The Anti-Diabetic Effects of Palmitic Acid Hydroxy Stearic Acid (PAHSA) Lipids are Transmissible by Fecal Microbiota Transplantation (FMT) in Mice

Title: The Anti-Diabetic Effects of Palmitic Acid Hydroxy Stearic Acid (PAHSA) Lipids are Transmissible by Fecal Microbiota Transplantation (FMT) in Mice
Authors: Jennifer Lee, Kerry Wellenstein, Barbara B. Kahn
Affiliations: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston MA 02215.

Objective: A newer class of lipids called PAHSAs have anti-diabetic effects in high-fat diet (HFD)-fed mice and circulating PAHSA levels strongly associated with insulin sensitivity in humans. Whether the gut microbiome contributes to the beneficial effects of PAHSAs on improving glucose homeostasis is unknown. We aimed to determine whether the insulin- sensitizing properties of PAHSAs are transmissible by fecal microbiota transplantation (FMT) in mice.

Methods: Fecal pellets collected from male mice treated with insulin-sensitizing PAHSAs or vehicle (50% PEG400, 0.5% Tween80 in water) for 21 days were used for FMT into recipient germ-free (GF) HFD-fed male mice. Donor feces from PAHSA or vehicle-treated mice were Dounce homogenized and resuspended in 100µL PBS under anaerobic conditions. Recipient GF-HFD mice were conventionalized with two doses of donor feces at days 0 and 35 by oral gavage. Body weight and in vivo glucose homeostasis were assessed in GF-HFD conventionalized mice.

Results: GF-HFD mice conventionalized with PAHSA donor feces gained less weight and were more glucose tolerant and insulin sensitive than GF-HFD mice conventionalized with vehicle donor feces. In addition, GF-HFD-PAHSA mice have reduced glycemia following a 5-hour food removal compared to control mice. Improved glucose tolerance was independent of effects on insulin secretion, suggesting that microbiota in feces from PAHSA-treated mice improves insulin sensitivity possibly by promoting leaness.16S rRNA sequencing and metagenomics analyses of cecal samples from the same PAHSA-treated donor mice identify 26 fatty acids (out of 600 metabolites) and several microbial species and their metabolic pathways that correlated highly with PAHSA-mediated insulin sensitivity.

Conclusion: PAHSAs have beneficial effects on the gut microbiome and these insulin sensitizing effects can be conferred by FMT to improve glucose homeostasis in recipient HFD-fed mice. Identifying PAHSA-mediated microbes and their metabolites that improve host metabolism represent novel therapeutic strategies to treat diet-induced obesity and insulin resistance.