Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as , as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored and . , TDCA prevented myotube atrophy, whereas hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.
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http://dx.doi.org/10.1080/19490976.2025.2449586 | DOI Listing |
Gut Microbes
December 2025
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.
Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA).
View Article and Find Full Text PDFCancer Lett
January 2025
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address:
Anorexia is a major cause of cancer cachexia and is induced by growth differentiation factor-15 (GDF15), which activates the rearranged during transfection (RET) protein tyrosine kinase in the hindbrain through GDF family receptor α-like (GFRAL), raising the possibility of targeting RET for cancer cachexia treatment. RET-altered cancer patients treated with RET-selective kinase inhibitors gain weight, however, it is unclear whether this results from tumor regression that improves the overall health of patients. Thus, the potential of using a RET inhibitor to address cancer cachexia remains unknown.
View Article and Find Full Text PDFPharmacol Res Perspect
February 2025
Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany.
Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused by underlying illnesses such as cancer, heart failure, and renal failure. Inflammation, insulin resistance, increased muscle protein degradation, decreased food intake, and anorexia are the primary pathophysiological drivers of cachexia. Cachexia causes physical deterioration and functional impairment, loss of quality of life, lower response to active treatment, and ultimately morbidity and mortality, while the difficulties in tackling cachexia in its advanced phases and the heterogeneity of the syndrome among patients require an individualized and multidisciplinary approach from an early stage.
View Article and Find Full Text PDFBr J Nutr
January 2025
Academic Unit of Surgery, School of Medicine, University of Glasgow, New Lister Building, Royal Infirmary, Glasgow, G31 2ER, Scotland, United Kingdom.
An assessment of systemic inflammation and nutritional status may form the basis of a framework to examine the prognostic value of cachexia in patients with advanced cancer. The objective of the study was to examine the prognostic value of GLIM criteria, including body mass index (BMI), weight loss (WL) and systemic inflammation (mGPS), in advanced cancer patients. Three criteria were examined in a combined cohort of patients with advanced cancer and their relationship with survival was examined using Cox regression methods.
View Article and Find Full Text PDFNutrients
December 2024
UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.
Background: Patients with rectal cancer (RC) are at risk of developing cancer-related cachexia, a complex metabolic syndrome that can negatively impact quality of life (QoL), treatment tolerance, and clinical response.
Objectives: The aim of the study was to explore the possible associations of the novel European Organization for Research and Treatment of Cancer QoL Questionnaire-Cancer Cachexia (EORTC QLQ-CAX24) scores with body composition parameters and physical performance in patients with locally advanced RC (LARC).
Methods: This prospective observational study involved RC patients evaluated at the dedicated outpatient clinic of Clinical Nutrition at the Fondazione Policlinico Agostino Gemelli IRCCS.
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