Scientists discover how gut bacteria “train” the intestine to fight inflammation

New Northwestern Medicine research published in Nature Communications suggests that a substance produced by gut bacteria when they digest dietary fiber may leave a durable molecular imprint on intestinal cells. This imprint appears to promote immune tolerance and could protect against inflammatory bowel disease-like conditions even after the metabolite has left the system.

Yingzi Cong, PhD, the Stanley Gradowski Professor of Gastroenterology and a professor of Microbiology-Immunology and of Pathology, led the study along with Tianming Yu, PhD, a research assistant professor of Medicine in the Division of Gastroenterology and Hepatology.

Short-chain fatty acids (SCFAs), produced by gut bacteria during dietary fiber fermentation, are known to have anti-inflammatory effects. However, much of the butyrate generated by gut bacteria is absorbed and metabolized by intestinal epithelial cells, which limits the amount of free butyrate that can reach immune cells. This led the researchers to wonder if butyrate might act indirectly through these epithelial cells to regulate intestinal immunity.

To test this idea, the team administered butyrate to mice through their drinking water and then stopped the treatment. Two weeks later, even without continuous butyrate exposure, CD4+ T-cells in the treated mice continued to produce elevated levels of IL-10, an anti-inflammatory cytokine that helps control inflammation. The treated animals also showed greater resistance to chemically induced colitis compared to untreated mice.

This protective effect remained even in germ-free mice, suggesting that butyrate can create a lasting immune-regulating environment independent of continuous microbial stimulation.

Further experiments indicated that intestinal epithelial cells (IECs) exposed to butyrate induce a sustained immunoregulatory response, raising IL-10 production in both mouse and human T-cells. The researchers identified N1-acetylspermidine as a likely molecule contributing to this effect, as it increased IL-10 production in T-cells and contributed to the immune-regulating activity of butyrate-treated IECs.

Mechanistically, butyrate activates IECs to induce sustained transcriptional and epigenetic changes in an enzyme called Sat1, which promotes production of N1-acetylspermidine. This metabolite helps explain the long-lasting impact of butyrate on intestinal immune tolerance.