Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer

Abstract Background Short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are produced by the gut microbiota and are considered to fulfill crucial physiological roles. Previous pre-clinical studies also indicated bi-directional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. However, evidence from clinical studies in this field of research is scarce. This study investigated the effect of three cycles of capecitabine on fecal SCFA and BCFA levels and their associations with tumor response, nutritional status, physical performance, chemotherapy-induced toxicity, systemic inflammation, and bacterial abundances in patients with colorectal cancer (CRC). Methods Forty-four patients with metastatic or unresectable CRC, scheduled for treatment with capecitabine (± bevacizumab), were prospectively enrolled in a multicentre cohort study. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2), and after (T3) three cycles of capecitabine. Tumor response (based on CT/MRI scans), nutritional status (MUST score), physical performance (Karnofsky Performance Score), and chemotherapy-induced toxicity (CTCAE) were recorded. Additional data on clinical characteristics, treatment regimen, medical history, and blood inflammatory parameters were collected. Fecal SCFA and BCFA concentrations were determined by gas chromatography-mass spectrometry (GC-MS). Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. Results Fecal levels of the SCFA valerate and caproate decreased significantly during three cycles of capecitabine in our patient population. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance, and chemotherapy-induced toxicity were not statistically significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At the three sampling timepoints, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. Conclusions The present study provided the first indications for a role of SCFA and BCFA during treatment with capecitabine as well as implications and recommendations for further research. More knowledge in this field will contribute to the evidence-based design of interventions targeting the gut microbiota and/or SCFA/BCFA production to optimize chemotherapy efficacy. Trial registration The current study was registered in the Dutch Trial Register (NTR6957) on 17/01/2018 and can be consulted via the International Clinical Trial Registry Platform (ICTRP).