Bile acid metabolism dysregulation associates with cancer cachexia: roles of liver and gut microbiome

Abstract

Background Cancer cachexia is a multifactorial metabolic syndrome in which bile acid (BA) metabolism might be involved. The aim of the present study was to clarify the contribution of liver and gut microbiota to BA metabolism disturbance in cancer cachexia and to check the possibility of targeting BA metabolism using agents such as tauroursodeoxycholic acid (TUDCA) for cancer cachexia therapy. Methods The BA profiles in liver, intestine, and serum of mice with cancer cachexia induced by inoculation of colon C26 tumour cells were analysed using metabolomics methods and compared with that of control mice. Proteomic analysis of liver protein expression profile and 16S rRNA gene sequencing analysis of gut microbiota composition in cancer cachexia mice were conducted. Expression levels of genes related to farnesoid X receptor (FXR) signalling pathway in the intestine and liver tissues were analysed using RT–PCR analysis. The BA profiles in serum of clinical colon cancer patients with or without cachexia were also analysed and compared with that of healthy volunteers. The effects of TUDCA in treating cancer cachexia mice were observed. Results In the liver of cancer cachexia mice, expression of BA synthesis enzymes was inhibited while the amount of total BAs increased (P < 0.05). The ratios of conjugated BAs/un‐conjugated BAs significantly increased in cancer cachexia mice liver (P < 0.01). Gut microbiota dysbiosis such as decrease in Lachnospiraceae and increase in Enterobacteriaceae was observed in the intestine of cancer cachexia mice, and microbial metabolism of BAs was reduced. Increase in expression of FGF15 in intestine (P < 0.01) suggested the activation of FXR signalling pathway which might contribute to the regulation of BA synthesis enzymes, transporters, and metabolic enzymes. Increase in the BA conjugation was observed in the serum of cancer cachexia mice. Results of clinical patients showed changes in BA metabolism, especially the increase in BA conjugation, and also suggested compensatory mechanism in BA metabolism regulation. Oral administration of 50 mg/kg TUDCA could significantly ameliorate the decrease in body weight (P < 0.001), muscle loss (P < 0.001), and atrophy of heart and liver (P < 0.05) in cancer cachexia mice without influence on tumour growth. Conclusions Bile acid metabolism dysregulation such as decrease in BA synthesis, increase in BA conjugation, and decrease in BA microbial metabolism was involved in development of cancer cachexia in mice. Targeting BA metabolism using agents such as TUDCA might be helpful for cancer cachexia therapy.

New Horizon on Gut Microbiome and Cancers: Recent Information on Pathogenesis and Treatment

“…Gut dysbiosis such as depression of Lachnospiraceae and enhancement of Enterobacteriaceae were recognized in the gut of mice with cancer cachexia, and microbial metabolism of BAs was decreed. Enhanced expression of FGF15 in intestinal tissue suggested the activation of FXR signal pathway inducing the regulation of BA synthesis enzymes, transporters together with metabolic enzymes [47]. Enhancement of BA conjugation was noted in the serum of mice with cancer cachexia.…”

“…Cancer cachexia is considered as a multifactorial metabolic syndrome in which bile acid (BA) metabolism may be involved [47]. Gut dysbiosis such as depression of Lachnospiraceae and enhancement of Enterobacteriaceae were recognized in the gut of mice with cancer cachexia, and microbial metabolism of BAs was decreed.…”

“…Enhancement of BA conjugation was noted in the serum of mice with cancer cachexia. Studies in clinical patients revealed changes in BA metabolism, particularly the increase in BA conjugation and supposed compensatory mechanism in BA metabolism regulation [47].…”

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

“…Defects in hepatobiliary secretion, mainly due to a process termed “inflammation-induced cholestasis”, and in bile acid metabolism, which in turn fuel hepatic inflammation, have also been reported in cachectic mice ( Thibaut et al, 2020 , 2021 ). Accordingly, targeting bile acid metabolism relieves cancer cachexia manifestations in C26-bearing mice ( Feng et al, 2021 ). Overall, these findings point toward an interaction between tumor, immune cells and liver that might play key roles in the progression of cancer cachexia.…”

Murine breast cancers disorganize the liver transcriptome in zonated manners

“…Remote cancers affect the liver in various manners thereby disrupting host homeostasis [1][2][3][4][5][6][7][8][9][10][11] . For example, circadian gene expression rhythm is disrupted in a breast cancer model and a genetically induced lung cancer model 3,4 .…”