Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19^−/−] knockout (KO) mice were crossed to Apc^min/+ mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76–96 %) and incidence (72–95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apc^min/+ mice fed high-fat diet, also resulted in significant suppression of colonic (50–58 %) and SI (41–48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.

炎症和肥胖是促进结直肠癌（CRC）的两个主要因素。我们最近的数据表明，白细胞介素 (IL)-23 在 CRC 肿瘤中显着升高，并且与患者肥胖、肿瘤分级和生存相关。因此，我们假设肥胖和结直肠癌可能通过炎症相关，而 IL-23 可能是高危患者干预的潜在目标。评估 TCGA 数据集和患者血清的 IL-23A 水平。将IL-23A [IL-23 p19 ^{−/− ] 敲除 (KO) 小鼠与 Apc min/+}小鼠杂交，并用低脂或高脂饮食喂养后代。在终止时评估肠道的肿瘤发生。分别分析肿瘤、血清和粪便内容物的蛋白质生物标志物、细胞因子和微生物组概况。肥胖和结肠肿瘤患者血清中 IL-23A 水平升高。IL-23A 的基因消融显着抑制了雄性和雌性小鼠的结肠肿瘤多样性 (76-96%) 和发病率 (72-95%)。同样，IL-23A KO 小鼠的小肠肿瘤多样性和大小也显着降低。在喂食高脂肪饮食的Apc ^min/+小鼠中，IL-23A 敲低也导致结肠肿瘤 (50-58%) 和 SI (41-48%) 肿瘤多样性的显着抑制。细胞因子分析显示多种循环促炎细胞因子减少，包括 IL-23A 损失。生物标志物分析表明，与对照组相比，IL-23A KO 小鼠的肿瘤细胞增殖和免疫调节减少，肿瘤浸润 CD4+ 和 CD8+ T 淋巴细胞增加。粪便微生物组分析揭示了细菌种群概况的潜在有益变化。总之，我们的数据表明 IL-23 在 CRC（包括饮食引起的肥胖）中具有促肿瘤作用。随着多种 IL-23 靶向疗法进入临床试验，靶向这种细胞因子用于 CRC 预防和治疗具有巨大潜力。