Modulating the Gut-Muscle Axis: Increasing SCFA-Producing Gut Microbiota Commensals and Decreasing Endotoxin Production to Mitigate Cancer Cachexia

Abstract

Cancer cachexia is a multi-organ and multifactorial syndrome characterized by muscle wasting (with or without adipose tissue loss) and systemic inflammation in patients with advanced malignancies. Gut microbiota dysbiosis, particularly the depletion of short-chain fatty acid (SCFA)-producing bacteria, may contribute to the progression of cancer cachexia. Studies in both murine models and humans consistently associate cachexia with a decline in SCFA-producing gut microbiota commensals and an overgrowth of pro-inflammatory pathobionts. These microbial imbalances may lead to reduced levels of SCFAs and branched-chain amino acids (BCAAs) and alter the normal bile acid profile. BCAAs and the maintenance of a normal bile acid profile are associated with muscle synthesis and decreased breakdown. While SCFAs (acetate, propionate, and butyrate), contribute to intestinal barrier integrity and immune regulation. SCFA depletion may increase gut permeability, allowing bacterial endotoxins, such as lipopolysaccharide (LPS), to enter the bloodstream. This may lead to chronic inflammation, muscle catabolism, and impairment of anabolic pathways. Interventions targeting gut microbiota in preclinical models have mitigated inflammation and muscle loss. While clinical data are limited, it suggests an improvement in immune functions and better tolerance to anticancer therapies. Current evidence is predominantly derived from cross-sectional studies suggesting associations without causality. Thus, future longitudinal studies are needed to identify biomarkers and optimize personalized therapy.

Keywords: bile acids; branched chain amino acids (BCAAs); cancer cachexia; dysbiosis; fecal microbiota transplantation; gut microbiota; inflammation; intestinal barrier integrity; microbiome-based therapies; prebiotics; probiotics; short-chain fatty acids (SCFAs); synbiotics.

Figure 1

Cachexia feeds tumor progression. Muscle atrophy releases glutamine in the blood stream which is taken up the energy-demanding cancer cell where it is converted to glutamate. This is then further converted to α-ketoglutarate to feed the tricarboxylic acid cycle (TCA cycle) resulting in energy production for tumor cells in the form of ATP (adenosine triphosphate) [1]. Glutamate is also stored as N-acetyl-aspartyl-glutamate (NAAG) via the NAAG cycle and found in high levels in advanced-stage cancer [11]. Along with skeletal muscle degradation, adipose tissue degradation contributes to cancer progression via lipolytic breakdown of triacylglycerols producing non-essential fatty acids (NEFAs) used by cancer cells in TCA cycle, thereby maintaining its high energy demand and, as a result, proliferates [1]. Created using BioRender.com.

Figure 2

Gut microbiota interventions is a multi-modal approach focusing on mitigating multi-organ and multifactorial syndrome cancer cachexia. (a) Tumor progression increases pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) which fuels systemic inflammation cycle. Systemic inflammation further affects the gut by creating a pro-inflammatory environment supporting pro-inflammatory pathogens, thereby increasing LPS (lipopolysaccharide) production and decreasing the production of SCFAs (short-chain fatty acids). It prevents the energy supply to colonocytes, thereby damaging the gut barrier integrity, resulting in the LPS passing through the gut barrier. It again fuels the systemic inflammation, maintaining a chronic state of skeletal muscle inflammation, thereby increasing muscle atrophy gene expression. Hence, resulting in muscle wasting which again fuels the systemic inflammation cycle increasing tumor progression and the vicious cycle continues. (b) Gut-microbiota interventions can potentially “reset” gut microbiota towards that of a healthier, non-cachectic state. By enriching SCFA-producing commensals, preventing loss of BCAAs, and maintaining bile acid homeostasis which is generally marked by an increase of secondary bile acids (microbial metabolites) production. These changes bring the gut into an “eubiotic state”, which may break the vicious cycle of systemic inflammation, potentially reducing skeletal muscle wasting and tumor progression. Color and arrow legend: Red arrows indicate pro-inflammatory, pro-cachectic, or tumor-promoting pathways. Green arrows indicate therapeutic effects mediated by gut microbiome interventions. Purple arrows represent gut–muscle axis communication mediated by microbial dysbiosis and metabolites (e.g., SCFAs, LPS). Dashed arrows indicate indirect or modulatory effects (e.g., BCAA metabolism, bile acid modulation). Yellow boxes denote pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). Red tumor cells represent tumor burden. Maroon muscle fibers depict skeletal muscle undergoing wasting or recovery. Pink epithelial cells represent gut barrier integrity status. Green and red bacteria represent commensals and pathobionts, respectively. Orange border highlights compromised gut permeability and LPS translocation. Figure created with BioRender.com.