Abstract 4984: Celastrol inhibits high fat diet-induced obesity and intestinal tumorigenesis in APCMin/+ mice by modulating gut microbes and inflammation
Authors: Naveena B. Janakiram, Venkateshwar Madka, Yuting Zhang, Nicole Stratton, Hima Bezawada, Beth Griesel, Altaf Mohammed, Ann L. Olson, Chinthalapally V. Rao
Journal: Cancer Research (2018)

Abstract Obesity and inflammation play a vital role in colorectal cancer (CRC). Antiobesity agents may be beneficial for CRC prevention. Celastrol is a triterpene bioactive compound derived from Tripterygium wilfordii (TW) plant, which possesses antiobesity and anti-inflammatory properties. In the present study, we tested celastrol for its intestinal tumor inhibitory efficacy, modulation of intestinal microbiome, induction of UCP-1 in inguinal fat, and inflammation under obese conditions using APCMin/+ mouse model. For efficacy study, six-week-old male and female C57BL/6J-APCMin/+ mice (10 mice/group/gender) were fed high-fat diets (HFD; 60% Kcal fat) containing 0 and 150 ppm celastrol and a group of mice with a low-fat diet (LFD; 10% Kca fat) for 11 weeks. At termination, intestinal tumors were evaluated histologically and serum was assayed for fasting glucose, uric acid, liver enzymes (ALT, AST), triglycerides and cholesterol levels. Untreated and treated intestinal tumors were assayed for apoptosis and inflammatory markers by real-time PCR method. Results suggest that administration of LFD showed lower intestinal tumor formation by 52% (p&amp;lt;0.02) in males; 74% (p&amp;lt;0.0009) in females compared to HFD fed animals. Importantly, administration of HFD containing celastrol suppressed the intestinal polyp formation by 92% (p&amp;lt;0.0001) in males and 83.6% (p&amp;lt;0.0002) in females compared to control HFD fed mice. Also, significant inhibition of colonic tumor suppression was observed in (34%) male and (100%) female mice fed with celastrol. HFD fed animals showed 55% high-grade adenomas whereas HFD containing celastrol treatment showed 25% high-grade adenomas in colon. HFD containing celastrol treatment resulted in significantly reduced body weight gain, p&amp;lt;0.002, compared to HFD alone in both genders with upregulation of UCP1 protein in inguinal fat indicating increased thermogenesis. HFD celastrol treatment significantly reduced fasting glucose and triglycerides levels with an increase in uric acid with no effect on cholesterol, ALT and AST levels compared to control HFD fed mice. A sequence-based analysis of fecal microbiota of mice fed with HFD celastrol showed significantly decreased number of inflammation-causing microbes belonging to genus Prevotella (84%), Dorea (77%), Allobaculum (74%), and Aneroplasma (100%) and increased number of beneficial microbes belonging to genus Bifidobacterium (100%), Akkermansia (99.9%), Mucispirillum (94%) and Coprococcus (97%) compared to control HFD fecal samples. Celastrol treatment altered mRNA expression of IFN-γ, Ccl6, TGFβ1, and Aimp1. This is first study to report the chemopreventive properties of celastrol against the small intestinal and colonic neoplasia, modulation of gut microbiome and inflammation in APCMin/+ mice. Stephenson Cancer Center Grant. Citation Format: Naveena B. Janakiram, Venkateshwar Madka, Yuting Zhang, Nicole Stratton, Hima Bezawada, Beth Griesel, Altaf Mohammed, Ann L. Olson, Chinthalapally V. Rao. Celastrol inhibits high fat diet-induced obesity and intestinal tumorigenesis in APCMin/+ mice by modulating gut microbes and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4984.