Abstract 5953: Modulation of the gut microenvironment by water-soluble dietary fiber alleviates cancer-induced muscle wasting in mice

Abstract Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss in age-related sarcopenia may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism, the so-called ‘gut-muscle axis’. However, limited evidence is available on the relationship between cancer-related sarcopenia and the gut environment. Dietary fiber, a non-digestible nutrient including polysaccharides which modulate composition and activity of the gut microbiota, are now noticed for its beneficial effects. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared to a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet attenuated body weight and skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the significant retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. Moreover, cecal short chain fatty acid (SCFA) levels were relatively low in cachectic mice, although the reduction was mitigated when PHGG supplementation was given. To explore the effects of SCFAs on skeletal muscle mass, we used a well-established in vitro myotube culture model. Exposure of C2C12 myotubes to LPS induced a significant decrease in the diameter, but was reversed on administering a cocktail of SCFAs by suppressing the elevation of Atrogin-1, and upregulating the expression of PGC1α and Tfam, markers of mitochondrial biogenesis. Taken together, our findings suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future. Citation Format: Tomoki Sakakida, Takeshi Ishikawa, Toshifumi Doi, Ryuichi Morita, Yasuko Hirai, Katsura Mizushima, Yasuki Higashimura, Ken Inoue, Tetsuya Okayama, Kazuhiko Uchiyama, Tomohisa Takagi, Aya Abe, Ryo Inoue, Yoshito Itoh, Yuji Naito. Modulation of the gut microenvironment by water-soluble dietary fiber alleviates cancer-induced muscle wasting in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5953.