The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60) on the intestinal barrier function and gut peptides in breast cancer patients: an observational study

Francesco Russo, Michele Linsalata, Caterina Clemente, Benedetta D'Attoma, Antonella Orlando, Giovanna Campanella, Francesco Giotta, Giuseppe Riezzo, Francesco Russo, Michele Linsalata, Caterina Clemente, Benedetta D'Attoma, Antonella Orlando, Giovanna Campanella, Francesco Giotta, Giuseppe Riezzo

Abstract

Background: Several GI peptides linked to intestinal barrier function could be involved in the modification of intestinal permeability and the onset of diarrhea during adjuvant chemotherapy. The aim of the study was to evaluate the circulating levels of zonulin, glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF) and ghrelin and their relationship with intestinal permeability and chemotherapy induced diarrhea (CTD).

Methods: Sixty breast cancer patients undergoing an FEC60 regimen were enrolled, 37 patients completed the study. CTD(+) patients were discriminated by appropriate questionnaire and criteria. During chemotherapy, intestinal permeability was assessed by lactulose/mannitol urinary test on day 0 and day 14. Zonulin, GLP-2, EGF and ghrelin circulating levels were evaluated by ELISA tests at five time-points (days 0, 3, 10, 14, and 21).

Results: During FEC60 administration, the lactulose/mannitol ratio was significantly higher on day 14 than at baseline. Zonulin levels were not affected by chemotherapy, whereas GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than those on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline. In contrast, the total concentrations of ghrelin increased significantly at day 3 compared to days 0 and 21, respectively. Ten patients (27%) suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in CTD(+) patients compared to CTD(-) patients. With regards to circulating gut peptides, the AUCg of GLP-2 and ghrelin were significantly lower and higher in CTD(+) patients than CTD(-) ones, respectively. Finally in CTD(+) patients a significant and inverse correlation between GLP-2 and La/Ma ratio was found on day 14.

Conclusions: Breast cancer patients undergoing FEC60 showed alterations in the intestinal permeability, which was associated with modifications in the levels of GLP-2, ghrelin and EGF. In CTD(+) patients, a different GI peptide profile and increased intestinal permeability was found in comparison to CTD(-) patients. This evidence deserves further studies for investigating the potentially different intestinal luminal and microbiota conditions.

Trial registration: Clinical trial NCT01382667.

Figures

Figure 1
Figure 1
Intestinal permeability after 14 days of FEC60. Decreased intestinal permeability after 14 days of FEC60. Small intestinal permeability was probed by measuring the urinary cumulative 5-hour amount of lactulose (Lactulose% = percentage of ingested lactulose), mannitol (Mannitol% = percentage of ingested mannitol) and the Lactulose to Mannitol ratio. Data are reported as medians and the range and analyzed with Wilcoxon matched-pairs signed rank test.
Figure 2
Figure 2
Intestinal permeability in patients with or without chemotherapy induced diarrhea. Intestinal permeability in patients who suffered from chemotherapy induced diarrhea, CTD(+), and those who did not, CTD(−). Small intestinal permeability was probed by measuring the urinary cumulative 5-hour amount of lactulose (Lactulose% = percentage of ingested lactulose), mannitol (Mannitol%) and the Lactulose to Mannitol ratio. Data are reported as medians and the range and analyzed with Wilcoxon matched-pairs signed rank test.
Figure 3
Figure 3
Basal plasma values of gut hormones during FEC60 protocol. Basal plasma values of gut hormones at baseline (day 0) and during the scheduled days (day 3, day 10, day 14, day 21). Values not showing a common letter differ significantly. Data are reported as median and the range and analyzed with Friedman test and Dunn’s Multiple Comparison Test.
Figure 4
Figure 4
Gut hormone profiles in patients with or without chemotherapy induced diarrhea. Basal plasma values of gut hormones at baseline (day 0) and during the scheduled days (day 3, day 10, day 14, day 21) in patients who suffered from chemotherapy induced diarrhea, CTD(+), and those who did not, CTD(−). Values not showing a common letter differ significantly. Data are reported as median and the range and analyzed with Friedman test and Dunn’s Multiple Comparison Test.
Figure 5
Figure 5
Correlation between Lactulose to Mannitol ratio and GLP-2. Negative and significant correlation (r = −0.854, p = 0.0029 Spearman correlation coefficient) between intestinal permeability as expressed by Lactulose to Mannitol ratio and the circulating levels of GLP-2 recorded on day 14 in the group of patients who suffered from chemotherapy induced diarrhea, CTD(+).

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