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. 2010 Aug;299(2):G440-8.
doi: 10.1152/ajpgi.00098.2010. Epub 2010 May 27.

Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation

Claire Barbier de La Serre  1 , Collin L Ellis, Jennifer Lee, Amber L Hartman, John C Rutledge, Helen E Raybould
Affiliations

Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation

Claire Barbier de La Serre et al. Am J Physiol Gastrointest Liver Physiol. 2010 Aug.

Abstract

Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic "low-grade" systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.

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Figures

Fig. 1.
Fig. 1.
Effect of consumption of a high-fat (HF) diet on body weight, adiposity, and food intake in low-fat (LF) and HF-fed animals after 8 or 12 wk on respective diets A: there was a significant increase in body weight in diet-induced obesity-prone (DIO-P) rats compared with diet-induced obesity-resistant (DIO-R) or LF animals (DIO-P vs. LF, P < 0.001, DIO-P vs. DIO-R, P < 0.01). B: adiposity index was calculated as the sum of the fat pads expressed as a percentage of total body weight. After 8 or 12 wk on the diets, DIO-P rats showed a significantly higher adiposity than LF and DIO-R rats (DIO-P vs. LF or DIO-R, P < 0.01 at 8 wk, P < 0.001 at 12 wk). There was a significant increase in adiposity after 12 wk compared with 8 wk (*P < 0.05) in DIO-P rats. C: starting at week 4, the DIO-P group had a significantly higher energy intake than LF and DIO-R animals (week 4: DIO-P vs. LF, P < 0.001, DIO-P vs. DIO-R, P < 0.01; week 7: DIO-P vs. LF or DIO-R, P < 0.05; week 10: DIO-P vs. LF or DIO-R, P < 0.001). Data are means ± SE; n, no. of rats. Different letters denote significant differences between groups.
Fig. 2.
Fig. 2.
A: myeloperoxidase (MPO) activity in the ileum in LF, DIO-R, and DIO-P rats after 12 wk on respective diets. There was a significantly higher level of MPO activity in DIO-P rats compared with LF or DIO-R animals (DIO-P vs. LF, P < 0.01, DIO-P vs. DIO-R, P < 0.05). B: plasma levels of lipopolysaccharide (LPS) were increased in DIO-P but not DIO-R rats after 12 wk on a HF diet (DIO-P vs. LF or DIO-R, P < 0.05). C and D: photomicrographs of toll-like receptor (TLR)4/MD2 complex immunoreactivity in transverse sections of ileal crypts from LF, DIO-R, and DIO-P rats after 12 wk on respective diets. E: quantification of TLR4/MD2 immunoreactivity expressed as a percentage of positive pixels from 4–6 images/rat; n = 4/group. There was more immunoreactivity in DIO-P than LF and DIO-R tissue (DIO-P vs. LF or DIO-R, P < 0.05). Different letters denote significant differences between groups.
Fig. 3.
Fig. 3.
Duodenal intestinal alkaline phosphatase (IAP) activity in LF, DIO-R, and DIO-P rats after 8 wk on respective diets. DIO-P rats had significantly lower IAP activity than LF and DIO-R animals (DIO-P vs. LF, P < 005, DIO-P vs. DIO-R, P < 001). Different letters denote significant differences between groups.
Fig. 4.
Fig. 4.
Phosphorylated myosin light chain (p-MLC) expression in the ileum in LF, DIO-R, and DIO-P rats after 12 wk on respective diets. A: p-MLC expression was measured by Western blot and quantified as a proportion of control glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The DIO-P group showed an increase in p-MLC expression compared with LF and DIO-R rats (DIO-P vs. LF, P < 0.01, DIO-P vs. DIO-R, P < 0.05). Different letters denote significant differences between groups. B: blot showing GAPDH and p-MLC expression in LF, DIO-R, and DIO-P rats after 12 wk on respective diets.
Fig. 5.
Fig. 5.
Immunolocalization of occludin in ileal sections in LF, DIO-R, and DIO-P rats after 12 wk on respective diets. A: photomicrographs of ileal mucosa in LF, DIO-R, and DIO-P rats showing immunolocalization of occluding to tight junctions; in ileum from DIO-P rats, immunoreactive occludin can be seen within the cytoplasm of the enterocytes. B: occludin localization was quantified by determination of %positive pixels in the cytoplasm. DIO-P rats showed an increase in occludin localization to the cytoplasm compared with LF and DIO-R (DIO-P vs. LF or DIO-R, 3–6 cells/image, 5 images/rat, n = 4/group; P < 0.001). Different letters denote significant differences between groups.
Fig. 6.
Fig. 6.
Measurement of gut permeability by appearance of FITC-labeled dextran in plasma in LF, DIO-R, and DIO-P rats after 10 wk on respective diets. DIO-P rats exhibited a significant increase in gut permeability compared with LF and DIO-R animals (DIO-P vs. LF or DIO-R, P < 0.001). DIO-R rats also exhibited a significant increase in gut permeability compared with the LF control group (DIO-R vs. LF, P < 0.001). Different letters denote significant differences between groups.
Fig. 7.
Fig. 7.
Quantification of total bacterial-universal 16S rRNA gene copies and proportion of bacterial order in cecal samples from LF, DIO-R, and DIO-P after 8 wk on respective diets. A: no significant difference in total bacterial 16S copies in LF, DIO-R, and DIO-P (LF vs. DIO-R, P = 0.3, LF vs. DIO-P, P = 0.1, DIO-R vs. DIO-P, P = 0.5); however, there was a significant decrease in total bacterial 16S copies in HF- vs. LF-fed rats (P < 0.05). B: Bacteroidales order as a relative percentage of total bacteria in cecal samples from rats after 8 wk on respective diets; there was no significant difference between LF, DIO-R, and DIO-P but a significant decrease in HF- vs. LF-fed rats (P < 0.01). C: Clostridiales order as a percentage of total bacteria in cecal samples from LF, DIO-R, and DIO-P after 8 wk on respective diets. DIO-R and DIO-P animals showed a significant increase in Clostridiales order compared with LF rats (DIO-R vs. LF, P < 0.05, DIO-P vs. LF, P < 0.01). There were no differences between DIO-R and DIO-P (P = 0.3), and there was a significant increase in Clostridiales order in HF vs. LF. rats (P < 0.001). D: Enterobacteriales order as a percentage of total bacteria in cecal samples from LF, DIO-R, and DIO-P after 8 wk on respective diets showing a significant increase in HF-fed DIO-P rats only (DIO-P vs. LF or DIO-R, P < 0.05).
Fig. 8.
Fig. 8.
Proposed model by which ingestion of HF diets leads to hyperphagia and obesity. It is proposed that ingestion of a HF diet leads to changes in gut microbiota, which, possibly with a decrease in IAP, leads to an increase in luminal LPS and TLR4 activation in epithelial cells. The resulting gastrointestinal (GI) inflammation results in altered intestinal barrier function and an increase in passage of LPS from the lumen to the lamina propria. The precise mechanism by which this low but chronic increase in plasma LPS leads to altered regulation of food intake, hyperphagia, and obesity is not clear. TJs, tight junctions.
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