The gut microbiome can impact host metabolic health, partly due to diet-bacterial interactions that impinge on intestinal nutrient-sensing pathways. Similar to the ability of ingested nutrients to lower food intake via a gut-brain axis, small intestinal lipids can activate a gut-brain-liver neuronal axis to lower hepatic glucose production. High-fat (HF)-feeding abolishes the suppressive effects of small intestinal lipids on hepatic glucose production, which has recently been attributed to changes in the small intestinal gut microbiota. However, it is currently unknown if dietary fiber supplementation could restore nutrient-sensing mechanisms that regulate glucose homeostasis via changes in the gut microbiome. We hypothesized that HF-fed rats supplemented with oligofructose (OFS) would induce shifts in the small intestinal microbiota to restore expression of lipid sensors to improve gut peptide secretion and gut-brain signaling to reduce hepatic glucose production during a meal. To test this, we treated HF-fed rats acutely with OFS, and tested the ability of a small intestinal intralipid infusion to improve glucose tolerance or to lower hepatic glucose production during a euglycemic basal insulin glucose clamp. Additionally, using different approaches during the glucose clamp, we examined the role of the small intestinal microbiome, as well as intestinal CD36 and Glucagon-like peptide-2 (GLP-2) signaling in mediating the glucoregulatory role of intestinal lipid sensing. Lastly, utilizing intestinal organoids derived from either HF-fed mice with or without OFS supplementation, we explored the mechanisms by which GLP-2 improves nutrient sensing. We found that the OFS treatment restored the ability of small intestinal lipids to improve glucose tolerance and lower glucose production and demonstrated that this was likely due to shifts in the small intestinal microbiota. Our clamp studies demonstrated that CD36 signaling is necessary for intestinal lipids to lower glucose production as co-infusion of CD36 antagonist abolished the effect of intralipid infusion. Furthermore, by co-infusing either a GLP-2 agonist or antagonist, we found GLP-2 is sufficient to restore small intestinal lipid sensing to decrease glucose production, possibly via increased intestinal CD36 expression, and may be necessary for OFS-mediated improvements. Lastly, we were able to replicate in-vivo phenotypes in the organoid model, as HF-OFS mice had increased gut peptide secretion following lipid exposure compared to HF-mice organoids. Lastly, we found that while GLP-2 treatment had no direct effect on lipid sensing, GLP-2 is known to induce secretion of IGF-1, and IGF-1 treatment increased expression of nutrient sensors and slightly improved the HF-mice organoid GLP-1 secretion response to oleic acid treatment. Taken together, this work demonstrates that OFS treatment restores intestinal lipid sensing mechanisms that impact glucose homeostasis, possibly via a GLP-2 and IGF-1 dependent pathway. This work was supported by a New Investigator Award (ADHS17-00007401) from the Arizona Department of Health Services, Arizona Biomedical Research Commission (ABRC). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Orm et al. (Fri,) studied this question.