Dietary butyrate improves colonic mucosal homeostasis under HFD feeding, accompanied by gut microbial remodeling and increased colonic IAA levels; together with the PPARγ-dependent epithelial response to IAA in Caco-2 cells, these findings suggest a potential mechanistic framework linking butyrate-associated microbial changes, IAA metabolism, and epithelial PPARγ signaling.
Dietary sodium butyrate improved multiple colonic barrier-associated parameters in HFD-fed APOE*3-Leiden.CETP mice.
Dietary butyrate reduced body weight gain and fat mass accumulation and improved glucose metabolism in HFD-fed mice.
Fecal microbiota transplantation from butyrate-treated donors partially reproduced the beneficial effects in HFD-fed recipients.
Metagenomic analysis showed butyrate enriched Bacteroidota and Bacteroides, particularly B. uniformis and B. thetaiotaomicron, accompanied by increased colonic IAA levels.
In Caco-2 cells, IAA increased expression of PPARγ, Reg4, and CLDN2.
PPARγ mediates IAA-induced REG4 and CLDN2 upregulation in Caco-2 cells.
The findings suggest a potential mechanistic framework linking butyrate-associated microbial changes, IAA metabolism, and epithelial PPARγ signaling.
This study asked how butyrate, a short-chain fatty acid made by gut bacteria and available as a supplement, might protect the gut lining in mice fed a high-fat diet. Mice that received 5% sodium butyrate in their high-fat diet had healthier colon structure, lower blood levels of a bacterial toxin (LPS), less inflammation-related gene activity, and higher levels of genes tied to gut barrier function. They also gained less weight and body fat and handled glucose better. Transferring gut bacteria from butyrate-treated mice to other mice partly reproduced the benefits, suggesting that changes in gut microbes contribute. Butyrate increased certain Bacteroides species and raised colon levels of indole-3-acetic acid (IAA), a microbial compound. In human colon-derived cells (Caco-2), IAA boosted PPARγ and barrier-related genes REG4 and CLDN2, and these effects were reduced when PPARγ was knocked down, pointing to PPARγ as a mediator. This research suggests a possible pathway from butyrate to microbes to IAA to PPARγ signaling in gut lining cells. However, the work was done in mice and cell lines, the FMT effect was only partial, and the pathway is described as a potential framework, so it does not show that the same effects would occur in people.
Li G, Dong S, Liu C, Yan H, Yang J, Rensen P, et al.. (2026). Dietary butyrate alleviates high-fat diet-induced colonic mucosal impairment accompanied by increased gut-derived indole-3-acetic acid and enhanced PPARγ signaling.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1971187