Polygonatum cyrtonema Hua polysaccharides alleviate muscle atrophy and fat lipolysis by regulating the gut microenvironment in chemotherapy-induced cachexia

RONGRONG ZHOU ^1* Tingting Liu ² You Qin ² Jing Xie ² Shuihan Zhang ² Yi Xie ² Jia Lao ³ Wei He ³ Hongliang ZENG ² Xue-yang Tang ² Xuefei Tian ⁴ Yuhui Qin ²

• ¹ The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
• ² Hunan Academy of Chinese Medicine, Changsha, China
• ³ The ResGreen Group, Changsha, Anhui Province, China
• ⁴ Hunan University of Chinese Medicine, Changsha, Anhui Province, China

Polygonatum cyrtonema Hua (PC) is an essential herbal medicine in China for improving muscle quality and enhancing physical function, whose active ingredients are polysaccharides (PCP).Previous study revealed the anti-atrophy effects of PCP in cachectic mice. However, whether the effects of PCP on anti-atrophy is associated with gut microenvironment remains elusive. This research endeavored to assess the medicinal efficacy of PCP in alleviating muscle atrophy, fat lipolysis and the potential mechanisms. The cancer cachexia model was induced by male C57BL/6 mice bearing with Lewis lung tumor cells and chemotherapy. The pharmacodynamics of PCP (32, 64 mg/kg/day) was investigated by tumor-free body weight, gastrocnemius muscle weight, soleus muscle weight, epididymal fat weight, tissue histology analysis, and pro-inflammatory cytokines.Immunohistochemistry and Western blotting assays were further used to confirm the effects of PCP.16S rRNA sequencing, LC-MS and GC-MS based metabolomics were displayed to illustrate the gut microbiota composition and alterations in metabolites. Additionally, free fatty acid receptor FFAR2 (a crucial SCFA signaling molecule) agonist was used to confirm the role of gut microbiota metabolites SCFAs in the treatment of cancer cachexia and compared with PCP. This study demonstrated that PCP significantly mitigated body weight loss, restored muscle fiber atrophy and mitochondrial disorder, alleviated adipose tissue wasting, strengthened the intestinal barrier integrity as well as decreased the intestinal inflammation in chemotherapy-induced cachexia. Furthermore, the reversal of specific bacterial taxa including Klebsiella, Akkermansia, norank_f__Desulfovibrionaceae, Enterococcus, NK4A214_group, Eubacterium_fissicatena_group, Eubacterium_nodatum_group, Erysipelatoclostridium, and Lactobacillus, Monoglobus, Ruminococcus, Odoribacter, Enterorhabdus, along with alterations in metabolites such as amino acids (AAs), eicosanoids, lactic acid and shortchain fatty acids (SCFAs), were related to the therapeutic effects of PCP. Our findings indicated the use of PCP as a prebiotic drug targeting the microbiome-metabolomics axis for cancer patients receiving chemotherapy.