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Enterochromaffin cells act as intestinal signal integration hubs for microbial metabolites

ABSTRACT: The intestinal epithelium senses and responds to the myriad of signals from gut microbiota, but it remains unclear how these signals are integrated to drive physiological responses. In this work, we found that enterochromaffin (EC) cells in the gut serve as signal integration hubs for microbial metabolites. EC cells coordinate responses to combinations of microbial metabolites, resulting in complex alterations in serotonin signaling that drive changes in GI physiology. We found that microbial metabolites either directly trigger responses or alter the expression of receptors for other microbial metabolites in EC cells. The microbiota-derived purine derivative hypoxanthine triggers a signaling pathway by activating G-protein coupled receptor A1R, which in turn activates the calcium channel TRPC4, resulting in increased serotonin release and accelerated GI transit. On the other hand, bacteria-derived butyrate does not evoke EC cell calcium influx by itself, but drives epigenetic changes that upregulate TRPC4 expression, thereby enhancing response to metabolites like hypoxanthine and norepinephrine that act via TRPC4. Since the expression TRPC4 is limited to EC cells, these cells function as specialized epithelial sensors that integrate signals from regulatory (butyrate) and effector metabolites like hypoxanthine and norepinephrine. These findings offer new microbiota-driven therapeutic avenues for conditions associated with altered GI function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286305 | GEO | 2025/02/10

REPOSITORIES: GEO

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Project description:Chronic diseases arise when pathophysiological processes achieve a steady state by self-reinforcing. Here, we explored the possibility of a self-reinforcement state in a common condition, chronic constipation, where alterations of the gut microbiota have been reported. The functional impact of the microbiota shifts on host physiology remains unclear, however we hypothesized that microbial communities adapted to slow gastrointestinal transit affect host functions in a way that reinforces altered transit, thereby maintaining the advantage for microbial self-selection. To test this, we examined the impact of pharmacologically (loperamide)-induced constipation (PIC) on the structural and functional profile of altered gut microbiota. PIC promoted changes in the gut microbiome, characterized by decreased representation of butyrate-producing Clostridiales, decreased cecal butyrate concentration and altered metabolic profiles of gut microbiota. PIC-associated gut microbiota also impacted colonic gene expression, suggesting this might be a basis for decreased gastrointestinal (GI) motor function. Introduction of PIC-associated cecal microbiota into germ-free (GF) mice significantly decreased GI transit time. Our findings therefore support the concept that chronic diseases like constipation are caused by disease-associated steady states, in this case, caused by reciprocating reinforcement of pathophysiological factors in host-microbe interactions. We used microarrays to detail the global gene expression profile in the proximal colon smooth muscle tissues of germ-free, conventionalized, or specific pathogen free mouse C57Bl/6 female and male specific pathogen free (SPF) mice were bred and housed in the animal care facility at the University of Chicago. Mice of 8–10 weeks of age were treated with 0.1% loperamide in the drinking water for 7 days. Age matched, germ-free (GF) C57Bl/6 mice were gavaged orally with cecal luminal contents harvested from control or loperamide-treated C57Bl/6 donor mice. Recipient mice were sacrificed 4 weeks post-colonization.

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Enterochromaffin cells act as intestinal signal integration hubs for microbial metabolites

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