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doi: 10.3390/cells8080876.

Oligosaccharides Modulate Rotavirus-Associated Dysbiosis and TLR Gene Expression in Neonatal Rats

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Oligosaccharides Modulate Rotavirus-Associated Dysbiosis and TLR Gene Expression in Neonatal Rats

Ignasi Azagra-Boronat et al. Cells..

Abstract

Colonization of the gut in early life can be altered through multiple environmental factors. The present study aimed to investigate the effects of 2'-fucosyllactose (2'-FL), a mixture of short-chain galactooligosaccharides/long-chain fructooligosaccharides (scGOS/lcFOS) 9:1 and their combination (scGOS/lcFOS/2'-FL) on dysbiosis induced during rotavirus (RV) diarrhea in neonatal rats, elucidating crosstalk between bacteria and the immune system. The dietary interventions were administered daily by oral gavage at days 2-8 of life in neonatal Lewis rats. On day 5, RV SA11 was intragastrically delivered to induce infection and diarrhea assessment, microbiota composition, and gene expression of Toll-like receptors (TLRs) in the small intestine were studied. All dietary interventions showed reduction in clinical variables of RV-induced diarrhea. RV infection increased TLR2 expression, whereas 2'-FL boosted TLR5 and TLR7 expressions and scGOS/lcFOS increased that of TLR9. RV-infected rats displayed an intestinal dysbiosis that was effectively prevented by the dietary interventions, and consequently, their microbiota was more similar to microbiota of the noninfected groups. The preventive effect of 2'-FL, scGOS/lcFOS, and their combination on dysbiosis associated to RV diarrhea in rats could be due to changes in the crosstalk between gut microbiota and the innate immune system.

Keywords: HMOs; TLR; microbiota; rotavirus; scGOS/lcFOS.

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Conflict of interest statement

The authors declare that they have a financial relationship with the organization that sponsored the research. K.K., B.L., S.T., B.S., J.K., and J.G. are employees of Danone Nutricia Research. J.G. is head of the Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science at the Utrecht University and partly employed by Danone Nutricia Research. B.L., as indicated by the affiliations, is leading a strategic alliance between University Medical Centre Utrecht/Wilhelmina Children’s Hospital and Danone Nutricia Research. The other authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Clinical variables of severity and incidence of diarrhea on day 8: (a) The Diarrhea Index (DI) is based on scoring fecal samples from 1 to 4 depending on the color, texture, and abundance. Scores of DI ≥ 2 indicate the presence of diarrhea, whereas scores < 2 indicate the absence of diarrhea. (b) The percentage of diarrheic animals (%DA) is based on the percentage of animals displaying DI scores ≥ 2 in each group. (c) The mean fecal weight was calculated in each group as an objective indicator of diarrhea severity. The results are expressed as mean ± S.E.M. (n = 8–12/group, depending on the number of fecal samples obtained) *p < 0.05 compared to the reference (REF) group; #p < 0.05 compared to the RV group ((a) by ANOVA; (b) by the Chi Squared test; and (c) by the Mann–Whitney U test).
Figure 2
Figure 2
Small intestine gene expression of Toll-like receptors (TLRs) at the peak of diarrhea (day 8): The transcription of TLR2, 4, 5, 7, and 9 were quantified by real-time PCR. (a) The ∆Ct of TLR expression compared toGusb was calculated in REF animals. (b) The relative gene expression in the experimental groups was calculated with respect to REF, which corresponded to 100% of transcription. Results are expressed as mean ± S.E.M. (n = 8/group). *p < 0.05 compared to the REF group; #p < 0.05 compared to RV group (by the Mann–Whitney U test).
Figure 3
Figure 3
Main taxonomic ranks showing the proportion of bacterial populations in the fecal content at the peak of diarrhea (day 8): The sequencing of the amplicon targeting the V3–V4 region of the 16S rRNA was performed following the 16S Metagenomic Sequencing Library Illumina 15044223 B protocol. The relative proportion of the bacteria was calculated in each taxonomic rank: (a) phylum, (b) family, (c) genus, and (d) species. The results are expressed as mean (n = 3/group). Significant differences are shown only in the text (by the Mann–Whitney U test).
Figure 4
Figure 4
Summary of genera variation in fecal microbiota at the peak of diarrhea (day 8): A heat map of the mean relative abundances of the prominent OTUs assigned to the genus level is represented. The rows represent the genera and the columns the experimental groups. The log2 of the fold change with respect to the RV group was calculated and assigned a color following the legend. Genera which were present in a group but not in the RV group were assigned the maximum variation (>3.5, marked with a “+”), whereas the genera which were presented in the RV group and not in the other groups were assigned the minimum variation (<−3.5, marked with a “-“). The results are derived from n = 3/group. VM:Verrucomicrobia.
Figure 5
Figure 5
Analysis of the fecal microbiota diversity in genera and species at the peak of diarrhea (day 8): (a) Representation of Venn diagrams and (b) Principal Components Analysis (PCA) of all genera and species. To estimate the presence or the absence of these taxa in the experimental groups, it was agreed that all groups displaying 2 or 3 animals (out of the 3 analyzed in each group) with a bacterial proportion were computed as present, while the groups displaying 1 animal or none were computed as absent. The results are derived from n = 3/group.
Figure 6
Figure 6
Analysis of the main bacterial species with probiotic activity found in the fecal microbiota at the peak of diarrhea (day 8): The heat map displays the relative abundance of bacteria with probiotic activity, where the group with the highest abundance was set at 100% and the group with the lowest abundance was set at 0%. The results were derived from n = 3/group.
Figure 7
Figure 7
Summary of the effects of the RV and the scGOS/lcFOS and 2’-FL on microbiota composition and crosstalk: (a) Microbial imbalance produced by the RV infection in the neonatal rat model in terms of crosstalk alterations and microbiota composition with respect to a noninfected group (REF) and (b) Preventive effects of scGOS/lcFOS and 2’-FL on the dysbiosis caused by the RV.
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