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A microbial protein that alleviates metabolic syndrome
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Download the PDF here
Download the PDF here
A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice
Akkermansia muciniphila is one of the most abundant members of the human gut microbiota, representing between 1% and 5% of our intestinal microbes......Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. .....we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders......Finally, preliminary human data suggest that treatment with either live or pasteurized A. muciniphila grown on the synthetic medium is safe in individuals with excess body weight, as no changes in relevant safety clinical parameters or reported adverse events were observed after two weeks of treatment. These results pave the way for future human studies investigating A. muciniphila as a therapeutic tool in the management of the metabolic syndrome.
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A microbial protein that alleviates metabolic syndrome
blunted LPS leakage.....improved gut function and metabolic health.....potential treatment of human obesity and metabolic syndrome....to fight obesity and other chronic inflammatory conditions.....
Nature Medicine
06 January 2017
A recent study shows that pasteurization of Akkermansia muciniphila enhances the bacterium's ability to reduce fat mass and metabolic syndrome in mice with diet-induced obesity, and that Amuc_1100*, a thermostable outer-membrane protein of A. muciniphila, can reproduce these beneficial effects.
Akkermansia muciniphila is a gram-negative, strict anaerobe and mucin-degrading bacterium that colonizes the guts of humans and rodents. Although Akkermansia species are conserved in the gut microbiota throughout the animal kingdom1, A. muciniphila represents the sole member of the Verrucomicrobia phylum identified in the human and murine intestines. Moreover, A. muciniphila thrives in the outer mucus layer in proximity to the host's cells, and it has been shown to rely preferentially on host-derived mucin as an energy source2. A. muciniphila is highly abundant in the gut microbiota (possibility as a result of an ecological advantage) and represents 1–5% of all intestinal bacteria3. Such a successful coevolution between Akkermansia and its hosts clearly indicates a relevance of this genus to host gut function and physiology. Lower abundance of A. muciniphila has been found in the feces of children with autism4, patients with inflammatory bowel disease (IBD) and individuals with obesity, when compared to feces of healthy individuals5. Furthermore, studies in mice show an increased abundance of A. muciniphila in the fecal microbiota of lean animals relative to those with obesity6, and oral administration of A. muciniphila to mice fed a high-fat diet (HFD) reverses HFD-induced obesity6, blunts metabolic endotoxemia—that is, it reduces proinflammatory bacterial lipopolysaccharides (LPSs) in the circulation—and alleviates insulin resistance6, 7 and cardiometabolic complications8. In a study in Nature Medicine, Plovier et al.9 showed that pasteurization of A. muciniphila augments its beneficial effect on obesity and insulin resistance when administered to HFD-fed mice, and that Amuc_1100*, a thermostable outer-membrane protein of A. muciniphila, recapitulates most of these effects.
Plovier et al.9 first showed that both A. muciniphila grown in a mucus-based medium or in a synthetic medium were able to reduce fat-mass accretion and improve glucose tolerance when administered to HFD-fed mice. This ability to grow the bacteria in a synthetic medium is important because it allows for large-scale production of A. muciniphila without the need for mucin extraction from animals. Furthermore, the authors discovered that administration of A. muciniphila heated at 70 °C for 30 min, which they termed pasteurized A. muciniphila, exerted more pronounced effects on HFD-induced obesity, glucose tolerance and insulin resistance than did live A. muciniphila cultured in a mucus-based or a synthetic medium. Moreover, unlike live A. muciniphila, treatment with the pasteurized bacterium decreased adipocyte diameter, increased the number of intestinal goblet cells (which are responsible for mucus production) and decreased the capacity of the host to harvest energy from the diet.
In a previous publication, the same authors have shown that administering heat-killed (i.e., autoclaved) A. muciniphila to HFD-fed mice could not recapitulate the beneficial effects of A. muciniphila administration6, which suggested that the use of live A. muciniphila was required. However, the finding that nonreplicative pasteurized A. muciniphila is more effective against obesity and its related comorbidities than live A. muciniphila led the authors to suspect that a bacterial protein—one resistant to pasteurization—was involved in conferring the benefits of A. muciniphila to the host. By applying genomic and proteomic approaches10, the authors found that proteins encoded by a specific Type IV pili gene cluster were particularly abundant in the outer membrane of A. muciniphila. Furthermore, they found that recombinant Amuc_1100*, one of the most abundant proteins in the outer membrane of A. muciniphila, could recapitulate the effect of this bacterium on toll-like receptor 2 (TLR2) activation in vitro. Amuc_1100* is thermostable at 70 °C, which implies that it could mediate the effect of pasteurized A. muciniphila. Importantly, the administration of Amuc_1100 in vivo reproduced the beneficial effects of pasteurized A. muciniphila on fat-mass gain, plasma-triglyceride level, glucose tolerance, insulin resistance and metabolic endotoxemia (i.e., it increased LPS leakage to circulation) in HFD-fed mice, which suggests that the effects of A. muciniphila on gut-barrier integrity and metabolic syndrome are mediated by Amuc_1100* through the activation of TLR2 (Fig. 1).
Left, obesity is associated with lower abundance of A. muciniphila in the gut microbiota than in healthy mice. This promotes a dysbiotic state in the intestinal microbiota, accompanied by disruption of the intestinal barrier, which favors the leakage of bacterial lipopolysaccharides (LPSs) into the circulation (i.e., metabolic endotoxemia). These mice also have increased visceral adiposity and impaired insulin sensitivity in muscle and liver when compared to healthy mice. Right, Plovier et al.9 show that the administration of either pasteurized A. muciniphila or its outer-membrane protein Amuc_1100* activates toll-like receptor 2 (TLR2), which, in the murine intestine, is localized to the apical border of villi and crypts. Treatment with pasteurized A. muciniphila or Amuc_1100* increased the expression of genes encoding the tight-junction proteins claudin 3 and occludin potentially as a result of signaling through TLR2 (as indicated by question mark). Both pasteurized A. muciniphila and Amuc_1100* alleviated metabolic endotoxemia in HFD-fed mice, which markedly improved glucose and lipid metabolism and reduced fat mass.
The authors then investigated the effects of A. muciniphila and Amuc_1100 on gut barrier function. The administration of either pasteurized A. muciniphila or Amuc_1100* to mice with HFD-induced obesity blunted LPS leakage to the same extent as live A. muciniphila grown in synthetic medium. Furthermore, both pasteurized A. muciniphila and Amuc_1100* administration increased the expression of genes encoding jejunal and ileal tight-junction proteins, which suggests that pasteurized A. muciniphila and Amuc_1100* alleviate metabolic endotoxemia by strengthening the gut barrier. Acylglycerols that integrate the endocannabinoid system were previously shown to be increased in the gut of HFD-fed mice treated with live A. muciniphila, a finding associated with increased mucus layer thickness and improved intestinal barrier6 as compared to untreated mice with obesity. In the same study, the authors also reported increased expression of the gene encoding the antimicrobial peptide Reg3g in the colon6. Here Plovier et al.9 found that pasteurized A. muciniphila and Amuc_1100*differently affect the endocannabinoid system and the profile of antimicrobial peptides in the gut. These data indicate that Amuc_1100* and pasteurized A. muciniphila improve gut-barrier function through different mechanisms that will be important to further delineate in future studies. These findings also suggest that pasteurization-resistant outer-membrane proteins other than Amuc_1100* may be involved in the beneficial interaction between A. muciniphila and the host, which then leads to improved gut function and metabolic health. Moreover, it remains to be investigated whether Amuc_1100* administration can recapitulate the effects of pasteurized A. muciniphila on the host's capacity to harvest energy from the diet; on the abundance of goblet cells in the intestine; or on mucus-layer thickness6.
Thus far, two obvious limitations hindering the use of A. muciniphila as a probiotic for metabolic diseases were the need to use animal-derived mucin for its production and its extreme sensitivity to oxygen. These major hurdles are now circumvented by the possibility of large-scale production of A. muciniphila using a synthetic medium, and the fact that pasteurization of A. muciniphila enhances its beneficial properties against obesity and insulin resistance. The authors also showed that treatment of overweight humans for 2 weeks with either live A. muciniphila grown in a synthetic medium or pasteurized A. muciniphila is safe and well tolerated, which brings us even closer to using A. muciniphila, or a protein derived from this bacterium, for the potential treatment of human obesity and metabolic syndrome. Although studies of longer duration are under way to validate the clinical efficacy of A. muciniphila as a method to reduce weight gain and alleviate metabolic syndrome in humans, the current work opens the door for the potential pasteurization of other bacterial strains to enhance their probiotic activity against multiple inflammatory diseases that are linked to impaired gut-barrier integrity. Finally, the reported strategy for isolating bacterial proteins, such as Amuc_1100*, that can reproduce the beneficial effects of A. muciniphila should be exploited further by mining other beneficial gut bacteria to identify more microbial proteins to fight obesity and other chronic inflammatory conditions.
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