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The epidemic of obesity and type 2 diabetes mellitus is dramatically increasing. Environmental factors, such as sedentary life-style, hypercaloric, fat-rich diet and genetic susceptibility are considered major determinants of type 2 diabetes mellitus. Obesity and peripheral insulin resistance are hallmarks and major risk factors for development of type 2 diabetes mellitus. Cardiovascular complications (eg, atherosclerosis, coronary heart disease) of both metabolic disorders are associated with chronic subclinical inflammation.1 2 The low degree of inflammation in obesity and type 2 diabetes mellitus results from increased expression and production of cytokines and acute phase reactants such as C-reactive proteins, interleukins (ILs), tumour necrosis factor (TNF)α, or lipopolysaccharides (LPS).1 2 Inflammatory cytokines induce peripheral insulin resistance by impairing the insulin receptor (IR)-dependent signalling.1 2 For instance, experimental application of TNFα leads to the phosphorylation of the serine residues of the insulin receptor substrate-1 (IRS-1) with the consecutive inhibition of insulin-stimulated tyrosine autophosphorylation of the IR. The consequence of the impaired IR signalling is a blunted glucose uptake by peripheral tissues. The resulting chronic hyperglycaemia causes deleterious effects on pancreatic beta-cell function and morphology. Inflammatory cytokines reduce insulin secretion, induce apoptosis of pancreatic beta-cells in type 2 diabetes mellitus.3 Administration of anti-inflammatory agents (eg, high doses of aspirin) or experimental deletion of receptors for inflammatory cytokines results in increased insulin sensitivity and improved pancreatic beta-cell function, which is paralleled by a reduction of hyperglycaemia and loss of body weight.4 5 Despite numerous studies describing the activation of proinflammatory cytokines in both major metabolic disorders little is known about the underlying mechanisms.
Recently, it became apparent that a high-fat diet, low intake of fibre and the lack of exercise can contribute to subclinical inflammation. In contrast, proinflammatory cytokine production is suppressed by n-3 and n-6 fatty acid supplementation (eg, fish oil), a fibre-rich diet and physical exercise.6 However, what are the specific stimuli of proinflammatory processes and from where do these stimuli originate?
Previous studies demonstrated that administration of antibiotics reduced obesity and insulin resistance.7 8 The effects correlated with the quantitative and qualitative changes of caecal microbiota and endotoxin content, and were accompanied by reduced translocation of LPS into the circulation.7 Rodents fed a normocaloric diet and maintained in a germ-free environment had markedly reduced body weights, as compared to germ-free animals colonised with intestinal flora derived from conventionally bred mice.9 Even feeding a high-fat diet to germ-free rodents resulted in a lower increase of body weight and less prominent development of insulin resistance, as compared to conventionally maintained mice.9 These data suggest that intestinal microbiota play a pivotal role in conferring diet-induced obesity and insulin resistance. In agreement with this observation, it was demonstrated that the intestinal flora of obese is colonised by different microbiota as compared with normal weight individuals.10 Feeding a high-fat diet, preferentially encountered in obese individuals, favours the colonisation of the intestine with Gram-negative microbiota, whereas the quantity of bifidobacteria decreases.10 11 Colonisation of the intestine with Bifidobacterium spp. has been demonstrated to reduce intestinal endotoxin formation and to improve intestinal barrier function. The question arises about the causative relationship between dietary composition, intestinal microbiota, insulin resistance, and obesity.
Cani et al address this question in the current issue of Gut (see page 1091) evaluating the effects of prebiotic feeding in leptin-deficient ob/ob mice, an animal model of obesity and type 2 diabetes mellitus.12 Prebiotics are defined as non-digestible food ingredients (typically carbohydrates) that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improve host health. In their study, Cani et al12 demonstrate that a prebiotic diet can reduce the expression of proinflammatory cytokines and oxidative stress markers in ob/ob mice. Prebiotics modified the intestinal microbiota composition, favouring the colonisation with Bifidobacterium spp. in ob/ob mice. The changes were accompanied by the reduced intestinal permeability, which correlated with the increased expression of tight-junction proteins (ZO-1 and occludin). Improved intestinal tight junction integrity and the barrier function provide a morphological basis for the decreased translocation of bacterial endotoxins into the circulation and could explain the decreased circulating proinflammatory cytokines. Among the factors contributing to an enhanced intestinal barrier, the short-chain fatty acids (eg, butyrate) appear to be relevant. Butyrate, which is produced by the bacterial fermentation of mainly undigested dietary carbohydrates, has been shown to enhance the growth and proliferation of colonocytes and mucin synthesis.13 Due to anticarcinogenic, anti-inflammatory activity, which at least in part is mediated via inhibition of nuclear factor kappa B (NF-κB) and interferon γ production, and by increased peroxisome proliferator response element (PPAR)γ expression, butyrate has been tested for its ability to treat inflammatory bowel disease.13 However, discrepant results have been reported in clinical trials, precluding the clinical introduction of butyrate for the treatment of inflammatory bowel diseases at the current stage.
An important physiological intestinotrophic factor, which enhances the intestinal integrity is glucagon-like peptide 2 (GLP-2).14 GLP-2, which is co-secreted together with GLP-1, is encoded by the proglucagon gene, and released from intestinal L-cells upon nutrient ingestion or by variety of hormones.14 Due to a potent colonotrophic and antiapoptotic activity GLP-2 has been tested for its ability to restore colonic integrity in humans with short-bowel disease and in animal models of colitis and colonic mucosal atrophy.14 GLP-2 enhanced the adaptative response to experimentally induced intestinal injury and facilitated transepithelial resistance in the normal gut. Cani et al12 observed that prebiotics stimulated the proglucagon gene expression, and the synthesis of GLP-1 and GLP-2 in ob/ob mice. An increase of intestinal barrier function correlated with the reduced translocation of bacterial antigens into the circulation. The effects of prebiotics on the intestinal permeability and on endotoxin translocation were mimicked by exogenous GLP-2. The role of GLP-2 in mediating the beneficial effects of prebiotics on the intestinal integrity is further strengthened by the use of a GLP-2 antagonist, which neutralised the beneficial effects of prebiotics on plasma LPS concentration, hepatic inflammation and oxidative stress factors. The GLP-2 antagonist reduced the expression of tight-junction proteins in the intestine. The results of this elegant study suggest that GLP-2 is as a mediator of prebiotic-induced improvement of the intestinal barrier function and the consecutive reduction of the inflammation processes in ob/ob mice. Further questions arise about the mechanisms; whether prebiotics, their fermentation end-products or changes in the composition of the intestinal flora provide the stimulus of GLP-2 synthesis. Short-chain fatty acids (eg, butyrate) are able to stimulate GLP-2 plasma concentration. Detection of increased production of butyrate in animals receiving prebiotics favours the hypothesis that butyrate may be the mechanism that confers the effects of prebiotics on intestinal function.
In summary, the study by Cani et al12 rediscovers prebiotic nutrients as an alternative approach to causally target type 2 diabetes mellitus and obesity. A low degree of inflammation appears to be a common phenomenon of both metabolic disorders. Nutrients that modify bacterial flora of the intestine are able to alleviate the systematic inflammation processes, thereby enhancing peripheral insulin action and preventing further body weight gain. Whether the principle of diet-induced anti-inflammation and modification of gut microbiota in human obesity and type 2 diabetes mellitus is of value needs to be further validated in preclinical and large-scale clinical trials.
Competing interests: None declared.
Funding: MZS was supported by the DFG (STR 558/6-1).
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