Guide Toll-Like Receptors: Practice and Methods

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Fluxogram describing the methods of data collection and articles selection.. Main characteristics of animal and clinical studies included in the systematic revision.. The principal summary measures in an outcome level were different risk ratios of developing obesity, diabetes, dyslipidaemia or metabolic syndrome in every experimental conditions used, difference in means of RNA or biochemical expression levels of markers studied and differences on histological or phenotypical assessment of major organs studied in a variety of experimental conditions.

Subgroup analyses within the selected studies were also considered and taken into account.. It is well known that the TLRs comprehend an extended family of pathogen-associated molecular patterns recognition PAMP receptors of the innate immunity. These receptors allow the prompt activation of downstream signalling of MyDdependent and MyDindependent pathways in response to several antigens, mainly of Gram-positive and Gram-negative bacteria, and they are all linked to production of cytokines and enhancement of the inflammation..

Since it is established that subclinical inflammatory processes are major contributors to metabolic syndrome, obesity and diabetes, several lines of investigation were made to confirm the role of innate immunity receptors and prompt activation in the pathogenesis of metabolic disturbances. This phenomenon persisted even when its values were statistically adjusted to waist circumference and body mass index.

This study also reveals that this TLR increased activity was significantly correlated with significant higher blood pressure and plasma glucose levels, and with interleukin-1b IL-1b , Monocyte Chemoattractant Protein-1 MCP-1 and Necrosis Factor-kB NF-kB activity, concluding that the activation of the TLR can count as an independent factor not only to metabolic syndrome but also to the cardiovascular risk of these patients.

The impact of TLRs is also verified in other clinical situations that are strongly related to metabolic syndrome and that can explain its participation as a causative factor through indirect pathways.. On one hand, Cristina Cuda et al showed that different polymorphisms of TLR4, with different activation rates of this receptor, were statistically associated to different serum insulin levels and insulin sensitivities.

The individuals with TLR4 with Gly allele were found to have higher levels of insulin and lower levels of insulin sensitivity in comparison to the considered normal Asp homozygotes. They also found that a second polymorphism, an intronic SNP rs can even modulate the relationship between dietary saturated fatty acids and HDL cholesterol, showing that an increased intake of saturated fatty acids was inversely related to significant lower levels of HDL cholesterol, in these individuals.

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These remarkable results, however, were not so strongly verified in the smoking population, and the authors point this factor as a potential confounding variable that must be considered in future studies.. A strong association has been also described between the expression and activity of TLRs and the development of type 1 and type 2 diabetes, major factors in the metabolic syndrome pathogenesis.

Interestingly, insulin sensitivity in TLR2 knockout mice was conserved in the liver causing a significant statistical reduction of hepatic glucose production and lower risk of developing hepatosteatosis under high-fat diet.

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This same study also stated that mice that knockout to TLR2 were associated to a phenotype of decreased body weight, fat mass, lower number 1. The study concluded that the DG-variant was, in the Caucasian subgroup, associated to a reduced risk of diabetes type 2 and metabolic syndrome. However the results were not reproducible in other subgroups and the authors stated that it could be explained by the differences in the allele frequency among different populations. Recently, the intestinal microbiota has been progressively studied and knowledge of its profound influence in maintaining the human physiology and nutrition has astonishingly increased.

In fact, it has become apparent that the microbiota can change metabolically the way we acquire nutrients or our ability to harvest energy through several mechanisms.

Interestingly, two studies by Backhed et al. The authors also verified that these mice had statistical elevations of liver mRNAs encoding enzymes that were participants in the fatty acid biosynthetic pathway, leading to an increase of triglycerides production in their livers. These facts point to influences on different energetic inputs, nutrients availability and metabolic modulations by intestinal microbiota, showing an important contribution to metabolic disturbances similar to those described in obesity and diabetes..

Furthermore, it has become apparent that in spite of its location in the human intestine, the microbiota plays important systemic changes that are directly linked to the low-grade chronic inflammatory state, hugely present in the metabolic syndrome..

Original Research ARTICLE

It was also found that the gut bacteria were able to induce the suppression of fasting-induced adipocyte factor, thereby limiting the inhibition of Lipoprotein lipase in the adipocytes and promoting the body fat accumulation. Analogous results were obtained by Remely et al study, since higher prevalence of Firmicutes and lactic bacteria were encountered in type 2 diabetic mice in opposition to Bacteroidetes and F.

The authors also tested the influence of these population changes in the methylation of exons of TLR2 and 4 in the intestinal epithelium and described significant statistical lower methylations rates for TLR2 in diabetic mice and lower methylation rates for TL4 in obese mice, suggesting that there are important epigenetic modulations by the intestinal bacteria and that those modulations could probably incur in exacerbated risks of diabetes and obesity. These results support the previous data from Zhang et al study that showed reduced levels of gut-protecting Bifidobacteria , a phylum associated with resistance to the effects of LPS from the gut microbiota, in mice with a high-calorie diet.

In fact the study points that a high inflammatory state was present in all animals with impaired glucose tolerance and increased body fat, on high-fat diet. The authors also revealed a predominance of Desulfovibrionaceae , sulphate-reducing bacteria, in high-calorie diet mice, a fact that could be related to the development of metabolic syndrome in these mice, since the disruptive properties of the sulphate in the intestinal barrier were present. Backhed et al aimed to test the importance of microbiota during infancy in the development of obesity later in life.

This study showed that breastfeeding seems responsible for the colonization of the intestine mainly by Bifidobacteria and for a decrease in the Enterobacteriaceae family members. Also, the study shows that the use of antibiotics in infants can cause the elimination of Bacteroids and a reduction in Bifidobacterium population levels, thereby reducing two important antiobesogenic families in the intestinal microbiota. The activation of innate immunity through the TLR cannot be dissociated from the intestinal microbiota and its mutual crosstalk playing a decisive factor in the development of metabolic syndrome..

In fact, the modulation and interaction between microbiota and TLR activation were investigated in a TLR2 knockout mice study that revealed that, in spite of the genetic predetermination to insulin sensitivity by these mice reported in studies before, 18,19 this phenotype could be drastically reversed by gut microbiota. The study confirmed that these TLR2 knockout mice, in non-germ-free facilities, had higher levels of Firmicutes and Bacteroidetes in comparison to wild-type mice, and increased lipopolysaccharides absorption, glucose intolerance, insulin resistance and obesity.

The authors stated that these results can be explained by an increased activation of TLR4 receptors in the absence of TLR2 activation. They also verified increased endoplasmic reticulum stress and JNK activation by the TLR4, which had effects that could be inhibited by a TLR4 antisense oligonucleotide causing an increase in glucose tolerance and sensitivity when compared to the controls.

Furthermore, in TLR2 knockout mice, the use of a mixture of antibiotics resulted in an improvement of insulin sensitivity and metabolic status. Another recent study by Ubeda et al further revealed that using knock-out mice to a specific TLR, the impact of the absence of that certain TLR was initially minimal in the bacteria communities at the intestine, after a treatment with antibiotics, when compared to their respective wild-type mice.

Interestingly, the authors also stated that differences in mice's colonies with different TLR deficiencies were only verified after long-term breeding in isolation from each other, and probably with great influence from maternal transmission. The authors attribute these results to differential exposures in husbandry conditions and mice types.

To add to this complex network of relations between host genetic expression and the environment, Kellermayer et al. The authors pointed out that these epigenetics and metagenomic effects, along with the modulation of the bacterial populations, could explain the loss of the protective barrier function of the intestine and changes in the microbiome environment observed in the Metabolic Syndrome. As the importance of the intestinal microbiome in the metabolic syndrome becomes more apparent, new lines of investigation have appeared, aiming the bacterial populations as a therapeutic hypothesis in the Metabolic Syndrome..

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A study by Wang et al used high-fat diet mice in which was induced metabolic syndrome and subjected them to administration of one of three probiotics Lactobacillus paracasei , L. The results showed that these strains were able to reduce the weight gain, increase insulin sensitivity and limit hepatic steatosis, and also that they were able to modulate innate immunity and the pro-inflammatory state, through the reduced infiltration of macrophages in the adipose tissue. Moreover, the probiotic treatment was capable of reducing key phylotypes keen to cause metabolic syndrome as are Desulfovibrionaceae and Clostridium examples , and capable of reducing inflammatory processes associated to sulphate sodium-induced lesion by these bacteria.

Inflammatory cell expression of Toll-like receptor-2 (TLR2) within refractory periapical granuloma.

On the other hand, certain strains and also certain combinations of probiotic strains can probably provide different benefits in reversing the metabolic syndrome by a different impact on certain mechanisms, such as the increase of acetate, a known molecule shown to be able to improve obesity and diabetes on these mice.

Another study, performed in humans, reported that infusion of intestinal microbiota collected from lean donors into the intestine of Metabolic Syndrome subjects was able to increase insulin sensitivity median rate of glucose disappearance changed from These changes were associated to an increase of butyrate-producing bacteria in the gut's recipients, which is known to influence directly the glucose metabolism.

A randomized pilot study by Leber et al. However, in spite of the significant increase of the gut permeability in the metabolic syndrome group of patients, the investigators did not find any difference of the endotoxin, C-reactive protein, neutrophil function and TLR expression levels between the group who had received the probiotic and the control group. The liver is a major organ of the human organism and it has a profound impact in its metabolic and immune homeostasis.

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Furthermore it has been progressively verified that these same functions can be unbalanced in the metabolic syndrome. In fact, a prompt activation of several immune receptors on the hepatic immune system occurs in response to a break of the intestinal epithelial barrier function and to an increase of certain bacterial populations and their translocation through the vascular system. Therefore, this immune mechanism to disrupted intestinal homeostasis can explain the development of non-alcoholic fatty liver disease the development of several comorbidities such as diabetes, dyslipidaemia and obesity, and its increased risk to metabolic syndrome.

The authors reported a significant statistical increase in the inflammatory cytokines and TLR2, 4, 5 and 9 expressions in the liver of week mice, but no differences in the liver of 4- and 8-week mice. The study also revealed that, in the intestine, exactly the opposite could be observed, since all parameters were significantly decreased indicating that these pathways are probably inhibited in mice with NAFLD.

Immune Response, Toll Like Receptors (TLR) Pathway - IMGENEX

Moreover, the treatment of these mice with antibiotics could attenuate the higher expression of those inflammatory markers and TLRs in the liver but it had little impact on the expression of these molecules in the small intestine of NAFLD mice. The authors further stated that, the increase on the liver TLRs expression appears to be selective since TLR2, 4, 5 and 9 were upregulated in primary Kupffer cells while only TLR4 and 9 were increasingly expressed in the primary hepatocytes. The results stated that, compared with wild-type, the TLR4 mutated mice were resistant to the development of macrovesicular and microvesicular steatosis, hepatocellular ballooning and a fivefold increase in NASH scores.

This phenotype was even associated to a decreased TLR4 function mainly in Kupffer cells, and consequential lower levels of macrophages and cytokines. Interestingly, the study also included the measurement of a transcription factor named XBP-1, known to be stimulated by reactive oxygen species and a part of the responsive pathway to that oxidative stress through the unfolded protein response cascade. This protein was abrogated in the TLR4 mutant mice, with a simultaneously decrease of NF-kB activation and cytokine production.

Also, TLR4 has been described as a signalling way to NAFLD development, in high-fat diet mice, and linked to hepatic steatosis, hepatic insulin resistance and hepatic weight gain in these experimental circumstances. The authors point out that bacterial components translocation and the prompt activation of TLRs and TLR-dependent pathways support a chronic inflammatory state that could, in the liver, end with the development of non-alcoholic liver disease.

Tumor and Vaccine Site With a Toll Like Receptor (TLR) Agonist

Further studying the participation of the inflammasome pathway in the NAFLD pathology, Henao-Mejia et al tested two inflammasome molecules and its effector protein in bacterial modulation and metabolic syndrome outcome. These mice also had more hepatic steatosis, obesity and glucose intolerance and higher rate of Porphyromonadaceae in the intestinal gut, a known bacterial family that increases the risk of metabolic syndrome in both mice and humans.

A recent study by Liang et al. It also revealed that hepatic steatosis was reduced with significantly lower hepatic triglyceride content and improved histology, with the use of this probiotics. Another study by Xie et al used normal and liver cirrhosis mice that were subjected to liver transplantation.

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The authors found that not only the liver cirrhosis groups had higher endotoxin levels and higher numbers of total bacteria, but also, the referred group had an increased number of bacteria in liver and lymph nodes. Astonishingly, these parameters had not improved until 1 month after the liver transplantation and, surprisingly, had not improved with the use of a lactobacillus-enriched probiotic, suggesting probably the need of longer times of therapy or search for different probiotic compositions specific for each metabolic level of disturbance, either hepatic or systemic.

For all the data stated, it is well apparent that the interaction between intestinal microbiota and the innate immunity might have a pivotal role in the metabolic syndrome, which had impact that could go way beyond the limits of the intestine and have a direct and systemic impact through several organs Table This dysbiotic environment can promptly activate several immune receptors present in the intestinal barrier though the recognition of PAMPs and bacterial antigens, culminating in an increased activation of TLR2, 4, 5 and 9, and other synergic inflammatory signalling pathways that were not described yet.

The local pro-inflammatory profile can explain the altered phenotypic expression of these receptors at the intestine surface, the metabolic absorption disturbances observed, the increase of cytokines and inflammatory markers levels and the loss of barrier function of the intestine, which are all described in metabolic syndrome models. With this break of intestine mechanic defences, this dysbiotic bacteria and its products will have an easy access to the vascular space, raising the level of exogenous provocative antigens to the immune innate system and through its translocation influence the homeostasis of different organs, specially the liver because of its metabolic preponderance and privileged location 43 Fig.

Consequences and inflammatory pathways activated during the development of metabolic syndrome in intestinal and liver tissues. This causes a loss barrier function of the intestine and bacterial translocation to other organs especially the liver. This chronic inflammatory state can justify the appearance of macrovesicular and microvesicular steatosis, and hepatocellular ballooning that counts for the NASH transformation. On the other hand, throughout the organism, the antigenic activation of TLR2 and TLR4 in various cells can be a major way of explaining the glucose intolerance, insulin resistance and the increased risk of diabetes, and co-morbidity associated to this syndrome.

Furthermore, the MyD88 pathway activated by these receptors seems to be preponderant to this outcome, since the absence of its signalling participants or TRIF could account for a reduced risk of diabetes developed. The innate immunity activation can even influence the milieu of the adipose tissue, being responsible for a pro-inflammatory state with increased activation of TLR4, the recruitment of different inflammatory cells and the production of inflammatory molecules.

This can be the cause of the decreased adiponectine levels expression, the increased lipoprotein lipase functions and the explanation of the dyslipidaemia and obesity present in these patients 45 Fig. Consequences and inflammatory pathways activated during the development of metabolic syndrome in adipose and other tissues. Present in the metabolic syndrome development are increased mRNA expression of TLR4 and inflammatory cytokines and decreased adiponectine production and lipoprotein lipase, in the adipose tissue.

A macrophage invasion and inflammatory pathways activation within this tissue are also present. Systemically a prompt activation of Myd88 signalling pathways also occurs with mRNA expression of TLR2 and 4 and inflammatory cytokines that globally causes glucose intolerance and decreased insulin sensitivity throughout the human organism.. These factors can further influence the regulation of delivering nutrients and energetic substrates to the cells and its internal management, causing a most profound impact in the homeostatic equilibrium of the human body.

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These new data open interesting lines of evidence that a modulation of intestinal microbiota can be a powerful therapeutic way of influence or even reverse the progression of metabolic syndrome. The use of probiotics has revealed that through changes in the intestinal dysbiosis, a lower pro-inflammatory profile can be achieved with expressive benefits in glucose tolerance, insulin sensitivity, lower weight and lower hepatic steatosis.

Although several lines of investigation are still needed on this behalf, the data collected so far are consistent with a potential therapeutic target in the clinical control of metabolic syndrome development and treatment. In conclusion, this review detects several lines of evidence of the profound preponderance of early activation of TLR receptors and its interactions with a dysbiotic intestinal microbiota in causing several disturbances known to be implicated in metabolic syndrome. Thus, in the near future, the understanding if there is a specific set of TLR overexpression associated to the different chronic metabolic diseases that coexist in the metabolic syndrome, the characterization of the modulation of hepatic immune receptors and cytokine production and the clarification of which are the major bacterial molecules that work as a factor to propagate or ameliorate the metabolic syndrome state, shall be preponderant points in the breakthrough of the investigation in metabolic syndrome medical area..

The authors declare that no experiments were performed on humans or animals for this study.. The authors declare that no patient data appear in this article..