Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

Cancer represents a major disease burden worldwide. Despite continuous advances obtained in medical therapies recently, resistance to standard drugs and adverse effects still represent important causes of therapeutic failure. There is growing evidence that the gut microbiota can affect the response to chemo‐ and immunotherapeutic drugs by modulating efficacy and/or toxicity, and diet is the most important factor affecting the gut microbiota. In this study, we assessed the auxiliary antitumor effects of immunomodulatory fungal proteins from Hericium erinaceus (HEP) administered with the chemotherapy drug 5‐Fluorouracil (5‐Fu), and we attempted to identify new potential prebiotic bacteria for auxiliary antitumor treatment. There were 1,455 proteins identified from H. erinaceus. In a xenografted mouse model of cancer, HEP with 5‐Fu significantly suppressed tumor growth, inhibited inflammatory markers such as interferon (IFN)‐γ, interleukin (IL)‐1β, IL‐2, IL‐6, tumor necrosis factor (TNF)‐α, and lipopolysaccharide (LPS), and regulated the expression of Akt, CCDN1, CKD4, FOXM1, MMP7, MYC, PPAR‐α, and PPAR‐γ. 16S rRNA sequencing showed that HEP ameliorated the dysbacteriosis induced by 5‐Fu, as it inhibited certain aerobic and microaerobic bacteria including Parabacteroides, Flavobacteriaceae, Christensenellaceae, Anoxybacillus, Aggregatibacter, Comamonadaceae, Planococcaceae, Desulfovibrionaceae, Sporosarcina, Staphylococcus, Aerococcaceae, and Bilophila in the xenografted mice, and increase some probiotic bacteria such as Bifidobacterium, Gemellales, Blautia, Sutterella, Anaerostipes, Roseburia, Lachnobacterium, Lactobacillus, and Desulfovibrio. This demonstrates that HEP could promote the antitumor efficacy of 5‐Fu by improving the microbiota composition, the immune inflammatory response, and homeostasis.