Mutual reinforcement of pathophysiological host‐microbe interactions in intestinal stasis models

Abstract

Chronic diseases arise when there is mutual reinforcement of pathophysiological processes that cause an aberrant steady state. Such a sequence of events may underlie chronic constipation, which has been associated with dysbiosis of the gut. In this study we hypothesized that assemblage of microbial communities, directed by slow gastrointestinal transit, affects host function in a way that reinforces constipation and further maintains selection on microbial communities. In our study, we used two models – an opioid‐induced constipation model in mice, and a humanized mouse model where germ‐free mice were colonized with stool from a patient with constipation‐predominant irritable bowel syndrome (IBS‐C) in humans. We examined the impact of pharmacologically (loperamide)‐induced constipation (PIC) and IBS‐C on the structural and functional profile of the gut microbiota. Germ‐free (GF) mice were colonized with microbiota from PIC donor mice and IBS‐C patients to determine how the microbiota affects the host. PIC and IBS‐C promoted changes in the gut microbiota, characterized by increased relative abundance of Bacteroides ovatus and Parabacteroides distasonis in both models. PIC mice exhibited decreased luminal concentrations of butyrate in the cecum and altered metabolic profiles of the gut microbiota. Colonization of GF mice with PIC‐associated mice cecal or human IBS‐C fecal microbiota significantly increased GI transit time when compared to control microbiota recipients. IBS‐C‐associated gut microbiota also impacted colonic contractile properties. Our findings support the concept that constipation is characterized by disease‐associated steady states caused by reinforcement of pathophysiological factors in host‐microbe interactions.

Fecal imaging demonstrates that low-methoxyl pectin supplementation normalizes gastro-intestinal transit in mice given a liquid diet

“…), charcoal suspensions (Touw et al. ), and carmine red (Thys et al. ), mean GITT in mice measured by ICG imaging in the present study closely corresponded to previously reported values in mice.…”

Deletion of choline acetyltransferase in enteric neurons results in postnatal intestinal dysmotility and dysbiosis

“…Direct measurement of ChAT activity in homogenates of myenteric ganglia indicates that we achieved a reduction of .99% in ChAT-Null animals compared with WT littermates. The absence of a reduction of ChAT Additionally, using fecal microbiota transplant experiments and a model of loperamide-induced constipation, Touw et al (32) found that reduced motility altered the microbial community of the gut and that this resulted in a feed-forward loop whereby the slowed transit was exacerbated or maintained by microbial metabolites. In our study, WT and ChAT-Het animals had similar microbiota a and b diversity in both the colon and cecum, whereas only ChAT-Null animals displayed dysbiosis at both these sites.…”

The Gut Microbiome in Adult and Pediatric Functional Gastrointestinal Disorders

“…In turn, accelerated GI transit can alter the composition and spatial organization of microbial communities by creating luminal conditions suited for the growth of specific bacterial taxa or by affecting bacterial adherence 1 . Interestingly, GI motility related changes in the gut microbiome can further perpetuate the alteration in GI motility as a positive feedback effect 53 . Several microbial mediators ( Table 1 ) of GI motility have been identified ( Figure 3 ), including short chain fatty acids (SCFAs) and bile acids.…”

“…The findings suggest a potential role for gut microbiota in the pathogenesis of chronic constipation via increased expression of 5-HT transporter 158 . Interestingly, gut microbiota changes resulting from constipation can further impact GI motility, suggesting a more complex interaction with feedforward regulation rather than a simple cause-effect relationship 53 .…”