Gut microbiota-dependent phenylpropanoic acid derivatives reduced in cancer cachexia protect against myotube atrophy
- 1UCLouvain, Louvain Drug Research Institute, LDRI, Metabolism and Nutrition Research Group, MNut, Brussels, Belgium - Walloon Excellence in LifeSciences and BIOt
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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BibTeX
@misc{degraeve2026microbiotadependent,
title = {{Gut microbiota-dependent phenylpropanoic acid derivatives reduced in cancer cachexia protect against myotube atrophy}},
author = {A. L. Degraeve and X. Li and C. Lefevre and E. Piron and A. L. Loriot and N. Delzenne and A. M. Neyrinck and L. Bindels},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752337},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752337v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Gut microbiota-dependent phenylpropanoic acid derivatives reduced in cancer cachexia protect against myotube atrophy
AU - A. L. Degraeve
AU - X. Li
AU - C. Lefevre
AU - E. Piron
AU - A. L. Loriot
AU - N. Delzenne
AU - A. M. Neyrinck
AU - L. Bindels
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752337
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752337v1
AB - 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.
ER -