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. 2015 May 15;308(10):G840-51.
doi: 10.1152/ajpgi.00029.2015. Epub 2015 Mar 6.

Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent

M Kristina Hamilton  1 , Gaëlle Boudry  2 , Danielle G Lemay  3 , Helen E Raybould  4
Affiliations

Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent

M Kristina Hamilton et al. Am J Physiol Gastrointest Liver Physiol. .

Abstract

A causal relationship between the pathophysiological changes in the gut epithelium and altered gut microbiota with the onset of obesity have been suggested but not defined. The aim of this study was to determine the temporal relationship between impaired intestinal barrier function and microbial dysbiosis in the small and large intestine in rodent high-fat (HF) diet-induced obesity. Rats were fed HF diet (45% fat) or normal chow (C, 10% fat) for 1, 3, or 6 wk; food intake, body weight, and adiposity were measured. Barrier function ex vivo using FITC-labeled dextran (4,000 Da, FD-4) and horseradish peroxidase (HRP) probes in Ussing chambers, gene expression, and gut microbial communities was assessed. After 1 wk, there was an immediate but reversible increase in paracellular permeability, decrease in IL-10 expression, and decrease in abundance of genera within the class Clostridia in the ileum. In the large intestine, HRP flux and abundance of genera within the order Bacteroidales increased with time on the HF diet and correlated with the onset of increased body weight and adiposity. The data show immediate insults in the ileum in response to ingestion of a HF diet, which were rapidly restored and preceded increased passage of large molecules across the large intestinal epithelium. This study provides an understanding of microbiota dysbiosis and gut pathophysiology in diet-induced obesity and has identified IL-10 and Oscillospira in the ileum and transcellular flux in the large intestine as potential early impairments in the gut that might lead to obesity and metabolic disorders.

Keywords: HF diet; gut barrier; gut microbiota; intestinal permeability; obesity.

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Figures

Fig. 1.
Fig. 1.
Effect of a high-fat (HF) diet on body weight (A), food intake (B), adiposity (C), and lipopolysaccharide binding protein (LBP; D). Adiposity index [(mesenteric + epididymal + retroperitoneal fat/body weight) × 100]. C, chow. Values are means ± SE. Two-way ANOVA (P values displayed for diet, time, and interaction), followed by Bonferroni's post hoc test, *P < 0.05 or ***P < 0.001, significant difference; n = 18/group (A and B) n = 6/group (C and D).
Fig. 2.
Fig. 2.
Effect of a HF diet on gut barrier function in the small (A and B) and large (C and D) intestine. FITC-dextran 4000 (FD4) flux (=paracellular pathway) (A and C) and horseradish peroxidase (HRP) flux (=transcellular pathway) (B and D) was measured ex vivo in Ussing chambers. Values are means ± SE. Two-way ANOVA (P values displayed for diet, time, and interaction), followed by Bonferroni's post hoc test, *P < 0.05, significant difference; n = 5–6/group.
Fig. 3.
Fig. 3.
Gut microbiota changes due to location and diet. A: principal component analysis (PCA) plot showing microbiota communities cluster with location and diet, determined by unweighted UniFrac analysis. B: average relative abundance at phylum level in ileum and colon of rats ingesting either chow or a HF diet. C: significant changes in relative genus abundance in cecum and ileum (>0.4%), labeled [phylum, (genera)] unless otherwise noted. Circle color indicates change in abundance: yellow, no change; red, elevated in chow; and green, elevated in HF. Linear discriminant analysis (LDA) effect size analysis (LEfSe) score >3 was considered significant.
Fig. 4.
Fig. 4.
Microbiota shifts at the genus level in the cecum due to HF diet and time can be characterized in 3 types of response: immediate and sustained change in abundance, e.g., Prevotella [LDA = 5] (A) and Bacteroides [LDA = 4.8] (B); immediate change in abundance at week 1 followed by restoration to chow levels at weeks 3 and 6, e.g., unclassified genus in Lachnospiraceae family [LDA=4.5] (C) and Oscillospira [LDA = 3.9] (D); and immediate change in abundance at week 1 restored to chow levels by week 6, e.g., unclassified genus in Bacteroidales order [LDA = 4.6] (E) and Blautia [LDA = 4.2] (F). Abundance of bacterial genera across time in chow-fed animals did not differ significantly; therefore, time points were combined. LEfSe LDA score >3 was considered significant.
Fig. 5.
Fig. 5.
PCA chow-fed animals (A), rats fed HF diet for 1 wk (B), and rats fed HF diet 3 or 6 wk (C) clustered, yet still show distinct populations. Only bacteria genera with an average abundance >0.4% was taken into account.
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