Multi‐compartment metabolomics and metagenomics reveal major hepatic and intestinal disturbances in cancer cachectic mice

Abstract

Background Cancer cachexia is a multifactorial syndrome characterized by multiple metabolic dysfunctions. Besides the muscle, other organs such as the liver and the gut microbiota may also contribute to this syndrome. Indeed, the gut microbiota, an important regulator of the host metabolism, is altered in the C26 preclinical model of cancer cachexia. Interventions targeting the gut microbiota have shown benefits, but mechanisms underlying the host-microbiota crosstalk in this context are still poorly understood. Methods To explore this crosstalk, we combined proton nuclear magnetic resonance ( 1 H-NMR) metabolomics in multiple compartments with 16S rDNA sequencing. These analyses were complemented by molecular and biochemical analyses, as well as hepatic transcriptomics.Results 1 H-NMR revealed major changes between control (CT) and cachectic (C26) mice in the four analysed compartments (i.e. caecal content, portal vein, liver, and vena cava). More specifically, glucose metabolism pathways in the C26 model were altered with a reduction in glycolysis and gluconeogenesis and an activation of the hexosamine pathway, arguing against the existence of a Cori cycle in this model. In parallel, amino acid uptake by the liver, with an up to four-fold accumulation of nine amino acids (q-value <0.05), was mainly used for acute phase response proteins synthesis rather than to fuel the tricarboxylic acid cycle and gluconeogenesis. We also identified a 35% reduction in hepatic carnitine levels (q-value <0.05) and a lower activation of the phosphatidylcholine pathway as potential contributors to the hepatic steatosis present in this model. Our work also reveals a reduction of different beneficial intestinal bacterial activities in cancer cachexia. We found decreased levels of two short-chain fatty acids, acetate and butyrate (72% and 88% reduction in C26 caecal content; q-value <0.001), and a reduction in aromatic amino acid metabolites, which may contribute to the altered intestinal homeostasis in these mice. A member of the Ruminococcaceae family (ASV 2) was identified as the main bacterium responsible for the drop in butyrate. Finally, we report a two-fold intestinal transit acceleration (P-value <0.001) as a key factor shaping the gut microbiota composition and activity in cancer cachexia, which together lead to a faecal loss of proteins and amino acids. Conclusions Our work highlights new metabolic pathways potentially involved in cancer cachexia and further supports the interest of exploring the gut microbiota composition and activity, as well as intestinal transit, in cancer patients with and without cachexia.

Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration

“…In the last years, a number of studies focused on the possibility that altered energy metabolism could be the trigger of muscle wasting. Indeed, metabolomic analyses have shown that energy and protein metabolism are markedly perturbed in the skeletal muscle and in the liver of tumor-bearing animals [7,8]. Consistently, hypermetabolism associated with altered energy balance has been detected in about 50% of newly diagnosed cancer patients [9].…”

Exercise—A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights

“…Under pathological conditions of excessive adipose tissue lipolysis, the liver acts as a major sink for adipose tissue-derived FFA. Accordingly, hepatic lipids and triglycerides were elevated 3-5 fold in colon (C26) tumor-bearing mice, an effect that was not due to reduced food intake [56,74]. The hepatic steatosis could be explained by a reduction in carnitine and carnitine biosynthesis, decreased VLDL excretion, reduction in lipogenic genes, and an upregulation fatty acid transporters in the liver [56,74].…”

“…Increased hepatic glucose output may be due to increased gluconeogenesis because increased metabolicintermediates and increased gene-expression of markers of gluconeogenesis have been observed in the liver of tumor-bearing animals [55]. A recent proton nuclear magnetic resonance (1H-NMR) metabolomics study of cachexia in the mouse colon carcinoma 26 (C26) model revealed reduced glucose metabolism and increased lipid metabolism in the liver [56]. Whether hepatic metabolic changes in cancer is induced by insulin resistance or is a contributing factor to insulin resistance remain unidentified.…”

“…Accordingly, hepatic lipids and triglycerides were elevated 3-5 fold in colon (C26) tumor-bearing mice, an effect that was not due to reduced food intake [56,74]. The hepatic steatosis could be explained by a reduction in carnitine and carnitine biosynthesis, decreased VLDL excretion, reduction in lipogenic genes, and an upregulation fatty acid transporters in the liver [56,74]. Within the hepatocyte, non-esterified FAs are oxidized to mitochondrial acetyl CoA resulting in elevated gluconeogenic flux.…”

Biomarkers for Cancer Cachexia: A Mini Review

“…Not only is predicting cachexia important, being able to monitor the progression of the condition is also essential. Microbial dysbiosis has been observed in preclinical cancer cachexia models [ 111 , 112 ], which could be a potential diagnostic reference for cancer cachexia. Enterobacteriaceae levels were increased, while a reduction of lachnospiraceae and ruminococcaceae were found in C26 cancer cachexia model [ 111 , 112 ].…”