Immunity and Metabolism

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In this week (22.5.24) Diabetes UK announced that there are now almost 168,000 people aged under 40 years in the UK who live with type 2 diabetes, an increase of more than 47,000 since 2016-17. Diagnoses up 39% in 6 years, with the condition fuelled by obesity, health inequalities and junk food – meaning ultra processed food. According to the report, the total cost associated with diabetes in the UK currently stands at £23.7 billion and is predicted to rise to £39.8 billion by 2035/6. To put this in perspective we spend £52 billion on our armed forces!

Ultra-processed foods

The Brazilian nutritional scientist Carlos Monteiro is responsible for the term “ultra-processed foods” (UPFs) 15 years ago, establishing what he calls a “new paradigm” for assessing the impact of diet on health[1]. Monteiro had observed that although Brazilian households were spending less on sugar and oil, obesity rates were rising. The paradox he proposed could be explained by increased consumption of food that had undergone high levels of processing, such as the addition of preservatives and flavourings or the removal or addition of nutrients.

Monteiro’s food classification system, “Nova”, a framework for grouping edible substances based on the extent and purpose of food processing applied to them, assessed not only the nutritional content of foods but also the processes they undergo before reaching our plates. The system laid the groundwork for two decades of scientific research linking the consumption of UPFs to obesity, cancer and diabetes[2].

The rising concern (at least amongst scientists and nutritionally interested people) about the health impact of UPFs has recast the debate around food and public health, giving rise to books, policy campaigns and thousands of academic papers. It also presents the most concrete challenge yet to the business model of the food industry, for whom UPFs are extremely profitable. This ‘profit’ is in effect a transferable cost to us the taxpayers, as each person diagnosed with Type 2 diabetes and obesity will cost the country between £1-3,000 a year, rising with inflation. The 47,000 recently diagnosed under 40-year-olds will generate a conservative cost over their average combined lifespan of £13m a year on hospital and medical costs, let alone the lost productivity.

Industry lobbying

The industry as you would imagine has responded with a concerted campaign against regulation. In part, it has used the same lobbying playbook as its fight against labelling and taxation of “junk food” high in calories: big spending to influence policymakers. In the US, the food and soft drinks industry spends nearly twice as much on lobbying than the tobacco and alcohol industries combined and, in the UK, current government members were heavily lobbied to draw back from the highly praised Dimbleby report.

Yet the UK and the USA remain the largest consumers of UPFs because respective governments accept the frankly ludicrous premise postulated by manufacturers who argue that the harm caused by their products is a result of a lack of personal willpower or failure to exercise, and nothing to do with the industry, or its UPF products, that overwhelm our internal systems that regulate appetite. Or that the most affected social economic groups will suffer further if they are forced to change production and development!

Outside of the politicking, there are serious mechanistic consequences of this ingestion strategy, and our immune systems are intricately linked to the metabolism we alter through poor food selection.

Immune dysfunction driven by metabolic signalling

Whilst it is obvious that one of the immediate consequences of this progressive manipulation of food selection is a driving factor in obesity and type 2 diabetes, there are many other related non-communicable health conditions with progressive loss of wellbeing related to systems immunology consequences.

Immunometabolism: The Nexus of Metabolism and Immunity

Metabolism is a core biological process, and the driving force behind virtually all functions within living organisms. At the forefront of immunology research lies the integration of metabolism with immunity, a field known as immunometabolism, which continues to reshape our understanding of the immune system and its effect on health and disease.

Over the past decade, extensive research has firmly established metabolism as a fundamental requirement underlying immune system function, both in health and disease. This critical link between metabolism and immunity is underscored by the findings that cellular metabolism profoundly influences the state and fate of immune cells and contributes to the development and progression of chronic and infectious diseases, inflammation, and cancer.

The Multifaceted Crosstalk: Immunometabolism Unveiled

The crosstalk between the realms of metabolism and immunity is a multifaceted phenomenon, unveiling intricate connections that shape tissue homeostasis, metabolic functions, and immune responses[3]. This intricate interplay has emerged as a central focus in the field of immunometabolism.

Immune Regulation of Tissue Homeostasis

One facet of this crosstalk lies in the role of immune cells present within the adipose tissue or liver[4]. These cells play a crucial role in regulating tissue homeostasis and metabolic functions, such as lipolysis or the actions of insulin.

Nutrient Intake and Immune Modulation

Another aspect of this crosstalk involves the impact of nutrient intake on immune responses. The excess consumption of various nutrients, including sugars, fats, or proteins, and their subsequent metabolism can both directly and indirectly modulate the activity and function of the immune system. This bidirectional relationship underscores the importance of dietary factors in shaping immune responses and overall health. While excessive energy intake and adiposity have been demonstrated to cause systemic inflammation, several clinical and experimental evidence show that calorie restriction (CR), not leading to malnutrition, is able to delay aging and exert potent anti-inflammatory effects in different pathological conditions.[5]

Metabolic Inflammation: The Central Hallmark

Chronic metabolic inflammation, also known as “metaflammation,” is a central hallmark of metabolic disorders. This inflammatory state, orchestrated by cellular and molecular components of the immune response, affects vital organs such as the adipose tissue, liver, or pancreas. Metaflammation plays a pivotal role in the pathogenesis and progression of all inflammatory conditions. Under both pathological conditions and metabolic disruption, there is persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metaflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve, as is evident in metabolic disorders, is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients.

Immunometabolism and nutrition

Immunometabolism and nutrition are closely intertwined fields that explore the intricate relationship between dietary components, metabolic pathways, and immune function. The following key points summarise the connections between immunometabolism and nutrition:

  1. Dietary composition shapes immunometabolism:

The macronutrient composition (proteins, lipids, and carbohydrates) of the diet can modulate immune cell metabolism and function[6].

Specific nutrients, such as amino acids, fatty acids, and micronutrients, can influence the metabolic pathways and differentiation of immune cells[7].

Dietary patterns, like malnutrition or obesity, can alter T-cell metabolism, survival, proliferation, and cytokine production[8].

  1. Nutrient sensing and immune cell regulation:

Immune cells can sense and respond to nutrient availability through intracellular nutrient sensors like mTOR.

Nutrient sensing pathways regulate immune cell activation, differentiation, and function, linking nutrition to immunometabolism[6].

  1. Gut immunometabolism and the microbiome:

The gut microbiome plays a crucial role in immunometabolism by metabolising dietary components and producing immunomodulatory metabolites[6].

Dietary fibre and prebiotics can shape the gut microbiome composition and influence gut immunometabolism[6].

  1. Metabolic inflammation (metaflammation):

Chronic metabolic inflammation, or metaflammation, is a hallmark of metabolic disorders like obesity and type 2 diabetes[6].

Metaflammation is orchestrated by immune cells and their metabolic pathways, affecting tissues like adipose tissue, liver, and pancreas[6].

  1. Nutritional interventions and immunometabolism:

Dietary interventions, such as calorie restriction, fasting, or specific nutrient supplementation, can modulate immunometabolism and immune responses[7].

Understanding immunometabolism opens avenues for developing novel nutritional strategies to target immune-related diseases[9].

Conclusion

In summary, the interplay between immunometabolism and nutrition is multifaceted, involving the impact of dietary components on immune cell metabolism, nutrient sensing mechanisms, gut microbiome interactions, metabolic inflammation, and the potential for nutritional interventions to modulate immune function through metabolic pathways.

 

References

[1] Monteiro CA, Cannon G, Levy RB, Moubarac JC, Louzada ML, Rauber F, Khandpur N, Cediel G, Neri D, Martinez-Steele E, Baraldi LG, Jaime PC. Ultra-processed foods: what they are and how to identify them. Public Health Nutr. 2019 Apr;22(5):936-941.

[2] Chang K, Gunter MJ, Rauber F, Levy RB, Huybrechts I, Kliemann N, Millett C, Vamos EP. Ultra-processed food consumption, cancer risk and cancer mortality: a large-scale prospective analysis within the UK Biobank. EClinicalMedicine. 2023 Jan 31;56:101840

[3] Lee YS, Wollam J, Olefsky JM. An Integrated View of Immunometabolism. Cell. 2018 Jan 11;172(1-2):22-40.

[4] Oishi Y, Manabe I. Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue. Clin Exp Pharmacol Physiol. 2016 Mar;43(3):294-303.

[5] Procaccini C, de Candia P, Russo C, De Rosa G, Lepore MT, Colamatteo A, Matarese G. Caloric restriction for the immunometabolic control of human health. Cardiovasc Res. 2024 Feb 17;119(18):2787-2800.

[6] Tan J, Ni D, Ribeiro RV, Pinget GV, Macia L. How Changes in the Nutritional Landscape Shape Gut Immunometabolism. Nutrients. 2021 Mar 2;13(3):823.

[7] Cohen S, Danzaki K, MacIver NJ. Nutritional effects on T-cell immunometabolism. Eur J Immunol. 2017 Feb;47(2):225-235.

[9] Articles on ‘Immunometabolism: Bridging the Gap Between Immunology and Nutrition’, https://www.frontiersin.org/research-topics/56159/immunometabolism-bridging-the-gap-between-immunology-and-nutrition/articles (accessed 23.5.24)

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