High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse

Department of Cell & Molecular Physiology, University of North Carolina at Chapel Hill, North Carolina, United States of America.
PLoS ONE (Impact Factor: 3.23). 08/2010; 5(8):e12191. DOI: 10.1371/journal.pone.0012191
Source: PubMed


Obesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance.
Conventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in GF NF-kappaB(EGFP) mice.
Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.

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    • "We have used a cholesterol-lowering diet, which has been reported to regulate T2Rs gene expression via the cholesterol-sensitive transcription factor SREB-2 [34]. We have also used a high fat, high caloric diet (45% or 60% fat, 4.7–5 kcal/g) which induces obesity [40] and is known to change gut microbiota with increase in the proportion of Gram-negative bacteria and to induce chronic inflammation [41]–[44]. Our study showed a differential level of expression of these T2Rs throughout the gut mucosa and changes in their expression in distinct regions of the gut in response to fasting and different types of feeding supporting our hypothesis that intraluminal contents regulate T2Rs expression and the concept that T2Rs have distinct roles depending on the gut region and diet manipulation. "
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    ABSTRACT: Bitter taste receptors and signaling molecules, which detect bitter taste in the mouth, are expressed in the gut mucosa. In this study, we tested whether two distinct bitter taste receptors, the bitter taste receptor 138 (T2R138), selectively activated by isothiocyanates, and the broadly tuned bitter taste receptor 108 (T2R108) are regulated by luminal content. Quantitative RT-PCR analysis showed that T2R138 transcript is more abundant in the colon than the small intestine and lowest in the stomach, whereas T2R108 mRNA is more abundant in the stomach compared to the intestine. Both transcripts in the stomach were markedly reduced by fasting and restored to normal levels after 4 hours re-feeding. A cholesterol-lowering diet, mimicking a diet naturally low in cholesterol and rich in bitter substances, increased T2R138 transcript, but not T2R108, in duodenum and jejunum, and not in ileum and colon. Long-term ingestion of high-fat diet increased T2R138 RNA, but not T2R108, in the colon. Similarly, a-gustducin, a bitter taste receptor signaling molecule, was reduced by fasting in the stomach and increased by lowering cholesterol in the small intestine and by high-fat diet in the colon. These data show that both short and long term changes in the luminal contents alter expression of bitter taste receptors and associated signaling molecules in the mucosa, supporting the proposed role of bitter taste receptors in luminal chemosensing in the gastrointestinal tract. Bitter taste receptors might serve as regulatory and defensive mechanism to control gut function and food intake and protect the body from the luminal environment.
    PLoS ONE 09/2014; 9(9). DOI:10.1371/journal.pone.0107732 · 3.23 Impact Factor
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    • "Indeed, TFAs are known for their ability to increase expression of inflammatory markers such as IL-6 and TNF-α [4, 52] and there is evidence that exposure to a high-fat diet increases inflammation in the colon [14, 15, 53] while high-polyphenol diet reduces this process [54]. Previous studies have shown that in adult offspring of mothers fed TFAs during pregnancy and lactation, high levels of LPS activate TLR-4 and mediate low-grade inflammation [7]. "
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    ABSTRACT: Maternal intake of trans-fatty acids (TFAs) in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C), control diet with 0.5% Jussara supplementation (CJ), diet enriched with hydrogenated vegetable fat, rich in TFAs (T), or T diet supplemented with 0.5% Jussara (TJ) during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups) reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF-α, gene expression of IL-6R, TNF-αR (P < 0.05), TLR-4 (P < 0.01), and increase Lactobacillus spp. (P < 0.05) in the colon of offspring compared to the T group. The IL-10 (P = 0.035) and IL-10/TNF-α ratio (P < 0.01) was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development.
    Mediators of Inflammation 09/2014; 2014:987927. DOI:10.1155/2014/987927 · 3.24 Impact Factor
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    • "The upregulation of TLR4 mRNA levels induced by HFD in the liver was shown to be counteracted by butyrate [35]. High-fat diet was associated with the upregulation of TNF-α and phosphorylation of NF-κB in the ileum [88], confirming that fat intake might increase mediators of intestinal permeability and inflammation. The dietary fibers can partly counteract these harmful effects, probably through production of SCFAs, particularly propionic and butyric acids, that could have anti-inflammatory effects in the body [33, 89]. "
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    ABSTRACT: In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion. In this review, we updated evidence on the effects of SCFAs potentially improving metabolic control in type 2 diabetes.
    Mediators of Inflammation 08/2014; 2014:162021. DOI:10.1155/2014/162021 · 3.24 Impact Factor
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