Indole compounds produced by gut microbiota after metabolizing tryptophan improve dysmotility in sepsis via the AHR-TRPA1 axis in enteric nerves.

BACKGROUND

Sepsis represents a major global health challenge, and the resulting impaired intestinal motility can lead to numerous adverse outcomes. Indole compounds produced by gut microbiota after metabolizing tryptophan may improve sepsis-induced intestinal dysmotility, though the underlying mechanism remains unclear. Here, we explored the role of 6-formylindolo[3,2-b]carbazole (FICZ), a gut-derived metabolite of tryptophan, in improving dysmotility in sepsis. We found that FICZ-activated aryl hydrocarbon receptor (AHR) on the Enteric Nervous System (ENS) may represent a future therapeutic target for treating dysmotility in sepsis.

METHODS

Five days post-fertilization (5dpf) zebrafish underwent intraperitoneal microinjection of Escherichia coli to induce sepsis. Subsequently, zebrafish were treated with varying concentrations of FICZ and Tol-huc-AHR1a overexpression plasmids. Primary methodologies included micro-filming for intestinal motility observation, immunofluorescence for detecting intestinal motility function-related indicators, and PCR for gene-level analysis. Key endpoints included intestinal peristalsis frequency, neutrophil infiltration, smooth muscle contractility, NO levels, and expression levels of AHR1a, AHR2, TRPA1b, and relevant inflammatory genes.

RESULTS

In septic zebrafish, FICZ reduced intestinal neutrophil infiltration, restored intestinal smooth muscle strength, increased intestinal peristalsis frequency, and enhanced the expression of intestinal AHR1a, AHR2, and transient receptor potential ankyrin 1b(TRPA1b) genes. Overexpression of the AHR1a gene in septic zebrafish reduced the production of the inhibitory neurotransmitter NO by restoring TRPA1b expression in the intestine, thereby restoring intestinal motility. It also restored the low expression level of inflammatory genes in immunocompromised septic zebrafish.

CONCLUSION

The gut microbial metabolite indole improved sepsis-induced intestinal dysmotility via the AHR-TRPA1 axis. AHR may be a future therapeutic target for treating the immunosuppressive state associated with sepsis.