Microbial changes from bariatric surgery alters glucose-dependent insulinotropic polypeptide and prevents fatty liver disease

ABSTRACT

Bariatric surgery remains a potent therapy for nonalcoholic fatty liver disease (NAFLD), but its inherent risk and eligibility requirement limit its adoption. Therefore, understanding how bariatric surgery improves NAFLD is paramount to developing novel therapeutics. Here, we show that the microbiome changes induced by sleeve gastrectomy (SG) reduce glucose-dependent insulinotropic polypeptide (GIP) signaling and confer resistance against diet-induced obesity (DIO) and NAFLD. We examined a cohort of NALFD patients undergoing SG and evaluated their microbiome, serum metabolites, and GI hormones. We observed significant changes in Bacteroides, lipid-related metabolites, and reduction in GIP. To examine if the changes in the microbiome were causally related to NAFLD, we performed fecal microbial transplants in antibiotic-treated mice from patients before and after their surgery who had significant weight loss and improvement of their NAFLD. Mice transplanted with the microbiome of patients after bariatric surgery were more resistant to DIO and NAFLD development compared to mice transplanted with the microbiome of patients before surgery. This resistance to DIO and NAFLD was also associated with a reduction in GIP levels in mice with post-bariatric microbiome. We further show that the reduction in GIP was related to higher levels of Akkermansia and differing levels of indolepropionate, bacteria-derived tryptophan-related metabolite. Overall, this is one of the few studies showing that GIP signaling is altered by the gut microbiome, and it supports that the positive effect of bariatric surgery on NAFLD is in part due to microbiome changes.

Graphical abstract

KEYWORDS:

• Akkermansia
• GIP
• NAFLD
• bariatric surgery
• sleeve gastrectomy

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval and Consent to participate

All patient research was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the UCLA Institutional Review Board (IRB#13-001552). All patients were given verbal and written consent to participate in the study.

Data availability statement

Raw sequencing data from the human cohort are available on the NIH NCBI BioProject (PRJNA885868). https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA885868.

Author contributions

Conceptualization: TSD, JPJ, JRP

Methodology: TSD, CS, ZL, EAM, JPJ, CC, JY

Investigation: TSD, WK, NA, VL, AB, YC, ED, CS, CC, JY

Visualization: TSD, JPJ

Funding acquisition: TSD, CS, EAM, JPJ

Project administration: TSD, CS, JPJ

Supervision: TSD, CS, JPJ

Writing – original draft: TSD, WK, JPJ

Writing – review and editing: ZL, EAM, JRP, CS, JPJ

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2167170

Additional information

Funding

National Institutes of Health grant DDRC P30 DK 41301 (CS) National Institutes of Health grant UL1TR000124 (CS) National Institutes of Health grant, T32 DK 718044 (TSD) National Institutes of Health grant R01 DK048351 (EAM) US Department of Veteran Affairs Career Development Award IK2CX001717 (JPJ).