Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet- induced obese mice but not in chow- fed mice

• 成果类型: Article
• 署名作者: Lee, Jennifer; Wellenstein, Kerry; Rahnavard, Ali; Nelson, Andrew T.; Holter, Marlena M.; Cummings, Bethany P.; Yeliseyev, Vladimir; Castoldi, Angela; Clish, Clary B.; Bry, Lynn; Siegel, Dionicio; Kahn, Barbara B.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; George Washington University; University of California System; University of California San Diego; Cornell University; University of California System; University of California Davis; University of California System; University of California Davis; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Universidade Federal de Pernambuco; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; United States Department of Agriculture (USDA); Tufts University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14903
• DOI: 10.1073/pnas.2318691121
• 发表日期: 2024-07-09
• 关键词: intestinal alkaline-phosphatase; insulin-resistance; fatty-acids; transplantation; host; sphingolipids; inflammation; bacteria; barrier

摘要

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are a family of lipids with antidiabetic and anti- inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating chow- fed female and male germ- free (GF) mice with PAHSAs improves glucose tolerance, but these effects are lost upon high fat diet (HFD) feeding. However, transfer of feces from PAHSA- treated, but not vehicle- treated, chow- fed conventional mice increases insulin sensitivity in HFD- fed GF mice. Thus, the gut microbiota is necessary for, and can transmit, the insulin- sensitizing effects of PAHSAs in HFD- fed GF male mice. Analyses of the cecal metagenome and lipidome of PAHSA- treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron ( Bt ) and with insulin sensitivity resulting from PAHSA treatment. Supplementing live, and to some degree, heat- killed Bt to HFD- fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation compared to HFD- fed controls. These effects were not observed in HFD- fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating the Bt probiotic effects. Altogether, these studies highlight the fact that PAHSAs can modulate the gut microbiota and that the microbiota is necessary for the beneficial metabolic effects of PAHSAs in HFD- fed mice.