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

 描述（由申请人提供）：减肥手术，如垂直袖状胃切除术（VSG），是目前最有效的肥胖长期治疗方法，可使2型糖尿病（T2 DM）缓解率达到约70%，通常发生在术后数天至数周内，然后体重显著减轻。此外，减肥手术降低了患癌症的终生风险，包括结直肠癌（CRC）。发生这种情况的机制仍然难以捉摸。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风险的机制的理解受到严重限制。 减肥手术（如VSG）导致循环胆汁酸浓度升高，循环胆汁酸谱中的代谢有益亲水性变化，这有助于减肥手术的代谢获益。TGR 5是一种胆汁酸受体，对介导胆汁酸的代谢益处至关重要。TGR 5维持葡萄糖稳态，减少炎性细胞因子分泌，并防止炎症性肠病。TGR 5的下游信号传导组分在人类减肥手术后增加。我们的初步数据显示，TGR 5信号通过促进循环胆汁酸池中的亲水性变化，有助于VSG的体重非依赖性血糖调节益处。重要的是，增加的胆汁酸疏水性与人类CRC的发展相关，并促进结肠炎症，结肠ER应激和全身胰岛素抵抗，所有这些都是CRC发展的风险因素。我们的初步数据显示，在VSG手术的小鼠中，结肠炎症、ER应激和Wnt/β-连环蛋白/APC信号转导的减少与体重无关。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ER应激的减少来降低CRC的发病率。在目标1中，我们将使用氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的Tgr 5 +/+和Tgr 5-/-CRC小鼠模型，确定VSG干扰CRC炎性促肿瘤发生环境的疗效，以及循环胆汁酸池中TGR 5介导的亲水性变化对此效应的贡献。为此，将评估组织学、胰岛素敏感性、ER应激信号传导和炎症信号传导。由于肠道微生物组在调节胆汁酸池组成中起关键作用，因此将评估结肠胆汁酸谱和微生物种群。将在结肠粘膜样品上进行RNAseq，以鉴定新的治疗靶点。在目标2中，我们将使用原位Tgr 5 +/+和Tgr 5-/-小鼠模型确定VSG干扰肿瘤发生和转移的功效以及循环胆汁酸池中TGR 5介导的亲水性变化对人CRC细胞中该效应的贡献。我们提出的工作有可能确定减肥手术降低CRC风险的机制，从而可以开发出模拟减肥手术降低CRC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.