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

Aarnoutse, Romy; Ziemons, Janine; Vos‐Geelen, Judith de; Iersel, Liselot Valkenburg-van; Wildeboer, Aurelia C. L.; Vievermans, Anne; Creemers, Geert-Jan; Baars, Arnold; Vestjens, H; Le, Ngoc-Giang; Barnett, David J.M.; Rensen, Sander S.; Penders, John; Smidt, Marjolein L.

doi:10.1016/j.clcc.2021.10.004

Cited by 10 publications

(11 citation statements)

References 30 publications

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“…Furthermore, it has been indicated that Fusobacterium nucleatum might be able to induce chemoresistance to 5-FU in CRC cells, while Lactiplantibacillus (previously Lactobacillus) plantarum-derived supernatant seemed to sensitize CRC cells to the anticancer effects of 5-FU [24][25][26]. In contrast to this, our research group did not detect consistent capecitabine-induced changes in gut microbiota composition and diversity in a relatively small and heterogeneous group of CRC patients [27]. Other clinical studies, using different chemotherapeutics, described that chemotherapy treatment affected gut microbiota composition and the abundance of prominent SCFA-producing bacteria such as Veillonella and Prevotella [14,28,29].…”

Section: Introductioncontrasting

confidence: 94%

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

et al. 2023

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Background Gut bacteria-derived short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are considered to have beneficial metabolic, anti-inflammatory as well as anti-carcinogenic effects. Previous preclinical studies indicated bidirectional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. 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. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2) and after (T3) three cycles of capecitabine. Tumor response (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. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance and chemotherapy-induced toxicity were not significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At all time points, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. Conclusions The present study provided first indications for a potential role of SCFA and BCFA during capecitabine treatment as well as implications for further research. 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).

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Section: Introductioncontrasting

confidence: 94%

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

et al. 2023

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“…However, evidence from clinical studies in this eld of research is scarce. Previously, our research group did not detect capecitabine-induced changes in gut microbiota composition and diversity in a relatively small and heterogeneous group of CRC patients (27). Other clinical studies, using different chemotherapeutics, described that chemotherapy treatment affected gut microbiota composition and the abundance of prominent SCFA-producing bacteria such as Veillonella and Prevotella (14,28,29).…”

Section: Introductionmentioning

confidence: 70%

“…Analysis of the gut microbiota was performed as previously described (27). In short, metagenomic DNA from fecal samples was isolated using the Ambion MagMax™ Total Nucleic Acid Isolation Kit (Thermo Fisher Scienti c).…”

Section: Analysis Of Gut Microbiota Composition and Bacterial Abundancesmentioning

confidence: 99%

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

Ziemons

Aarnoutse

Heuft

et al. 2023

Preprint

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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).

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“…Metabolites produced by a healthy gut microbiota, such as short-chain fatty acids (e.g., acetic, propionic, and butyric acids), play important roles in maintaining the intestinal barrier, ( 43 ) providing energy ( 44 ) and immune homeostasis ( 45 ). It is well-recognized that gut microbiota also participate in modulating the intestinal microenvironment and host metabolism, while the gut microecology is vulnerable to the effects of unhealthy diet ( 46 ) and antibiotic treatments ( 47 ). Furthermore, the disruption of gut microbial homeostasis may result in metabolic shifts, ultimately leading to the pathological development of metabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

Shifts in Fecal Metabolite Profiles Associated With Ramadan Fasting Among Chinese and Pakistani Individuals

Chen

Ikram

et al. 2022

Front. Nutr.

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The human gut microbiota has been proposed to serve as a multifunctional organ in host metabolism, contributing effects to nutrient acquisition, immune response, and digestive health. Fasting during Ramadan may alter the composition of gut microbiota through changes in dietary behavior, which ultimately affects the contents of various metabolites in the gut. Here, we used liquid chromatography–mass spectrometry-based metabolomics to investigate the composition of fecal metabolites in Chinese and Pakistani individuals before and after Ramadan fasting. Principal component analysis showed distinct separation of metabolite profiles among ethnic groups as well as between pre- and post-fasting samples. After Ramadan fasting, the Chinese and Pakistani groups showed significant differences in their respective contents of various fecal metabolites. In particular, L-histidine, lycofawcine, and cordycepin concentrations were higher after Ramadan fasting in the Chinese group, while brucine was enriched in the Pakistani group. The KEGG analysis suggested that metabolites related to purine metabolism, 2-oxocarboxylic acid metabolism, and lysine degradation were significantly enriched in the total subject population pre-fasting vs. post-fasting comparisons. Several bacterial taxa were significantly correlated with specific metabolites unique to each ethnic group, suggesting that changes in fecal metabolite profiles related to Ramadan fasting may be influenced by associated shifts in gut microbiota. The fasting-related differences in fecal metabolite profile, together with these group-specific correlations between taxa and metabolites, support our previous findings that ethnic differences in dietary composition also drive variation in gut microbial composition and diversity. This landscape view of interconnected dietary behaviors, microbiota, and metabolites contributes to the future development of personalized, diet-based therapeutic strategies for gut-related disorders.

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

Cited by 10 publications

References 30 publications

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

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

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

Shifts in Fecal Metabolite Profiles Associated With Ramadan Fasting Among Chinese and Pakistani Individuals

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