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: 3.53). 08/2010; 5(8):e12191. DOI: 10.1371/journal.pone.0012191
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: A causal relationship between the pathophysiological changes in the gut epithelium, 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 weeks; food intake, body weight and adiposity were measured. Barrier function ex vivo, using FITC-labelled dextran (4,000 kDa, FD-4) and horseradish peroxidase (HRP) probes in Ussing chambers, gene expression, and gut microbial communities were assessed. After one week, there was an immediate but reversible increase in paracellular permeability, decrease in IL10 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 IL10 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. Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    AJP Gastrointestinal and Liver Physiology 03/2015; 308(10):ajpgi.00029.2015. DOI:10.1152/ajpgi.00029.2015 · 3.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Being overweight and obese has become an increasingly serious clinical and socioeconomic problem worldwide. The rapidly rising prevalence of obesity has prompted studies on modifiable, causative factors and novel treatment options for this disorder. Recent evidence indicates that excessive weight gain that leads to being overweight and obese may result from alterations in gut microflora. Studies in humans and animals demonstrated that the composition of gut microbiota may differ in lean and obese subjects, suggesting that these differences result in the increased efficiency of caloric extraction from food, enhanced lipogenesis, and impaired central and peripheral regulation of energy balance. Other studies revealed an excessive increase in body weight in a significant percentage of people infected with human adenoviruses SMAM-1 and Ad-36. Dysregulation of adipocyte function by viruses appears to be the most likely cause of excessive fat accumulation in these individuals. Studies on the pathomechanisms related to the pathogenesis of obesity indicated that a high-fat diet triggers the inflammatory response in the hypothalamus, an event that promotes weight gain and further defends elevated body weight through the initiation of central leptin and insulin resistance and impairment of regenerative capacity of hypothalamic neurons. Exposure to a high-calorie diet appears to predispose individuals to obesity not only because of excessive caloric intake but also because of the induction of microbiota- and central inflammatory response-dependent changes that lead to a dysregulation of energy balance.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2014; 68:271-9. DOI:10.5604/17322693.1093928 · 0.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the last decades the rising occurrence of metabolic diseases throughout the world points to the failure of preventive and therapeutic strategies and of the corresponding molecular and physiological concepts. Therefore, a new paradigm needs to be elucidated. Very recently the intimate cross talk of the intestinal microbiota with the host immune system has opened new avenues. The large diversity of the intestinal microbes' genome, i.e. the metagenome, and the extreme plasticity of the immune system provide a unique balance which, when finely tuned, maintains a steady homeostasis. The discovery that a new microbiota repertoire is one of the causes responsible for the onset of metabolic disease suggests that the relationship with the immune system is impaired. Therefore, we here review the recent arguments that support the view that an alteration in the microbiota to host immune system balance leads to an increased translocation of bacterial antigens towards metabolically active tissues, and could result in a chronic inflammatory state and consequently impaired metabolic functions such as insulin resistance, hepatic fat deposition, insulin unresponsiveness, and excessive adipose tissue development. This imbalance could be at the onset of metabolic disease, and therefore the early treatment of the microbiota dysbiosis or immunomodulatory strategies should prevent and slow down the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences.
    Seminars in Immunology 02/2012; 24(1):67-74. DOI:10.1016/j.smim.2011.11.011 · 6.12 Impact Factor