Prebiotic fibre mixtures counteract the manifestation of gut microbial dysbiosis induced by the chemotherapeutic 5-Fluorouracil (5-FU) in a validated in vitro model of the colon.

BACKGROUND: 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient's prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. METHODS: A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. RESULTS: We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. CONCLUSIONS: These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.

Microbiota-dependent influence of prebiotics on the resilience of infant gut microbiota to amoxicillin/clavulanate perturbation in an in vitro colon model.

Antibiotic exposure disturbs the developing infant gut microbiota. The capacity of the gut microbiota to recover from this disturbance (resilience) depends on the type of antibiotic. In this study, infant gut microbiota was exposed to a combination of amoxicillin and clavulanate (amoxicillin/clavulanate) in an in vitro colon model (TIM-2) with fecal-derived microbiota from 1-month-old (1-M; a mixed-taxa community type) as well as 3-month-old (3-M; Bifidobacterium dominated community type) breastfed infants. We investigated the effect of two common infant prebiotics, 2'-fucosyllactose (2'-FL) or galacto-oligosaccharides (GOS), on the resilience of infant gut microbiota to amoxicillin/clavulanate-induced changes in microbiota composition and activity. Amoxicillin/clavulanate treatment decreased alpha diversity and induced a temporary shift of microbiota to a community dominated by enterobacteria. Moreover, antibiotic treatment increased succinate and lactate in both 1- and 3-M colon models, while decreasing the production of short-chain (SCFA) and branched-chain fatty acids (BFCA). The prebiotic effect on the microbiota recovery depended on the fermenting capacity of antibiotic-exposed microbiota. In the 1-M colon model, the supplementation of 2'-FL supported the recovery of microbiota and restored the production of propionate and butyrate. In the 3-M colon model, GOS supplementation supported the recovery of microbiota and increased the production of acetate and butyrate.

The Role of Intestinal Microbiota in Metastatic Colorectal Cancer Patients Treated With Capecitabine.

BACKGROUND: Previous pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment. PATIENTS AND METHODS: Patients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region. RESULTS: Thirty-three patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. Of the 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (ß-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine. CONCLUSION: This is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.