Trends in Immunology
ReviewEnemy or ally? Fasting as an essential regulator of immune responses
Section snippets
Diet as an immune regulator
The acquisition of external nutrients is key to providing the energy required for the homeostatic maintenance of all organisms. In addition, it ensures the supply of crucial molecules, such as vitamins, that cannot be synthesized internally but are necessary for fundamental biological processes [1,2]. However, beyond being an immediate supply of energy and micronutrients and macronutrients, diet is being increasingly recognized as a key direct modulator of immune functions [3]. In particular,
Fasting as a crucial immunomodulatory program
While severe dietary restriction, resulting in malnutrition, has a profound impact on the functionality of the immune response [13,22], the consequences for the immune system caused by refraining from dietary intake for a defined period are less well understood. In this regard, the latest research in mice suggests that dietary and metabolic adaptations, activated in the context of infection, may increase tolerance and thus survival of the host [23., 24., 25., 26., 27., 28.]. Thus, a distinction
The ketogenic diet as a putative treatment for chronic inflammation
An important step in the analysis of the fasting response through a defined dietary intervention was the development of the ketogenic diet (KD): a diet with reduced carbohydrate and protein contents but increased fat (Box 1) [59., 60., 61.].
βOHB can promote immune memory
Besides regulating the effector function of immune cells, the ketone body βOHB can also drive the development of CD8+ T memory cells in both mice and humans, as demonstrated in a recent report [77]. β-Hydroxybutyrylation of histones was recently discovered as a novel form of histone modification [78], in addition to the previously reported histone deacetylase inhibitor activity of βOHB [79]. Feeding mice with KD or intraperitoneal administration of βOHB resulted in β-hydroxybutyrylation of
Concluding remarks
Immune responses that harm rather than benefit the host are unlikely to have withstood the selective pressure of evolution. This leads us to the assumption that the mechanisms underlying chronic inflammation are a fundamental part of host protection, ensuring the survival of our species in the past. However, we hypothesize that such mechanisms might nowadays operate in a different way to cause immunopathology, and identifying such contextual changes might be the key to treating certain
Acknowledgments
This work was supported by the Ministry for Science and Education of North-Rhine-Westphalia, the Human Frontiers Science Program (HFSP), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048 and SPP1937. We thank Dr Meghan Lucas and the Wilhelm laboratory for critical discussions regarding the manuscript.
Declaration of Interests
There are no interests to declare.
Glossary
- 5′-AMP-activated protein kinase
- an energy sensor activated by increasing ratios of AMP/ATP and ADP/ATP that regulates catabolic metabolism to increase the generation of ATP.
- Apoptosis-associated speck-like protein (ASC) oligomerization
- the ASC protein consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). The oligomerization of ASCPYD into filaments and the cross-linking of these filaments by ASCCARD leads to the formation of ASC specks and inflammasome activation.
References (81)
Nutritional control of immunity: balancing the metabolic requirements with an appropriate immune function
Semin. Immunol.
(2015)Diet, metabolites, and “Western-lifestyle” inflammatory diseases
Immunity
(2014)A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan
Cell Metab.
(2015)Time-restricted feeding influences immune responses without compromising muscle performance in older men
Nutrition
(2018)The bone marrow protects and optimizes immunological memory during dietary restriction
Cell
(2019)Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression
Cell Stem Cell
(2014)A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms
Cell Rep.
(2016)Immune dysfunction as a cause and consequence of malnutrition
Trends Immunol.
(2016)Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation
Cell
(2016)GDF15 Is an inflammation-induced central mediator of tissue tolerance
Cell
(2019)
Pathogen-mediated inhibition of anorexia promotes host survival and transmission
Cell
Cytokine, sickness behavior, and depression
Immunol. Allergy Clin. N. Am.
Infection-induced anorexia: active host defence strategy
Appetite
The concept of sickness behavior: a brief chronological account of four key discoveries
Vet. Immunol. Immunopathol.
GDF15 provides an endocrine signal of nutritional stress in mice and humans
Cell Metab.
The immune system as a sensor of the metabolic state
Immunity
Energetic trade-offs and hypometabolic states promote disease tolerance
Cell
Homeostasis, inflammation, and disease susceptibility
Cell
Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota
Cell Metab.
Dietary intake regulates the circulating inflammatory monocyte pool
Cell
Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma
Free Radic. Biol. Med.
Fasting-refeeding impacts immune cell dynamics and mucosal immune responses
Cell
The ketogenic diet: metabolic influences on brain excitability and epilepsy
Trends Neurosci.
Lipid-droplet formation drives pathogenic group 2 innate lymphoid cells in airway inflammation
Immunity
Lipid homeostasis, lipotoxicity and the metabolic syndrome
Biochim. Biophys. Acta
The gut microbiota mediates the anti-seizure effects of the ketogenic diet
Cell
Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells
Cell
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics
Cell Metab.
Hepatocyte-macrophage acetoacetate shuttle protects against tissue fibrosis
Cell Metab.
β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares
Cell Rep.
Acetate attenuates inflammasome activation through GPR43-mediated Ca(2+)-dependent NLRP3 ubiquitination
Exp. Mol. Med.
Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation
Mol. Cell
Immunometabolism: a multi-omics approach to interpreting the influence of exercise and diet on the immune system
Annu. Rev. Food Sci. Technol.
Vitamin effects on the immune system: vitamins A and D take centre stage
Nat. Rev. Immunol.
Modulation of T cell and innate immune responses by retinoic acid
J. Immunol.
Metabolic regulation of innate lymphoid cell-mediated tissue protection-linking the nutritional state to barrier immunity
Front. Immunol.
Innate lymphoid cells-key immune integrators of overall body homeostasis
Semin. Immunopathol.
A review of micronutrients and the immune system-working in harmony to reduce the risk of infection
Nutrients
Caloric restriction research: new perspectives on the biology of aging
J. Gerontol. A Biol. Sci. Med. Sci.
Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity
Science
Cited by (23)
Key regulators of intestinal stem cells: diet, microbiota, and microbial metabolites
2023, Journal of Genetics and GenomicsElevated expression of immune and DNA repair genes in mated queens and kings of the Reticulitermes chinensis termites
2023, Experimental GerontologyMetabolism in type 2 immune responses
2023, ImmunityControl of immunity via nutritional interventions
2022, ImmunityCitation Excerpt :As such, the preferential induction of stemness in T cells in the context of limited nutrient exposure may represent an important evolutionary strategy aimed at providing maximum potential to both protect the host and preserve the immune system. While the detrimental impact of a western diet on our physiology and microbiota is now well established (Christ et al., 2019; Sonnenburg and Sonnenburg, 2019a), the impact of defined dietary regiments on host immunity remains surprisingly poorly understood (Collins, 2020; Lee and Dixit, 2020; Wilhelm et al., 2021). However, the intimate relationship between nutrition and our immune system offers an extraordinary opportunity to develop tailored therapeutic strategies to prevent and treat disease.