The Gut-Brain Axis in Ganoderma lucidum's Antidepressant Effects in Cancer Comorbidity: A Review

Depression is a common and serious comorbidity in patients with cancer and is associated with worse clinical outcomes and reduced quality of life. Gut microbiota dysbiosis has been implicated as a pathogenic factor, potentially driving depressive symptoms through metabolic alterations and disruption of the gut-brain axis-mechanisms that may also contribute to cancer progression. The medicinal mushroom Ganoderma lucidum has been investigated primarily for its immunomodulatory effects in patients with cancer, and emerging preclinical evidence suggests that it may possess antidepressant properties, positioning it as a candidate for microbiota-targeted intervention. Preclinical evidence indicates that G. lucidum can act as a gut microbiota modulator and alleviate depressive-like behaviors in animal models, with mechanisms involving the correction of dysbiosis and the normalization of key metabolic pathways, including those related to short-chain fatty acids and tryptophan, thereby improving inflammatory tone and neuroendocrine function. In contrast, human studies have largely focused on its immunomodulatory and quality-of-life effects in patients with cancer, with limited direct assessment of depression-related outcomes. Consequently, current mechanistic insights are derived predominantly from animal studies and require validation in large-scale human trials. This review proposes that gut microbiota modulation represents a plausible and potentially important mechanism through which G. lucidum may exert antidepressant effects in the context of cancer comorbidity, namely that the "G. lucidum-gut microbiota-depression" pathway is an inferred translational framework rather than an established clinical mechanism. Nonetheless, this framework provides a rationale for future efforts to develop G. lucidum and its active components into microbiota-based therapeutics for cancer-related depression.