Dataset Information

Inflammation-induced cholestasis in cancer cachexia.

ABSTRACT:

Background

Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.

Methods

We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51).

Results

In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor ? signalling via NF?B and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 ?M, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ? = 0.36, Padj = 0.017).

Conclusions

We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.

SUBMITTER: Thibaut MM

PROVIDER: S-EPMC7890151 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Inflammation-induced cholestasis in cancer cachexia.

Thibaut Morgane M MM Sboarina Martina M Roumain Martin M Pötgens Sarah A SA Neyrinck Audrey M AM Destrée Florence F Gillard Justine J Leclercq Isabelle A IA Dachy Guillaume G Demoulin Jean-Baptiste JB Tailleux Anne A Lestavel Sophie S Rastelli Marialetizia M Everard Amandine A Cani Patrice D PD Porporato Paolo E PE Loumaye Audrey A Thissen Jean-Paul JP Muccioli Giulio G GG Delzenne Nathalie M NM Bindels Laure B LB

Journal of cachexia, sarcopenia and muscle 20201222 1

<h4>Background</h4>Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.<h4>Methods</h4>We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two ...[more]

PMID: 33350058

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Dataset Information

Inflammation-induced cholestasis in cancer cachexia.

Background

Methods

Results

Conclusions

Publications

Inflammation-induced cholestasis in cancer cachexia.

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