# Stage-Dependent Metabolic Responses to Oral Nutritional Supplementation in Cancer Cachexia: A Single-Arm Pilot Study

## TL;DR

This pilot study explores how oral nutritional supplements affect metabolism and gut microbiome in cancer cachexia patients, finding stage-dependent responses.

## Contribution

The study is the first to show stage-dependent metabolic responses to ONS in cachexia, identifying fatty acids as potential biomarkers.

## Key findings

- ONS improved hand-grip strength and walking-speed in cancer cachexia patients.
- Non-severe cachexia patients showed reduced fatty acids after ONS, while severe patients showed increases.
- Fatty acid metabolism was identified as a key pathway affected by ONS in cachexia.

## Abstract

Background/Objectives: Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss and muscle wasting, leading to impaired quality of life and poor clinical outcomes. Although oral nutritional supplements (ONS) are recommended to support inadequate oral intake during chemotherapy, their effects on underlying metabolic alterations and gut microbiome composition, particularly across different stages of cachexia remain unclear. This single-arm pilot study aimed to evaluate the feasibility and metabolic effects of an 8-week ONS intervention in patients with cancer cachexia undergoing chemotherapy. Methods: This study was conducted at the Chungnam National University Hospital, Daejeon, Republic of Korea between January 2023 and October 2023. The primary endpoints were feasibility outcomes, including adherence, tolerability, attrition rate, and ONS-related adverse events. Secondary outcomes included body composition, physical performance, biochemical markers, quality of life, plasma GDF-15 levels, serum metabolomics, and gut microbiome composition. Assessment of secondary outcomes and multi-omics profiling was performed at baseline and after 8 weeks. Patients were stratified into severe and non-severe cachexia groups and analyzed. Results: A total of 10 patients (median age 65 years, range 42–76) participated. Primary cancer types included cholangiocarcinoma (n = 4), colorectal (n = 4), and gallbladder cancer (n = 2). Adherence was 82%, with excellent tolerability and no ONS-related adverse events. Body composition, quality of life, and gut microbiome showed no significant changes. Hand-grip strength and walking-speed were slightly improved after 8 weeks intervention (p = 0.014 for hand-grip strength; p = 0.021 for walking-speed, Wilcoxon signed-rank test) in overall cohort. Metabolomics identified 10 metabolites, predominantly fatty acids, with significant between-group differential responses (p < 0.05, Mann–Whitney U test). Non-severe cachexia patients showed reductions in circulating fatty acids following ONS, consistent with attenuated lipolysis and reduced endogenous fat mobilization, whereas severe cachexia patients demonstrated increases, suggesting limited metabolic responsiveness to nutritional intervention. Fatty acid metabolism emerged as the predominant discriminatory pathway. Conclusions: This study showed the feasibility of integrating ONS with multi-omics profiling. Our findings suggest that metabolic alterations might precede clinically detectable changes, potentially providing a rationale for early intervention. Specifically, certain fatty acids were identified as candidate biomarkers that warrant further validation in larger cohorts.