The gut microbiome contributes to host health and has therapeutic potential to treat metabolic disease. A newer class of lipids, PAHSAs, have antidiabetic effects in high-fat diet (HFD)-fed mice. We aimed to determine whether the gut microbiome contributes to the beneficial metabolic effects of PAHSAs and if these effects are transmissible by Fecal Microbiota Transplantation (FMT) in mice. In HFD-fed germ-free (GF) mice, PAHSA treatment for 35 days did not improve glucose homeostasis vs. vehicle-treated mice, in contrast to previous data in conventional HFD mice. Feces from conventional Chow fed mice with enhanced insulin sensitivity after PAHSA treatment for 21 days were used for oral FMT in HFD-GF mice. HFD-GF mice treated with feces from PAHSA-treated chow mice gained less weight, had reduced glycemia 5-hrs after food removal, and were more glucose tolerant and insulin sensitive than HFD-GF-mice that received feces from vehicle-treated Chow mice. Metagenome sequencing and metabolomics analysis performed on cecal contents from conventional Chow-fed PAHSA- and Vehicle-treated mice showed that 26 fatty acids (out of 600 metabolites) and several microbial species and their metabolic pathways correlated most highly with PAHSA-mediated insulin sensitivity. Also, Bacteroides thetaiotaomicron (Bt), a gut microbe associated with leanness in humans, and cecal C34:2 Phosphatidylethanolamine (PE), an abundant phospholipid class that is reduced in obese humans, were most strongly associated with the beneficial PAHSA effects. Initial studies with Bt treatment in male chow mice show improved glucose tolerance and lower glycemia 5-hrs after food removal vs. controls. Thus, the gut microbiota is necessary for the effects of PAHSAs to improve glucose homeostasis in HFD-fed mice. These effects can be conferred by FMT. PAHSA-associated microbes could provide novel gut-based therapeutic strategies to treat obesity and insulin resistance.


J. Lee: None. A. Rahnavard: None. K. Wellenstein: None. A.T. Nelson: None. C.B. Clish: None. D. Siegel: None. B. Kahn: Advisory Panel; Self; Harrington Discovery Institute, Janssen Pharmaceuticals, Inc., National Institute of Diabetes and Digestive and Kidney Diseases.


National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK114162-01A1, DK1NADK-057521-01 to J.L.); JPB Foundation (to B.K.)

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