Lactobacillus reuteri attenuates chronic diarrhea by modulating microbiota homeostasis and macrophage polarization through the cGAS/STING pathway dependent on D-lactate-mediated mitochondrial function.

Chronic diarrhea (CD) severely affects patients' quality of life and is linked to ulcerative colitis, inflammatory bowel disease, and colorectal cancer. Gut microbiota dysbiosis plays a crucial role in intestinal health, with Lactobacillus reuteri emerging as a key regulator. However, its role in chronic diarrhea remains unclear. In this study, we observed macaques with spontaneous diarrhea and investigated microbial and metabolic changes. We also developed a chronic diarrhea mouse model using dextran sulfate sodium. CD group of both models revealed a significant reduction of L. reuteri. L. reuteri transplantation alleviates intestinal injury in CD by secreting D-lactate and modulates macrophage polarization. L. reuteri-derived D-lactate binds to IARS2 in intestinal epithelial macrophages, reducing mitochondrial IARS2 activation and suppressing cGAS-STING pathway activation. This preserves mitochondrial function while decreasing M1 macrophage polarization. Our research revealed the significance of microbiota dysbiosis in CD with both non-human primate and murine model, and highlighted the critical role of L. reuteri, which is conducted with D-lactate-mediated modulation of macrophage function and offered new insights into probiotic therapy for CD.