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Metabolism

Host and microbes in a pickle

An Addendum to this article was published on 05 May 2010

Metabolic disorders such as obesity are characterized by long-term, low-grade inflammation. Under certain conditions, the resident microorganisms of the gut might contribute to this inflammation, resulting in disease.

In recent decades, the prevalence of metabolic syndrome has skyrocketed worldwide, mainly owing to rapid lifestyle changes1. This cluster of disorders includes abdominal obesity, insulin resistance, high blood levels of lipids, elevated blood pressure and non-alcoholic fatty-liver disease, which all significantly increase the risk of cardiovascular disease and type 2 diabetes. A complex interaction between genetic and environmental factors influences the development of metabolic syndrome. For instance, abnormal activation of the host's innate immune system, characterized by low-grade, chronic inflammation, and a role for the gut microbiota have both been implicated in the development of these disorders. In a paper published in Science, Vijay-Kumar et al.2 indicate that complex communication between the gut microbiota and the innate immune system is involved in metabolic homeostasis.

Trillions of microbes live harmoniously in the mammalian gut3. But disruption of interactions between the gut microbiota and the immune system has been implicated in diseases such as colon cancer, inflammatory bowel disease4 and type 1 diabetes5. Evidence for the potential role of gut microbiota in the development of obesity and related metabolic disorders is also continually emerging. For example, alterations in the gut microbiota that occur with obesity may enhance energy extraction from the diet6. Moreover, increased blood levels of lipopolysaccharides (carbohydrates in the cell wall of bacteria), due to impairment of the barrier function of the gut by altered gut microbiota, might trigger obesity-associated inflammation7.

Indeed, long-term, low-grade inflammation is a characteristic of metabolic syndrome, and is associated with increased production of inflammatory mediators and abnormal infiltration of immune cells into the adipose tissue8. The detailed molecular mechanisms underlying this metabolically triggered inflammation remain elusive. But abnormal activation of certain Toll-like receptors (TLRs) and of the double-stranded-RNA-dependent protein kinase (PKR) enzyme, which are part of the innate immune system and sense pathogens, have been linked to insulin resistance associated with metabolic syndrome in experimental models and in some human cases8. Mammals express more than ten TLRs, which differ in their selection of microbe-derived activator ligands, including bacterial lipopolysaccharides.

Vijay-Kumar et al.2 studied T5KO mice, which are genetically deficient in TLR5 — a TLR that is expressed by both intestinal epithelial cells and innate immune cells and that recognizes bacterial flagellin as a ligand. Compared with normal mice, T5KO mice showed increased adipose-tissue mass, reduced insulin sensitivity, increased blood levels of lipids and high blood pressure. A high-fat diet exacerbated these abnormalities and triggered the development of diabetes and fatty-liver disease, thus recapitulating some of the features of metabolic syndrome seen in humans.

Intriguingly, the authors also observed mild inflammation in the adipose tissue of T5KO mice, suggesting that malfunction of the innate immune system contributes to the development of metabolic disorders. What's more, TLR5 deficiency seems to have altered the composition of the gut microbiota. Could this change have enabled the microorganisms to promote inflammation and the development of metabolic syndrome? To answer this question, Vijay-Kumar and co-workers sterilized the gut of T5KO mice with broad-spectrum antibiotics and found that this treatment prevented metabolic syndrome. Conversely, transplanting the gut microbiota of the T5KO mice into the gut of germ-free normal mice led to metabolic syndrome in the recipient animals. These observations indicate that disruption of interactions between gut microbiota and innate immune cells alters the microbiota, which in turn promotes inflammation by signalling back to the innate immune system (Fig. 1).

Figure 1: Host–microbe communication in systemic inflammation.
figure1

Products or structural components of the gut microbiota, such as short-chain fatty acids (SCFA) and peptidoglycan (PG), could cross the intestinal epithelium to activate receptors, for example GPR43 and NOD1, of innate immune cells. Moreover, gut microbiota modulate circulating levels of lipopolysaccharides (LPS), possibly contributing to obesity-associated inflammation through TLR4. Vijay-Kumar et al.2 now add another layer of complexity to this picture by showing that, in the absence of TLR5, the crosstalk between the innate immune system and the gut microbiota alters the specific composition of the microbiota, which in turn contributes to inflammation by signalling back to the innate immune system through as-yet-unidentified pattern-recognition receptors (PRRs) or another cascade, resulting in metabolic syndrome.

A notable inference from these data is that, in a physiological setting, TLR-mediated signalling prevents inflammation — normally, it promotes inflammation in response to pathogens. So how do the altered gut microbiota initiate inflammation in T5KO mice? Could other TLRs mediate the effects of TLR5 deficiency? Vijay-Kumar et al. show that, in the absence of either TLR2 or TLR4, TLR5 deficiency still causes metabolic syndrome. However, mice lacking MyD88, a protein used for signalling by all TLRs except TLR3, did not develop any metabolic defects. This suggests that, in the absence of TLR5, activation of TLRs other than TLR2 and TLR4, or indeed MyD88-dependent immune mediators such as IL-1β and IL-18, might contribute to the inflammation associated with metabolic syndrome.

Enlightening as it might be, this work2 leads to new questions. What is the exact role of other TLRs? What are their ligands: components of the microbiota or of host nutrients metabolized by these bacteria? If MyD88-dependent immune mediators are involved, what signals trigger their secretion? Could cytoplasmic pathogen sensors such as NOD-like receptors or PKR be involved? Encouragingly, several relevant mechanisms related to the regulation of systemic inflammation by gut microbiota have been explored in recent studies (Fig. 1). For example, it was shown that short-chain fatty acids generated by the gut microbiota could modulate immune responses through the receptor GPR43 (ref. 9), and that peptidoglycan released from the microbiota could prime the innate immune system through NOD1 (ref. 10). It will be interesting to explore whether the current model2 is linked to any of these molecular pathways.

Another question relates to the relationship between the inflammation triggered by overeating and that described by Vijay-Kumar and colleagues. The observations that TLR4 deficiency can partially prevent diet-induced insulin resistance11, but has no effect on the metabolic syndrome that developed in T5KO mice2, indicate that these two types of inflammation may be of distinct origin. In addition, free fatty acids such as palmitate, which are usually increased in obese individuals, may activate pathogen sensors such as TLR4 and PKR, or promote inflammation through induction of stress in the endoplasmic reticulum8.

It is worth noting that the effects observed in T5KO mice — the changes in both food consumption and metabolic outcomes — were relatively mild. So it is unlikely that they could account for the full spectrum of the metabolic deterioration that is associated with obesity in established animal models or in humans. It would be interesting to explore the similarities and differences in the inflammatory responses associated with metabolic syndrome between T5KO and other animal models. Nevertheless, Vijay-Kumar et al.2 put forth a fascinating model of metabolic syndrome that arises as a result of altered communication between the host immune system and the gut microbiota. Clearly, recognition of the gut microbiota or their products by the host, and immune responses to their alterations, are complex phenomena. Deconvolution of these networks should keep the field lively in the coming years and will undoubtedly provide new perspectives towards a better understanding of metabolic syndrome.

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Gökhan Hotamisligil is on the scientific advisory board, is a shareholder and receives research support from Syndexa Pharmaceuticals.

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Li, P., Hotamisligil, G. Host and microbes in a pickle. Nature 464, 1287–1288 (2010). https://doi.org/10.1038/4641287a

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