Elsevier

Seminars in Immunology

Volume 24, Issue 1, February 2012, Pages 67-74
Seminars in Immunology

Review
Immuno-microbiota cross and talk: The new paradigm of metabolic diseases

https://doi.org/10.1016/j.smim.2011.11.011Get rights and content

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.

Highlights

► A new paradigm is needed for the treatment of metabolic diseases. ► Bacterial fragments such as lipopolysaccharides initiate high fat diet induced inflammation. ► Bacterial fragments could serve as biomarkers of metabolic diseases. ► The microbiota to immune relationship sets the tone of metabolic diseases.

Introduction

Understanding the molecular origin of metabolic diseases is a challenge complicated by the large genetic diversity and the social differences between human beings. Therefore, the many natural histories that exist are hurdles slowing down the research to identify the various causes of the actual epidemic of metabolic diseases. Hence, for over half a century, and ever since the advances made in molecular biology, the scientific community has been searching for the genetic origins of metabolic diseases. Despite the tremendous efforts made and the identification of some point mutations in the genome, an overall view of the precise molecular mechanisms causally involved in the development of diabetes and obesity has not been elaborated. Certainly, the discovery of candidate genes by genome wide association studies (GWAS) has shed some light and helped to identify new genes for diabetes sensitivity/resistance and extreme metabolic phenotypes [1]. However, these steps forward can still not account for the overall diversity of the natural histories of metabolic diseases essentially demonstrated by monozygotic twins who are discordant for type 2 diabetes or obesity [2], [3], [4].

A second step towards the understanding of the origin of metabolic diseases has been to consider environmental and epigenetic factors. A dramatic change in eating habits, whereby dietary fibers have been replaced by a fatty diet, certainly contributes to the origin of metabolic diseases. However, this simplistic concept cannot explain why some people are sensitive and others resistant to the development of metabolic diseases. In rodents, a metabolic adaptation is often observed [5]. Genetically identical mice within the same cage and fed a fat-enriched diet for 6–9 months can become either, obese and diabetic, remain lean but become diabetic, remain lean and non-diabetic, or become obese and with a proportion of each population which is different from one another. Hence, it seems that the development of metabolic disease is a matter of individuality where everyone is facing the genetic and environmental pressure. Consequently, there is a need for a new paradigm that should take into account the genetic diversity, the impact of environmental factors, the rapid development of metabolic diseases, and individual behavior in the face of the development of diabetes and obesity. This conclusion has led to the concept of individual medicine where individual traits should be identified to adapt an appropriate therapeutic strategy for small groups of patients.

Over the course of the last decade, several studies have causally linked intestinal and tissue microbiota to the development of metabolic diseases, diabetes, and obesity. The microbiome, which defines overall the genes encoded by the microbiota, includes a hundred times more genes than the human genome and ten times more cells than are present in our own body [6]. This notion does not even consider the intestinal virome which is characterized by 10–100 times more particles than the intestinal microbiota itself [7], [8] and has been shown to be diet-dependent [9]. At birth, this biome is involved in the programming and the control of many physiological functions such as the development of the intestinal epithelium, vascular blood flow, the innate and adaptive immune systems, and the nervous system, to cite a few [10], [11], [12], [13], [14]. Consequently, germ free mice (axenic mice) are characterized by many abnormal physiological features. A new paradigm would be that a given microbiota contributes to the physiological regulation of energy homeostasis. Along with genetic and environmental susceptibilities, the intestinal microbiota could trigger the programming and consequent development of an impairment in the energy homeostasis leading to metabolic diseases. The first set of analyses demonstrated that the intestinal microbiota was a signature of the metabolic phenotype [15], [16], [17], [18]. The change in the intestinal microbiota, according to the metabolic phenotype, had two origins. The first one was related to the genome of the host itself: mice with a null mutation of the leptin gene had different microbiota [15]. Similar observations were made in mice bearing mutations of genes involved in the control of inflammation such as NLRP6 [19], [20], [21]. The second one was related to the environment and essentially to the effect of the diet which modified the microbiota composition, and also the expression of the metagenome independently from the host genome, as shown in homozygote twins non-concordant for obesity [22] or in genetically identical mice fed a high-fat diet [5], [23]. Importantly, recent data show that diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. The mechanisms related to this convergence allow the understanding of the host evolutionary and dietary history. The pathological changes in the intestinal microbiota, as defined by an intestinal dysbiosis, initially led to the concept of energy harvesting [24]. A change in the ratio of the major phyla the Bacteroidetes to Firmicute led to a new microbiota with an increased capacity to digest some dietary fibers to produce carbonyl residues able to be absorbed by the host. This conclusion was in line with the observation that germ free mice fed a fat-enriched diet gained less weight than their conventional counterparts [25].

The molecular mechanisms responsible for hyperglycemia and increased body weight are linked to an inappropriate distribution of energy metabolism and energy expenditure. Therefore, type 2 diabetes is the consequence of increased hepatic glucose production, reduced insulin secretion and action. Numerous other physiological functions are altered such as the autonomic and central nervous systems leading to an impaired secretion of hormones like glucagon and the incretins. During obesity a reduced central regulation of food intake and energy expenditure are the main molecular characteristics leading to adipose tissue development and body weight gain. A first set of molecular mechanisms linking intestinal microbiota to obesity was related to the concept of “increased energy harvesting”. The specific intestinal microbiota described in obese humans and mice could more efficiently digest the dietary fibers and produce more short chain fatty acids that serve as substrates for the body [26]. Hence, more energy is harvested from food and taken up by the body [26]. Furthermore, is was also shown that the intestinal microbiota could down-regulate the production of Fat-Induced Adipocyte factor (FIAF) by the intestinal cells which in turn inhibited the activity of the lipoprotein lipase. The latter enzyme favors the release of free fatty acids to tissues such as the liver and adipose cells [27]. However, a change in energy storage is not a common phenotype to all metabolic diseases. Some type 2 diabetic patients, notably of Asian, are not always characterized by increased food intake and energy storage. However, a common trait to both obesity and type 2 diabetes is the presence of a low grade inflammatory tone that has been precisely described in tissues directly involved in the regulation of the metabolism such as the liver, adipose tissue and muscle [28]. Therefore, a role for the innate and adaptive immune systems has been proposed [28], [29], [30], [31], [32], [33], [34]. This metabolic inflammation is characterized by a moderate excess of cytokine production such as IL6, IL1, or TNFα that impairs cellular insulin signaling and hence contributes to insulin resistance and diabetes [33], [34]. Similarly, this low grade inflammation is also involved in the modeling of adipose tissue development which could lead to obesity. Therefore, the major question was to link metabolic diseases to the intestinal microbiota. We first showed that the lipopolysaccharides (LPS), which are highly inflammatory components of the cell-wall of the gram negative bacteria, were increased in the blood of patients at risk of becoming obese and diabetic such as those preferentially eating a fat-enriched diet [35]. In these patients a 2–3-fold increase in plasma LPS concentrations characterized a state defined as “metabolic endotoxemia”. Similar results were found in mice [23] and in mutant mice such as in leptin deficient mice even feeding on a normal diet [36] suggesting that a change in intestinal permeability to LPS could be a regulatory mechanism [36], [37]. The causal role for LPS was then demonstrated by inducing metabolic endotoxemia in mice fed a normal diet and continuously infused with a low rate of LPS using osmotic pumps. This experimental procedure was sufficient to induce hepatic insulin resistance, glucose intolerance, and increased adipose tissue weight [23]. Conversely, LPS infusion in LPS receptor CD14/TLR4 knockout mice did not trigger these metabolic features and could not initiate type 2 diabetes and obesity, showing the important role of the LPS-CD14/TLR4 mechanism [23], [38]. Furthermore, CD14 and TLR4 knockout mice were even more sensitive to insulin than wild type controls showing the role of the inflammatory tone on the control of glucose homeostasis [23], [38]. The role of intestinal microbiota was further demonstrated since a chronic antibiotic treatment reduced the intensity of the disease in high-fat diet and ob/ob mice [36], [39], [40] Furthermore, probiotic [41] and prebiotic [42] treatments further controlled the intestinal microbiota and metabolic diseases.

This new concept suggests that, in physiological situations such as during a fatty meal, some bacterial factors enter the host and trigger inflammation when binding to their cognate receptors such as the Toll-like receptors (TLRs). A first question concerns the mechanism of entry of bacteria-derived factors. Intestinal absorption of dietary lipids was found to facilitate the absorption of gut derived bacterial lipopolysaccharides (LPS) [43] (Fig. 1). The role of chylomicrons has been suggested [44]. Dietary long-chain fatty acids are transported from the absorptive enterocyte to extra-intestinal tissues after incorporation as triglycerides into chylomicrons that are released into mesenteric lymph. LPS may thus enter the body via a transcellular epithelial pathway. It is not known whether all epithelia intestinal cells can uptake intraluminal LPS and whether they are associated to chylomicrons during the synthesis of the lipoprotein particles. Interestingly, LPS translocation requires Toll-like-receptor-4 (TLR4) expression by epithelial intestinal cells [45]. Once in the blood, LPS-enriched chylomicrons exchanged LPS with other lipoproteins [46]. The mechanism involves the LPS-binding protein (LBP) that is present in the plasma [47]. LBP catalyzes the movement of LPS monomers from LPS aggregates to HDL particles, to phospholipid bilayers, and to a binding site on soluble CD14 [48]. Soluble CD14 can hasten transfer by receiving an LPS monomer from an LPS aggregate, and then by surrendering it to an HDL particle, thus acting as a soluble “shuttle” for an insoluble lipid [48]. Consequently, in situations of chronic exposure to high fat diet favoring lipid absorption, LPS can be continuously transported towards target tissues such as the liver [49] or blood vessels [50] and trigger inflammation. The LPS fragments would impair the overall metabolic status when reaching tissues such as the liver involved in glucose homeostasis and lipid synthesis, the pancreatic beta cells that secrete the insulin s the muscle responsible for most of the post prandial glucose clearance, and the adipose tissue where lipids are stored. Certainly other important functions such as those of the autonomic nervous system or the intestine itself could be impaired by LPS. Notably adipocytes treated with LPS produce cytokines that could generate inflammation [32], [51], [52]. The candidate cells responsible for the low grade inflammation and for their causal role in the development of metabolic diseases have been shown to originate from the immune system [28], [31], [53]. Firstly, metabolic diseases are characterized by increased infiltration of adipose tissue by inflammatory monocytes, a feature that defines and is responsible for the low grade inflammation [54], [55]. The infiltrating macrophages and dendritic cells (DC) secrete cytokines and factors issued from the oxidative stress. The expression of the monocyte chemo-attractant protein-1 (MCP-1; also called CCL2) mRNA is increased in adipose tissue of mice fed a high fat diet as well as in genetically obese (ob/ob) or diabetic (db/db) mice [56], [57], [58] and it has been demonstrated that low concentrations of LPS in the bloodstream drive CCR2-dependant emigration of monocytes from bone marrow [59]. An over-expression of CCL2 in adipose tissue leads to the infiltration of macrophages and insulin resistance. By contrast, in mice deficient for CCL2, macrophage infiltration and insulin resistance are reduced [56]. Furthermore, a deficiency in CCR2, the receptor for CCL2, attenuates the development of obesity, reduces macrophage infiltration and the inflammatory profile and improves insulin sensitivity [53]. Some data argue also for a role of dendritic cells in the initiation or the maintenance of adipose tissue inflammation during the development or the regression of the metabolic syndrome since weight loss results in a reduction in the number of these infiltrating cells with a decrease of pro-inflammatory adipokines in obese patients [60], [61]. Ablation of dendritic cells in high-fat diet-induced insulin-resistant mice, leads to a decrease in inflammatory markers and normalized insulin sensitivity [62]. In addition, other innate immune cells, such as mast cells, infiltrate adipose tissue during metabolic syndrome [63]. Genetically induced mast cell deficiency and pharmacological stabilization of mast cells reduced weight gain and improved insulin sensitivity and glucose tolerance [63]. Their regulatory role is multifactorial and could be linked to pro-angiogenetic, pro-inflammatory, and immunocompetent features, such as through the MHCII-dependent presentation of antigens that leads to the activation of CD4+ T lymphocytes. Altogether these factors are also involved in the recruitment of precursor cells, such as endothelial cells and preadipocytes, thus leading to the reshaping of the vasculature and the development of the overall adipose tissue [52], [64], [65].

As detailed above, the reason why cells from the immune system invade adipose depots and the liver is as yet unknown but could be related to the expression of Microbe-Associated Molecular Patterns (MAMPs) directly in the invaded tissues (adipose depots, liver). Phagocyte cells, would present the bacterial antigens to the lymphocytes that would be activated onsite. However, the precise antigens are yet unknown. Mice with deletions of the LPS receptor TLR4, or part of the TLR4 machinery such as CD14, were resistant to metabolic disease [38]. Similarly, both male and female Tlr2(−/−) mice were protected from the adverse effects of HFD [66]. Female Tlr2(−/−) mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding [66]. These effects were associated with an increased capacity of Tlr2(−/−) mice to preferentially burn fat, combined with reduced tissue inflammation. Recognition of the bacterial fragments by CD14 and the nuclear oligomeric domain protein NOD1 are also risk factors for the development of metabolic diseases since mice with deletions for these Microbe Associated Molecular Patterns (MAMPs) receptors resisted the occurrence of type 2 diabetes [41], [67]. The treatment of mice with an agonist of NOD1 further stimulated insulin resistance [67]. Activation of NOD proteins by meso-diaminopimelic acid-containing peptidoglycan (PGN) caused whole-body insulin resistance, bolstering the concept that innate immune responses to bacterial motifs lead to insulin resistance such as observed for TLR4 and CD14. Interestingly, muramyl dipeptide, an agonist of NOD2 was neutral or protected against insulin resistance. The deletion of the corresponding gene enhanced high-fat diet-induced type 2 diabetes [41]. Similarly, TLR5 might also protect against metabolic syndrome since mice genetically deficient in TLR5 exhibited hyperphagia and developed hallmark features of metabolic syndrome [68], [69] through mechanisms requiring inflammation. The metabolic phenotype was transmissible since the transplantation of the microbiota from TLR5-deficient to germ free mice resulted in obesity and reduced insulin sensitivity. These findings demonstrate that modulation of the immune system may affect host metabolism by altering gut microbiota. The impact of the host immune system on gut microbiota has been also well demonstrated in mice lacking NLRP3 and NLRP6 two molecules that control activation of the inflammasome [20], [70], [71].

An important role of lymphocytes in the control of metabolism has been shown recently so that obesity and type 2 diabetes can now be defined as immunometabolic diseases [72]. It was recently shown that proinflammatory T lymphocytes are present in visceral adipose tissue before the appearance of macrophages, and could either initiate and perpetuate adipose tissue inflammation as well as promote the development of insulin resistance. Following diet-induced metabolic diseases, an increase in pro-inflammatory CD4 and CD8 T lymphocytes is observed in adipose tissue and the secretion of IFNγ, a prototypical T-helper 1 cytokine, is increased [73], [74]. Kinetic analyses of adipose tissue infiltration following diet-induced insulin resistance have shown that infiltration by CD8 T cells preceded the accumulation of macrophages. CD8 T cell elimination reduced macrophage infiltration and adipose tissue inflammation and ameliorated glucose intolerance. Conversely, adoptive transfer of CD8 T cells aggravated adipose inflammation. The infiltrating CD8 and even CD4 T cells had a restricted TCR-Vbeta repertoire, suggesting that they were specific for an antigen [75]. These experiments suggest that obese adipose tissue activates CD8 T cells, which, in turn, promote the recruitment and activation of macrophages. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation. Other studies indicate that the number of regulatory T cells (Treg) is reduced in adipose tissue from obese mice. Treg are known to play critical roles in maintaining immunological unresponsiveness to self-antigens and in suppressing excessive immune responses deleterious to the host. They express Foxp3, which is critical for the initiation of a genetic program for the differentiation and function of Treg cells [76], [77]. In lean mice, Foxp3+Treg (fat Treg) are present in adipose tissue and even increase over time. Fat Treg strongly express the anti-inflammatory cytokine, IL-10. In animal models of obesity and insulin resistance (ob/ob and high-fat diet-fed mice), the number of fat Treg was substantially reduced compared to that of lean control mice. Conversely, the induction of regulatory cells ameliorated insulin sensitivity and inflammation [30], [78] while their deletion in adipose tissue was associated with the induction of many genes encoding inflammatory mediators and insulin resistance. Interestingly, a reduction in Foxp3 transcripts was also observed in the omental fat of obese humans compared with subcutaneous fat. Other lymphocytes might be involved in the development of metabolic diseases. Natural killer T cells (NKT) T cells that recognized lipids in the context of CD1d, are present in the adipose tissue of lean mice [29]. While NKT cells (NK1.1+CD3ɛ+ cells) are reduced in liver and increased in WAT following 3 weeks of high fat diet, CD1d deficient mice, devoid of NKT cells, are not protected against diet-induced obesity [79], [80]. The γδ T cells represent roughly 5% of CD3+ T cells in adipose tissue and most of them produce IL-17 upon stimulation. IL-17 deficiency enhances diet-induced obesity in mice and accelerates adipose tissue accumulation even in mice fed a low-fat diet [81]. B lymphocytes are present in adipose tissue of lean mice [29] but their number increases following diet-induced obesity [82], [83], and they accumulate in white adipose tissue (WAT) in obese mice. Notably, mice lacking B cells are protected from disease despite weight gain [83]. The deleterious effects of B cells on glucose metabolism were linked to the activation of pro-inflammatory macrophages and of T cells and to the production of pathogenic IgG antibodies [83]. Importantly, the mechanisms observed in adipose tissue do not preclude a role of the intestinal immune system in relationship with the microbiota. That metabolic diseases may result from altered interactions between microbiota and the host immune system was shown in type 1 diabetes [84], [85]. Thus development of type 1 diabetes in the Non Obese Diabetic mouse (NOD) did not occur in mice lacking MyD88 [85]. In these mutant mice, T lymphocytes from pancreas did not mature and did not elicit the autoimmune reaction against insulin secreting cells that is characteristic of the disease. Protection depended on commensal microbiota since MyD88(−/−) NOD mice devoid of gut microbiota developed robust type 1 diabetes. This result suggests that the interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition. Furthermore NOD mice show a disturbed tolerance to autologous commensal bacteria attested by colonic hyperplasia, and an increased number of inflammatory dendritic cells (DC) suggestive of a mild colitis. These phenomena are abolished when mice are fed with an anti-diabetogenic diet [86]. Hence, modulation of the intestinal microbiota by diet could regulate the intestinal immune response. In patients with type 1 diabetes, mucosal inflammation is also observed in the small intestine [87] and lamina propria DC are no longer able to convert T lymphocytes into regulatory cells [88]. These results suggest that microbiota-derived products are important modulators of the innate and adaptive immune systems [89]. Consequently, modulating intestinal microbiota could lead to a breakdown of intestinal tolerance due to impaired DC regulation (Fig. 2).

The microbiota influences DC development and recruitment and control intestinal T and B cell responses. At birth, intestinal colonization by the environmental microbiota is a key determinant of the education and development of the intestinal immune system [90]. The nature of intestinal bacteria can influence the function of DC and the induction of tolerance or inflammatory responses [91], [92], [93]. As an example different LPS from various bacteria can activate subsets of DC to produce distinct arrays of cytokines that induce different types of adaptive immunity [94]. Pretreatment of DC with commensal lactobacillus species induced a state of tolerance able to prevent intestinal inflammation due to pathogens [95], [96]. Furthermore, germ free mice are characterized by a low number of DC in the mesenteric lymph nodes [97] and less inflammatory DC in the colonic lamina propria when compared with conventional mice [98]. Therefore, during metabolic diseases changes in the intestinal microbiota might modify the properties of DC and promote inflammation.

Altogether, numerous arguments confirm that activation of innate immune cells by the microbiota can influence the development of metabolic diseases. There is still considerable discussion regarding the reason as to why immune cells are hosted into the adipose tissue. Which antigens are recognized? Why are chemo-attracting molecules produced in the adipose cells and in response to which stimuli? We and others recently showed that bacteria-derived products such as LPS or peptidoglycan-like molecules translocate into the blood in response to a fat-enriched diet [23], [67]. It is thus possible that changes in the intestinal microbiota might promote the translocation of a spectrum of bacterial products that can reach the adipose tissue and the liver via the lymph or the blood. They could then initiate inflammation and consequently a change in metabolic parameters in the tissue. Our recent data demonstrate that large amounts of live bacteria can be detected in the adipose depots and blood leucocytes [41] following a few days of a fat-enriched diet [41]. We have also observed an increased co-localization of intestinal bacteria and DC in the lamina propria of diabetic mice [41].

Consequently, intestinal innate immune and epithelial cells could act as sensors of microbial or metabolic/nutritional dangers leading to the production of inflammatory cytokines and chemokines which contribute to the recruitment of immune cells. Fat-enriched diets and changes in intestinal microbiota could overcome the intestinal immune barrier, allowing low grade invasion of lamina propria by enteric commensals with variable immunostimulatory properties. Increased bacterial translocation may promote excessive activation of innate and adaptive immune responses in the gut but also beyond the gut. Consequently low grade systemic inflammation may develop and promote metabolic syndrome.

Recent studies, using conventional and germ free mice, have suggested that the origin of metabolic disease could be localized in the intestine where a fat-enriched Western diet and gut bacteria would interact to promote intestinal inflammation and contribute to the progression of obesity and insulin resistance [99].

As already discussed above, we recently demonstrated that at the early onset of high-fat diet induced metabolic diseases, live bacteria can be translocated from the intestinal lumen towards the metabolically active tissues such as the adipose tissue [41]. The mechanism underlying bacterial translocation is unclear but may involvemucosal dysbiosis. For example, we showed that [41] an increased number of Escherichia coli can adhere to the intestinal epithelium of high-fat diet fed diabetic mice. These adherent bacteria can be phagocytosed by cells from the innate immune system. The originality is that some of the mucosal bacteria can remain alive or not fully degraded inside the phagocyte and then transported towards the adipose tissue and the corresponding lymph nodes. The quantity of bacteria present in the tissues was dramatically increased by 10–100 times during the transition from a normal to a high-fat diet. This bacterial translocation process is not observed in CD14 or NOD knockout mice suggesting that this mechanism requires the recognition of the bacterial fragments by CD14 and NOD1which binds peptidoglycan from gram negative bacteria only. Interestingly, NOD2, which bind all peptidoglycans, was not required for the bacterial translocation process. Altogether these results indicate that treatments able to correct dysbiosis and/or bacterial translocation might be considered for therapy or prevention of metabolic diseases. To test this hypothesis, we used a probiotic Bifidobacterium lactis B420 that displaced deleterious bacteria from the mucosal layer, and showed that high-fat diet-induced insulin resistance was prevented [100]. Another discovery was that the lack of leptin dramatically increased bacterial translocation [100]. The treatment with a probiotic delivering leptin directly in the intestine partly reversed the phenotype. In addition, the treatment with a probiotic reduced mucosal bacterial adherence and the overall number of bacteria present in the mucosa, improved insulin sensitivity and reduced inflammation. The increased bacterial translocation observed at the onset of metabolic diseases points to the importance of host–microbiota interactions for the control energy homeostasis. In diabetic mice, lamina propria dendritic cells contained Escherichia coli bacteria and migrated into the blood and the adipose tissue. Consequently, the quantity of bacterial DNA was considerably increased in the metabolically active tissues of diabetic mice. This accumulation of bacterial fragments could be responsible for the increased infiltration of immune cells and the triggering of inflammation.

Section snippets

Conclusions

Recent data support the hypothesis that a change in the homeostasis of the immune system is causal to the development of metabolic diseases. Therefore, it can be postulated that the vast adaptive characteristics of the immune system could account for the large heterogenic and rapid increase in metabolic diseases. In addition, we suggest here that the wide diversity of bacterial antigens from intestinal origin might activate the low grade metabolic inflammation that promotes metabolic diseases.

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