Efficacy of bariatric surgery to decrease the risk of colorectal cancer in mice

 描述(申请人提供)：减肥手术，如垂直袖状胃切除术(VSG)，是目前治疗肥胖症最有效的长期治疗方法，可导致约70%的2型糖尿病(T2 DM)缓解率，通常发生在手术后几天至几周内，然后显著减轻体重。此外，减肥手术可降低终身罹患癌症的风险，包括结直肠癌(CRC)。发生这种情况的机制(S)仍然难以捉摸。由于缺乏合适的临床前啮齿动物模型，我们对减肥手术降低CRC风险的机制的了解受到严重限制。减肥手术，如VSG，会导致循环胆汁酸浓度升高和循环胆汁酸谱中有利于代谢的亲水性改变，这有助于减肥手术的代谢效益。TGR5是一种胆汁酸受体，主要介导胆汁酸的代谢益处。TGR5可维持血糖平衡，减少炎性细胞因子的分泌，预防炎症性肠病。在人类减肥手术后，TGR5的下游信号成分增加。我们的初步数据显示，TGR5信号通过促进循环胆汁酸池中的亲水性变化，对VSG的非体重血糖调节益处做出贡献。重要的是，胆汁酸疏水性的增加与人类CRC的发展有关，并促进结肠炎、结肠ER应激和全身性胰岛素抵抗，所有这些都是CRC发生的危险因素。我们的初步数据显示，在vsg操作的小鼠中，结肠炎症、内质网应激和Wnt/β-catenin/apc信号的减少与体重无关。因此，我们假设VSG手术通过亲水性胆汁酸介导的结肠胰岛素抵抗、炎症和内质网应激降低结直肠癌的发生率。在目标1中，我们将使用偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)诱导的TGR5+/+和TGR5-/-小鼠结直肠癌模型，确定VSG干预结直肠癌炎性致瘤环境的有效性以及TGR5介导的循环胆汁酸池中的亲水性变化对这一效果的贡献。为此，将评估组织学、胰岛素敏感性、内质网应激信号和炎症信号。由于肠道微生物群在调节胆酸池组成方面起着关键作用，因此将对结肠胆汁酸谱和微生物种群进行评估。将对结肠粘膜样本进行RNASEQ，以确定新的治疗靶点。在目标2中，我们将利用原位TGR5+/+和TGR5-/-小鼠模型，确定VSG干预肿瘤发生和转移的有效性，以及TGR5介导的循环胆汁酸池中的亲水性变化对这一效应的贡献。我们建议的工作有可能确定减肥手术降低结直肠癌风险的机制，从而开发出在药理上模仿减肥手术的效果来降低结直肠癌风险的非手术疗法。

 DESCRIPTION (provided by applicant): Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is currently the most effective long-term treatment for obesity and results in a ~70% remission rate of type 2 diabetes (T2DM), often occurring within days to weeks after surgery before significant weight loss. In addition, bariatric surgery decreases the lifetime risk of developing cancer, including colorectal cancer (CRC). The mechanism(s) by which this occurs remain elusive. Our understanding of the mechanisms by which bariatric surgery decreases CRC risk has been severely limited by the lack of an appropriate preclinical rodent model. Bariatric procedures, such as VSG, result in elevated circulating bile acid concentrations and metabolically beneficial hydrophilic shifts in circulating bile acid profiles which contribute to te metabolic benefits of bariatric surgery. TGR5 is a bile acid receptor central to mediating the metabolic benefits of bile acids. TGR5 maintains glucose homeostasis, decreases inflammatory cytokine secretion and protects against inflammatory bowel disease. Downstream signaling components of TGR5 are increased after bariatric surgery in humans. Our preliminary data show that TGR5 signaling contributes to the body weight-independent glucoregulatory benefits of VSG by promoting hydrophilic shifts in the circulating bile acid pool. Importantly, increased bile acid hydrophobicity is associated with CRC development in humans and promotes colonic inflammation, colonic ER stress and systemic insulin resistance, all of which are risk factors for CRC development. Our preliminary data show body weight-independent reductions in colonic inflammation, ER stress and decreased Wnt/β-catenin/APC signaling in VSG-operated mice. Therefore, we hypothesize that VSG surgery reduces the incidence of CRC through hydrophilic bile acid-mediated reductions in colonic insulin resistance, inflammation and ER stress. In Aim 1 we will determine the efficacy of VSG to interfere with an inflammatory protumorigenic environment for CRC and the contribution of TGR5-mediated hydrophilic shifts in the circulating bile acid pool to this effect using an azoxymethane/dextran sodium sulphate (AOM/DSS) induced Tgr5+/+ and Tgr5-/- mouse model of CRC. To this end histology, insulin sensitivity, ER stress signaling and inflammatory signaling will be assessed. Since the gut microbiome plays a key role in modulating bile acid pool composition, colonic bile acid profiles and microbial populations will be assessed. RNAseq will be performed on colon mucosa samples to identify novel therapeutic targets. In Aim 2 we will determine the efficacy of VSG to interfere with tumorigenesis and metastasis and the contribution of TGR5-mediated hydrophilic shifts in the circulating bile acid pool to this effect in human CRC cells using an orthotopic Tgr5+/+ and Tgr5-/- mouse model. Our proposed work has the potential to identify the mechanisms by which bariatric surgery decreases the risk of CRC, so that non-surgical therapies that pharmacologically mimic the effect of bariatric surgery to decrease the risk of CRC can be developed.