Metabolism and Inflammation: New Synergies and Insights

Abstract

This special issue presents a range of papers exploring the inter-relationship between metabolism and inflammation in diet-related metabolic disease, as well as focusing on dietary modulation of metabolic-inflammation. As illustrated in Figure 1 and in the image of the back cover of this issue, a range of dietary and lifestyle factors impact cellular metabolism, which in turn re-configures the nature of the inflammatory response towards a pro-inflammatory state or the resolution of inflammation. This paradigm is relatively new, and I have no doubt that the full role of nutritional modulation of metabolic inflammation will evolve with further research. This issue provides a great range of perspectives. From the immunological angle, Charles-Messance and Sheedy introduce innate immune training, an important paradigm wherein metabolic challenges may configure innate immune memory.[1] This intriguing concept is probably most relevant in states of metabolic stress, including obesity, type 2 diabetes (T2D) and cardiovascular disease. Metabolic danger-associated molecular patterns (DAMPs) such as LDL cholesterol, fatty acids, and hyperglycemia induce trained immunity. Thus, immune cells may be primed or “trained” by metabolic DAMPs exposure which up- or down-regulates innate immune cell activity. Such concepts may explain inappropriate over-activation and heightened immune response, or “cytokine storm,” to COVID-19 in obese and T2D patients. Interestingly, it has been shown that blood glucose control improved the outcome of hyperglycaemic COVID-19 patients, clearly warranting more research to delineate mechanisms. Additionally, Shaikh's perspectives with respect to how obesity impairs B-cell-driven humoral immunity, coincident with chronic inflammation, which has consequences for responses to infections and efficacy of vaccines is noteworthy.[2] From the metabolic side, mitochondrial dysfunction is a key metabolic perturbation characteristic of non-alcoholic fatty liver disease (NAFLD). Meex and colleagues comprehensively review the evidence in relation to how saturated fat impedes the respiratory transport chain and mitochondrial efficiency, resulting in excessive reactive oxygen species and damage, in the form of inflammation, apoptosis, and hepatic scarring.[3] The challenge will be to define whether dietary interventions which manipulate saturated and/or unsaturated fats or complex carbohydrates can ameliorate established NAFLD via mitochondrial metabolism. In addition, Su's team describes how nutrient-surplus induced hyperactivation of CREBH (c-AMP responsive element binding protein H), greatly affects hepatic glucose metabolism and lipotoxicity with a concomitant acute-phase response.[4] Dietary intake is an important source of exogenous metabolites and can re-configure endogenous metabolite profiles. A nice example of this is demonstrated by Kundi et al. who showed that feeding dietary fibers can improve hepatic inflammation via short chain fatty acid and bile acid metabolism.[5] The impact of this is probably attributed to alterations of the gut microbes and/or their resultant metabolites, wherein fibers may partly ameliorate obesity-induced disturbances of metabolic inflammation. Indeed, one cannot ignore the gut microbiome in terms of fully understanding the interaction between metabolism and inflammation in man. Delzenne's team comprehensively describes the role of gut barrier integrity and resultant endotoxemia in determining metabolic inflammation.[6] She also describes the impact of a comprehensive suite of bioactive metabolites derived from the gut microbiota, including bile acid-, phenol-, polyphenol-, and amino acid-derived compounds which are not only altered in obesity, diabetes, and liver disease but probably also have relevance to gut integrity, immunity, and tolerance. Indeed, it is relatively easy to manipulate the microbiome composition with a range of dietary interventions including non-digestible carbohydrates and/or probiotics. There is a big challenge ahead in delineating the causal versus coincidental role of different microbiome- and nutrient-derived gut metabolites on metabolic inflammation and resultant health, with a view to fully understanding if/how we can attenuate the impact of obesity, T2D, and inflammatory bowel conditions. The implications of disrupted metabolic inflammation go well beyond the classical metabolic diseases. For instance, Reynolds’ team shows the implication of IL-1β mediated signaling in a gender-specific manner, wherein a lack of maternal IL-1RI signaling did not protect against glucose intolerance, despite previous reports of beneficial effects in young male mice.[7] Indeed, IL-1β mediated signaling differentially affected fetal growth in male and females, demonstrating sexual dimorphism prior to birth. Thus, IL-1R1 signaling is important for normal metabolic functioning in females, both during and beyond pregnancy. It is noteworthy that diet is a key source of exogenous metabolites, as well as endogenous derivatives. If it is the case that metabolism fundamentally determines inflammation and not vice-versa, then the suggestion that anti-inflammatory foods or nutrient supplementation can revert metabolic-inflammatory disease states may be somewhat naïve. Within the context of human nutrition, food, diet, and health—there is no doubt that metabolic inflammation will be a hot area of research. Key challenges will be to determine if/how the paradigm and elegant mechanisms illustrated herein extend to man. Is the metabolic inflammation only relevant in terms of halting progression of disease? Alternatively, are there opportunities to re-configure metabolism and inflammation to induce regression and/or promote resolution. To this end, the true impact of dietary stressors (excess energy as fats, fructose, etc.), as well as the putative health value of interventions such as vitamin E and related derivatives, novel β-glucans, etc., will be fully realized. I very much hope you enjoy the interesting insights provided by this Special Edition.

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