Rapamycin extenuates experimental colitis by modulating the gut microbiota.

Background and Aim: Autophagy and gut microbiota correlates closely with the inflammatory bowel disease. Herein, we aimed to study the roles of rapamycin on the gut microbiota in inflammatory bowel disease.
Methods: Acute colitis was induced with dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzenesulfonic acid solution in mice. Mice were administered with rapamycin or hydroxychloroquine. Weight loss, disease activity index scores, histopathological score, serum inflammatory cytokines, intestinal permeability, and colonic autophagy-related proteins were detected. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following the 16S DNA sequencing. The antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between autophagy activation and gut microbiota.
Results: Compared with the control group, the colonic autophagy-related proteins of P62, mTOR, and p-mTOR increased significantly, while the levels of LC3B and ATG16L1 decreased (all P < 0.05) in the model group. After rapamycin intervention, the colonic pathology of mice improved, while the disease activity index score decreased substantially; the colon length increased, and the expression of IL-6 and TNF-α decreased. Following hydroxychloroquine treatment, some indicators suggested aggravation of colitis. Principal coordinates analysis showed that the DSS group was located on a separate branch from the rapamycin group but was closer to the hydroxychloroquine group. Compared with the DSS group, the rapamycin group was associated with higher abundances of f&#95;Lactobacillaceae (P = 0.0151), f&#95;Deferribacteraceae (P = 0.0290), g&#95;Lactobacillus (P = 0.0151), g&#95;Mucispirillum (P = 0.0137), s&#95;Lactobacillus&#95;reuteri (P = 0.0028), and s&#95;Clostridium&#95;sp&#95;Culture&#95;Jar-13 (P = 0.0082) and a lower abundance of s&#95;Bacteroides&#95;sartorii (P = 0.0180). Linear discriminant analysis effect size showed that rapamycin increased the abundances of Lactobacillus-reuteri, Prevotellaceae, Paraprevotella, Christensenella and Streptococcus and decreased those of Peptostreptococcaceae and Romboutsia Bacteroides-sartorii. Besides, the improvement effect of autophagy activation on colitis disappears following gut microbiome depletion.
Conclusion: The therapeutic effects of rapamycin on extenuating experimental colitis may be related to the gut microbiota.
(© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)