Involvement of the gut microbiota in cancer cachexia

Abstract

Cancer cachexia, or the unintentional loss of body weight in patients with cancer, is a multiorgan and multifactorial syndrome with a complex and largely unknown etiology; however, metabolic dysfunction and inflammation remain hallmarks of cancer-associated wasting. Although cachexia manifests with muscle and adipose tissue loss, perturbations to the gastrointestinal tract may serve as the frontline for both impaired nutrient absorption and immune-activating gut dysbiosis. Investigations into the gut microbiota have exploded within the past two decades, demonstrating multiple gut-tissue axes; however, the link between adipose and skeletal muscle wasting and the gut microbiota with cancer is only beginning to be understood. Furthermore, the most used anticancer drugs (e.g. chemotherapy and immune checkpoint inhibitors) negatively impact gut homeostasis, potentially exacerbating wasting and contributing to poor patient outcomes and survival. In this review, we 1) highlight our current understanding of the microbial changes that occur with cachexia, 2) discuss how microbial changes may contribute to adipose and skeletal muscle wasting, and 3) outline study design considerations needed when examining the role of the microbiota in cancer-induced cachexia.

Keywords: Bifidobacterium; Lactobacillus; inflammation; microbiome; wasting.

Graphical abstract

Figure 1.

Working model of how gut microbes contribute to muscle and adipose tissue wasting with cachexia. The gastrointestinal mucosa plays a vital role not only in housing the gut microbiome but also in protecting the intestinal epithelium and shielding immune cells in the lamina propria (LP) from inappropriate activation. Dendritic cells sample luminal antigens and present to immune cells in the LP for activation (e.g., monocytes, neutrophils, and T-cells). Once activated, these cells can either extravasate or they can produce inflammatory cytokines (i.e., IL-6, TNF-α, and GDF15), which ultimately enter circulation and induce muscle and adipose tissue wasting. Resident immune cells (e.g., macrophages) can also be activated by invading microbes and/or pathogens (dysbiosis), causing the release of similar cytokines, which can further perpetuate cachexia. In addition, microbes (e.g., Firmicutes) can produce short-chain fatty acids and other metabolites, which can combat cachexia and are seen to be reduced in cachectic patients. Created with BioRender.com.

Figure 2.

Microbial changes are seen at different taxonomic levels with cachexia. A summary of the available literature on microbial changes in both murine and human studies occurring in cancer-induced cachexia include 1) changes to α- and/or β-diversity and 2) increases or decreases in specific microbes at various taxonomic levels (i.e., phylum, family, genus, and species levels). Pink indicates data are supported in murine models. Blue indicates data are supported in human models. Green indicates data are supported in both mice and humans. *changes have been correlated to loss of muscle mass; †changes have been correlated to adipose tissue loss. Created with BioRender.com.