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Background <p>Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss and tissue wasting; it was associated with adverse survival outcomes in patients with locally advanced rectal cancer (LARC). However, its biological basis and links to the gut microbiome, circulating metabolites, and body composition in LARC remain unclear.</p> Methods <p>We conducted a retrospective cohort study of 198 LARC patients, including 30 with cachexia. Gut microbial profiles were characterized using 16S rRNA sequencing with predictive functional inference. Serum metabolites were analyzed via orthogonal partial least squares–discriminant analysis (OPLS-DA) and validated by ROC analysis. Associations among microbial taxa, metabolites, body composition, and clinical indices were assessed using correlation analyses. Survival outcomes were evaluated by Kaplan-Meier curves and multivariate Cox regression models, with subgroup and sensitivity analyses performed to validate the robustness of findings.</p> Results <p>Cachectic patients exhibited marked reductions in BMI, circulating triglycerides and cholesterol, as well as visceral and subcutaneous adipose tissue (VAT and SAT) and skeletal muscle area (SMA) (all <i>P</i> &lt; 0.05). Microbial α- and β-diversity were comparable between groups, yet cachexia was associated with selective enrichment of Peptostreptococcaceae, Erysipelotrichaceae, Veillonella, and Fusobacterium, alongside depletion of Faecalibacterium, Roseburia, and Prevotella. Notably, UBA1819 (Ruminococcaceae) was enriched in cachectic patients and inversely correlated with Faecalibacterium, hemoglobin, and albumin, suggesting intra-family functional divergence. Specific cachexia-enriched taxa, including Veillonella and Erysipelotrichaceae, were inversely associated with SMA and VAT, whereas butyrate-producing genera showed positive correlations with muscle preservation. Functional predictions highlighted enrichment of N-acetylneuraminate degradation in cachexia versus TCA cycle pathways in non-cachectic patients. High abundance of Peptostreptococcaceae and Erysipelotrichaceae was associated with poorer overall survival. Metabolomic profiling identified lithocholic acid, cortisone, 3,5,9-trihydroxyergost-7-en-6-one, and 5,6-DHET as cachexia-associated metabolites (AUC 0.65–0.78), which formed cross-domain correlations with microbial taxa and host tissue measures.</p> Conclusion <p>Our findings reveal a coordinated linkage between the gut microbiome, metabolome, and host body composition in LARC cachexia. Specifically, selective microbial remodeling and metabolite perturbations are closely coupled with skeletal muscle and adipose tissue depletion and adverse survival. These results provide a conceptual foundation for future mechanistic and translational studies exploring the host–microbiome–metabolic interactions in cancer cachexia.</p>

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Microbiome and metabolome patterns centered on cancer cachexia link skeletal muscle and adipose tissue depletion to clinical outcomes in locally advanced rectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Zhixing Kuang,
  • Qing Zhan,
  • Jiannan Tu,
  • Anchuan Li,
  • Wei Guo,
  • Rong Zheng,
  • Hao Jiang,
  • Benhua Xu

摘要

Background

Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss and tissue wasting; it was associated with adverse survival outcomes in patients with locally advanced rectal cancer (LARC). However, its biological basis and links to the gut microbiome, circulating metabolites, and body composition in LARC remain unclear.

Methods

We conducted a retrospective cohort study of 198 LARC patients, including 30 with cachexia. Gut microbial profiles were characterized using 16S rRNA sequencing with predictive functional inference. Serum metabolites were analyzed via orthogonal partial least squares–discriminant analysis (OPLS-DA) and validated by ROC analysis. Associations among microbial taxa, metabolites, body composition, and clinical indices were assessed using correlation analyses. Survival outcomes were evaluated by Kaplan-Meier curves and multivariate Cox regression models, with subgroup and sensitivity analyses performed to validate the robustness of findings.

Results

Cachectic patients exhibited marked reductions in BMI, circulating triglycerides and cholesterol, as well as visceral and subcutaneous adipose tissue (VAT and SAT) and skeletal muscle area (SMA) (all P < 0.05). Microbial α- and β-diversity were comparable between groups, yet cachexia was associated with selective enrichment of Peptostreptococcaceae, Erysipelotrichaceae, Veillonella, and Fusobacterium, alongside depletion of Faecalibacterium, Roseburia, and Prevotella. Notably, UBA1819 (Ruminococcaceae) was enriched in cachectic patients and inversely correlated with Faecalibacterium, hemoglobin, and albumin, suggesting intra-family functional divergence. Specific cachexia-enriched taxa, including Veillonella and Erysipelotrichaceae, were inversely associated with SMA and VAT, whereas butyrate-producing genera showed positive correlations with muscle preservation. Functional predictions highlighted enrichment of N-acetylneuraminate degradation in cachexia versus TCA cycle pathways in non-cachectic patients. High abundance of Peptostreptococcaceae and Erysipelotrichaceae was associated with poorer overall survival. Metabolomic profiling identified lithocholic acid, cortisone, 3,5,9-trihydroxyergost-7-en-6-one, and 5,6-DHET as cachexia-associated metabolites (AUC 0.65–0.78), which formed cross-domain correlations with microbial taxa and host tissue measures.

Conclusion

Our findings reveal a coordinated linkage between the gut microbiome, metabolome, and host body composition in LARC cachexia. Specifically, selective microbial remodeling and metabolite perturbations are closely coupled with skeletal muscle and adipose tissue depletion and adverse survival. These results provide a conceptual foundation for future mechanistic and translational studies exploring the host–microbiome–metabolic interactions in cancer cachexia.