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bioRxiv · 10.64898/2026.09.17.752337

Gut microbiota-dependent phenylpropanoic acid derivatives reduced in cancer cachexia protect against myotube atrophy

Degraeve, A. L.·Li, X.·Lefevre, C.·Piron, E.·Loriot, A. L.·Delzenne, N.·Neyrinck, A. M.·Bindels, L.
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Abstract

Cancer cachexia is a debilitating disease characterized by muscle atrophy. Given the gut dysbiosis in cancer cachexia and the increasing evidence of a gut-muscle axis, we explored the potential beneficial effects of bacteria-dependent metabolites on myotube atrophy. Using both hypothesis-driven and hypothesis-free approaches, in-depth metabolomic analysis of blood samples from cachectic C26 tumor-bearing mice treated or not with antibiotics, as well as disease-free germ-free and conventionalized mice, identified 7 bacteria-dependent metabolites decreased under cachectic conditions. Such alterations were not mediated by reduced caloric intake. Among them, 2 metabolites, namely 2-phenylpropanoic acid (2PPA, also known as 2-phenylpropionic acid) and 3-(3,4-dihydroxyphenyl)propanoic acid (3,4OHPP, also known as 3,4-dihydroxyhydrocinnamic acid or dihydrocaffeic acid), demonstrated anti-atrophying effect, alone and in combination, on mouse C2C12 myotubes. Transcriptomics revealed that these 2 bacteria-dependent metabolites restored the amino acid homeostasis with an activation of ATF4 and the serine biosynthesis pathway. Pharmacological inhibition of the phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of this pathway, prevented the anti-atrophying effects of 2PPA and 3,4OHPP, indicating a causal role for PHGDH in this effect. By identifying microbiota-dependent metabolites as potential therapeutic levers, the current work not only advances our understanding of microbiome-host crosstalk in disease but also opens avenues for innovative, targeted interventions to mitigate muscle atrophy.

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Degraeve, A. L., Li, X., Lefevre, C., Piron, E., Loriot, A. L., Delzenne, N., Neyrinck, A. M., Bindels, L.. 2026-09-18. Gut microbiota-dependent phenylpropanoic acid derivatives reduced in cancer cachexia protect against myotube atrophy. https://doi.org/10.64898/2026.09.17.752337

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