Fungal Proteins from Hericium Erinaceus Show Auxiliary Antitumor Effects with 5-Fluoro-2,4(1H,3H)-Pyrimidinedione by Improving the Gut Microbiota in Mice

Cancer represents a major disease burden worldwide, and despite continuous advances in medical therapies, 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-fluoro-2,4(1H,3H)-pyrimidinedione (5-Fu), and we attempted to identify new potential prebiotic bacteria for auxiliary antitumor treatment. There were 1455 proteins identified from Hericium erinaceus. In a xenografted mouse model of cancer, HEP with 5-Fu significantly suppressed tumor growth, inhibited inflammatory factors 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 can significantly promote the antitumor efficacy of 5-Fu by improving the microbiota composition, immune inflammatory response and homeostasis and by activating the PPAR signaling pathway. Funding: This work was supported by funding from the National Natural Science Foundation of China (81701086), the Guangzhou Science and Technology Plan Projects (201504281708257; 201604020009; 201707020022), and the High-level Leading Talent Introduction Program of GDAS (2016GDASRC-0102; 2017GDASCX-0102). Declaration of Interest: All the authors declare that no competing interests exist. Ethical Approval: The experimental protocols were approved by the Guangdong Laboratory Animals Monitoring Institute, and all experimental procedures conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.