Cholera toxin remodels intestinal immunity and suppresses systemic metabolism

Cholera toxin (CTx) is a powerful enterotoxin and common mucosal adjuvant, yet the immediate host reaction to CTx, without any additional antigen, is unclear. To investigate this, researchers combined physiological and metabolic assessments with intestinal transcriptomics, epithelial imaging, immune profiling, liver gene-expression studies, and coordinated microbiome profiling in mice exposed to a single oral dose of CTx.

Within a mere 24 hours, CTx restructured the immune-cell makeup in both the epithelial and lamina propria regions, with the effects varying by sex and genetic makeup. This included a higher prevalence of group 3 innate lymphoid cells on the epithelial layer, a lower number of regulatory T cells in the lamina propria, and fewer epithelial ILC1/NK cells in males of both genetic backgrounds.

CTx also boosted the number of DCLK1+ tuft cells on the villi and lowered MUC2 expression. Analyzing the jejunal gene expression, researchers found an upsurge in inflammatory defensive, glycolytic, autophagy, and lipid-utilization activities, alongside a decrease in proliferative and mitochondrial activities – all indicative of a coordinated stress response.

These local modifications were paralleled by a swift reorganization of the fecal microbial population and a decline in systemic metabolism, regardless of the differences in hypothermic reactions across strains. CTx also triggered a specific hepatic stress and metabolic program, showing a consistent reduction of Cyp7a1 across all sexes and strains.

In summary, the study reveals that CTx, on its own, swiftly restructures the intestinal immune, epithelial, metabolic, and microbial conditions while simultaneously suppressing overall body metabolism. This provides a comprehensive framework for understanding the immediate response to CTx and interpreting its frequent use as a mucosal adjuvant.