that more complex models of host-microbemicrobiome interactions are needed to investigate this hypothesis.

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“…27,28 Exogenous perturbations may upset this balance further to induce acute disease pathogenesis. Such perturbations include withdrawal of dietary fiber (e.g.…”

Section: Resultsmentioning

confidence: 99%

TheBacteroides fragilispathogenicity island links virulence and strain competition

et al. 2017

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“…In contrast to Streptococcus, Akkermansia, Bacteroides, and other bacterial genera that have an extensive repertoire of enzymes devoted to catabolizing host-associated glycoproteins in the gut and oral cavity (24,(37)(38)(39)(40), the primary CF pathogen, P. aeruginosa, is not known to encode any glycosidases used in the breakdown of respiratory mucins. Indeed, we demonstrate here that strain PA14 uses intact mucins inefficiently compared to its carbohydrate and amino acid monomeric constituents (glucose and Casamino Acids).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, all mucosal sites throughout the human body harbor both commensal and pathogenic organisms that possess mucin-degrading enzymes capable of deriving nutrients from host (22)(23)(24). Indeed, several studies have described the degradation and utilization of mucins by CF-associated microbiota (25)(26)(27)(28)(29).…”

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confidence: 99%

Genome-Wide Survey of Pseudomonas aeruginosa PA14 Reveals a Role for the Glyoxylate Pathway and Extracellular Proteases in the Utilization of Mucin

2017

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Chronic airway infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. Although this bacterium has been extensively studied for its virulence determinants, biofilm growth, and immune evasion mechanisms, comparatively little is known about the nutrient sources that sustain its growth in vivo. Respiratory mucins represent a potentially abundant bioavailable nutrient source, although we have recently shown that canonical pathogens inefficiently use these host glycoproteins as a growth substrate. However, given that P. aeruginosa, particularly in its biofilm mode of growth, is thought to grow slowly in vivo, the inefficient use of mucin glycoproteins may be relevant to its persistence within the CF airways. To this end, we used whole-genome fitness analysis, combining transposon mutagenesis with high-throughput sequencing, to identify genetic determinants required for P. aeruginosa growth using intact purified mucins as a sole carbon source. Our analysis reveals a biphasic growth phenotype, during which the glyoxylate pathway and amino acid biosynthetic machinery are required for mucin utilization. Secondary analyses confirmed the simultaneous liberation and consumption of acetate during mucin degradation and revealed a central role for the extracellular proteases LasB and AprA. Together, these studies describe a molecular basis for mucin-based nutrient acquisition by P. aeruginosa and reveal a host-pathogen dynamic that may contribute to its persistence within the CF airways.KEYWORDS cystic fibrosis, glyoxylate pathway, mucin, Pseudomonas aeruginosa, TnSeq C ystic fibrosis (CF), a common and lethal autosomal recessive disease, results from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein (1). Impaired CFTR function leads to abnormal transepithelial ion transport and a thickened, dehydrated mucus layer that overlays the epithelium of several organs, including the lungs (2, 3). Within the airways, defective mucociliary clearance facilitates chronic colonization by a complex bacterial community, and the ensuing inflammatory response leads to bronchiectasis, progressive lung damage, and eventual respiratory failure in a majority of CF patients (2). Despite the recent surge in studies describing a polymicrobial etiology of CF, Pseudomonas aeruginosa continues to be widely recognized as the primary driver of disease progression (4). This opportunistic pathogen can reach densities of 10 7 to 10 9 CFU/g of sputum, particularly in late stages of disease, suggesting that the mucus environment of the lower airways provides the bacterium an ideal growth environment (5, 6). A deeper understanding of this milieu, and its ability to sustain P. aeruginosa growth in vivo is critically important for improved disease management.The mucosal layer covering the respiratory epithelium is a complex mixture of water,

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“…A recent study, using a simplified model of the human gut microbiome in gnotobiotic mice, found that low dietary intake of fibre increased the susceptibility of colitis by reducing the mucus layer [63]. Mice colonised with the simplified model of the human gut microbiome were fed a fibrerich or fibre-free diet.…”

Section: Diet Low In Fibre Confers Susceptibility For Colitismentioning

confidence: 99%

Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease

Andersen¹,

Hansen²,

Heitmann³

2017

Preprint

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Abstract:We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies for such investigations. PubMed was searched using specified search terms. One small prospective study on diet and anti-TNF treatment in 56 patients with CD found similar remission rates after 56 weeks among 32 patients with good compliance that received concomitant enteral nutrition and 24 with poor compliance that had no dietary restrictions (78% versus 67%, p = 0.51). A meta-analysis of 295 patients found higher odds of achieving clinical remission and remaining in clinical remission among patients on combination therapy with specialised enteral nutrition and Infliximab (IFX) compared with IFX monotherapy (OR 2.73; 95% CI: 1.73-4.31, p < 0.01, OR 2.93; 95% CI: 1.66-5.17, p < 0.01, respectively). In conclusion, evidence-based knowledge on impact of diet on anti-TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in observational, animal and interventional studies are warranted.

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A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility

Cited by 2,148 publications

References 51 publications

TheBacteroides fragilispathogenicity island links virulence and strain competition

TheBacteroides fragilispathogenicity island links virulence and strain competition

Genome-Wide Survey of Pseudomonas aeruginosa PA14 Reveals a Role for the Glyoxylate Pathway and Extracellular Proteases in the Utilization of Mucin

Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease

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