Bacterial constipation: Mucin-degrading intestinal commensal bacteria cause constipation

The contribution of gut microbes to constipation remains mechanistically underexplored, despite constipation being one of the most prevalent gastrointestinal disorders. Here, we identify cooperative induction of constipation by two mucin-degrading gut commensals: <i>Akkermansia muciniphila</i> and <i>Bacteroides thetaiotaomicron</i>. In constipated patients with Parkinson's disease (PD) and chronic idiopathic constipation (CIC), we observed that <i>A. muciniphila</i> and <i>B. thetaiotaomicron</i> were increased. Gnotobiotic mice colonized with either bacterium exhibited no constipation, whereas mice co-colonized with both bacteria developed constipation. Fecal mucins but not gastric mucins carry terminal sulfates. As fecal transcriptome of gnotobiotic mice suggested a sulfatase-dependent mechanism, we generated an anaerobic sulfatase-maturating enzyme (anSME)-deficient <i>B. thetaiotaomicron</i> strain that cannot catabolize the terminal sulfates of mucins. In the absence of anSME, constipation was ameliorated in co-colonized gnotobiotic mice. The synergic effect of the two bacteria is in accordance with our observation that <i>A. muciniphila</i> alone and constipation are not correlated in humans. As a bunch of intestinal bacteria other than <i>B. thetaiotaomicron</i> also catabolize mucin sulfates, they may substitute for <i>B. thetaiotaomicron</i> in patients with constipation. We propose bacterial constipation, in which cooperative degradation of colonic mucins by sulfatases and glycosylases by two commensal bacteria reduces lubrication and induces fecal dehydration, leading to the development of constipation. Targeting microbial sulfatase activity may be a promising therapeutic approach for patients with bacterial constipation.