Abstract 2910: A TGF-β-ALDH2 axis controls liver- brain-gut microbiome driven obesity, metabolic syndrome and cancer

Abstract Background/Aims: ALDH2 (Aldehyde dehydrogenase 2) is associated with multiple human diseases including cancers, Asian flush syndrome (deficiencies affect 35%-40% of East Asians), and alcoholic liver disease. Yet, oncogenic mechanisms and pathways that ALDH2 interacts with remain unclear. Previously we have demonstrated that TGF-β-deficient mutants derived from the loss of Smad3 and its adaptor Sptbn1 are exquisitely sensitive to alcohol, with impaired DNA damage repair. ALDH2 levels are altered in the liver tissues of the mouse mutants, and the Sptbn1-/- phenotype is similar to ALDH2-FancD2 mutants. We, therefore, hypothesized that disruption of TGF-β signaling combined with ALDH2 deficiency would increase the susceptibility of liver diseases and cancer. Methods: Aldh2-/- mice were intercrossed with Sptbn1+/-, Smad3+/- mice. Control mice and intercrosses were fed with high-fat diet (HFD) or chow diet or alcohol diet, or hepatic vagotomy followed by phenotypic and mechanistic analyses through RNA-seq, lipidomics, metabolomics, western blot analyses, RTPCR, structure modeling, cell fractionation, and immunohistochemistry. Fecal samples from these mice underwent shotgun metagenomic sequencing. Results: Strikingly, compared to WT, Aldh2-/-Sptbn1+/- (ASKO) mice on a normal diet develop metabolic syndromes with truncal obesity, insulin resistance, with increased blood glucose (272.3±28.6mg/dl vs 189.9 ±7.0mg/dl, p<0.05), serum triglyceride (185.2±40.0 mg/dl vs 83.7 ±7.8 mg/dl, p<0.05). Nonalcoholic steatohepatitis (NASH), and cancer, with raised ALT and AST levels, also develop in the mutant mice. HFD exacerbated obesity and NASH in Aldh2-/-Sptbn1+/- on HFD with substantial additional visceral fat accumulation and hyperglycemia with Zone 3 hepatic macro-steatosis and inflammation, which correlated with increased fatty acid metabolism and gluconeogenesis. ASKO mice had significantly altered neurotransmitter receptors in the liver including cholinergic receptors (e.g., Chrnb1, and Chrna2) and altered gut microbiome composition with increased abundance of S. pseudoporcinus (Aldh2-/-Smad3+/- vs WT: 85.6±29 vs 2.71 ±1.44, p<0.05) and decreased A. propionicum (ASKO vs WT: 65±21 vs 168±31, p<0.05). Conclusions: Aldh2-/-Sptbn1+/- mice develop metabolic syndrome with alterations in the cholinergic pathway and microbiome species, suggesting a disruption in afferent vagal activity. ALDH2/SPTBN1 is therefore potentially a major liver-brain-gut vagal regulator of obesity. Aldh2 and TGF-β signaling are important in maintaining normal gut microbiome composition. These studies highlight the potential role of the gut-liver axis in regulating obesity and liver disease. With > 35% Asian population harboring ALDH2 alterations, our studies potentially have a high impact on these patient populations with a high risk of metabolic syndrome. Citation Format: Shuyun Rao, Xiaochun Yang, Zhanhuai Wang, Kazufumi Ohshiro, Sobia Zaidi, Wilma Jogunoori, Bryan Nguyen, Keith A. Crandall, Patricia S. Latham, Kirti Shetty, Lopa Mishra. A TGF-β-ALDH2 axis controls liver- brain-gut microbiome driven obesity, metabolic syndrome and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2910.