Bile Acid Dysregulation Is Intrinsically Related to Cachexia in Tumor-Bearing Mice

SIMPLE SUMMARY: Cancer cachexia is considered a multi-organ syndrome. An improved understanding of how circulating molecules can affect tissues and mediate their crosstalk in the pathogenesis of cancer cachexia is emerging. Considering the various actions of bile acids on host metabolism and immunity, they could represent innovative targets in cancer cachexia. In this study, we investigated how bile acids could contribute to this syndrome by assessing the bile flow, by comparing the impact on bile acid pathways of cachexia-inducing and non-cachexia-inducing cell sublines, and by investigating the effects of ursodeoxycholic acid, a choleretic compound, in cachectic mice. Altogether, our analyses strengthen the importance of bile acids and their receptors as key players in the metabolic disorders associated with cancer, thereby laying the foundation for new therapeutic opportunities. ABSTRACT: Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.