Enemy or ally? Fasting as an essential regulator of immune responses

doi:10.1016/j.it.2021.03.007

Trends in Immunology

Volume 42, Issue 5, May 2021, Pages 389-400

https://doi.org/10.1016/j.it.2021.03.007 Get rights and content

Highlights

Disease-induced anorexia is a behavioral change employed by the host upon microbial infection that induces dietray restriction by decreasing food consumption. Recent experimental data utilizing force feeding in infected mice supports the notion that anorexic behavior is a fundamental host metabolic program that can mediate either detrimental or beneficial context-dependent effects, based on the type of pathogenic challenge model.
Growing evidence support the hypothesis that dietary restriction and fasting can modulate protective and pathogenic immune functions, thus improving chronic inflammation without impacting host defense against parasitic or viral infections.
The ketogenic diet (KD) is a dietary intervention efficiently used to mimic fasting which induces distinct metabolic alterations in host metabolism. Recent advances have highlighted the protective effect of KD in autoimmune, inflammatory, or viral diseases, and its potential as a single/complementary candidate therapeutic approach in the clinic.

Nutrition is essential for supplying an organism with sufficient energy to maintain its bodily functions. Apart from serving as an energy supply, the immunomodulatory effects of diet are emerging as a central aspect of human health. The latest evidence suggests that dietary restriction may play an important regulatory role by influencing the activation and effector functions of immune cells. However, depending on the context, nutrient restriction may have both pathogenic and beneficial effects. Here, we discuss the diverse roles of fasting programs, including ketogenesis in infection and chronic inflammation, aiming to clarify their detrimental and/or beneficial effects. Understanding these differences may help identify conditions under which dietary interventions might serve as putative effective approaches to treat various diseases.

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 ASC^PYD into filaments and the cross-linking of these filaments by ASC^CARD leads to the formation of ASC specks and inflammasome activation.

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Interactions between diet and the intestinal microbiome play an important role in human health and disease development. It is well known that such interactions, whether direct or indirect, trigger a series of metabolic reactions in the body. Evidence suggests that intestinal stem cells (ISCs), which are phenotypic precursors of various intestinal epithelial cells, play a significant role in the regulation of intestinal barrier function and homeostasis. The advent and evolution of intestinal organoid culture techniques have presented a key opportunity to study the association between the intestinal microenvironment and ISCs. As a result, the effects exerted by dietary factors, intestinal microbiomes, and their metabolites on the metabolic regulation of ISCs and the potential mechanisms underlying such effects are being gradually revealed. This review summarises the effects of different dietary patterns on the behaviour and functioning of ISCs and focuses on the crosstalk between intestinal microbiota, related metabolites, and ISCs, with the aim of fully understanding the relationship between these three factors and providing further insights into the complex mechanisms associated with ISCs in the human body. Gaining an understanding of these mechanisms may lead to the development of novel dietary interventions or drugs conducive to intestinal health.
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Elevated expression of immune and DNA repair genes in mated queens and kings of the Reticulitermes chinensis termites
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Studies have identified that mating induces a series of physiological changes in animals. In this period, males tending to invest more energy, immune peptides, and other substances to reduce the cost of living for females. This results in lower survival rates in later life than females. Meanwhile, both males and females shorten lifespans due to reproduction. However, the reasons why termites' queens and kings are both extremely long-lived and highly fecund are unclear. Therefore, this study aimed to examine the effects of mating on the expression of immune and DNA repair genes for lifespan extension in termite queens and kings. Here, we reported that mated queens show relatively higher expression of immune genes (phenoloxidase, denfensin, termicin, transferrin), antioxidant genes (CAT, SOD), detoxification genes (GST, CYP450) than virgin queens in the Reticulitermes chinensis. In addition, mated kings also highly expressed these genes, except for termicin, transferrin, GST, and CYP450. After mating, both queens and kings significantly upregulated the expression of DNA repair genes (MLH1, BRCA1, XRCC3, RAD54-like). Mismatch repair genes (MMR) MSH2, MSH4, MSH6 were considerably increased in mated queens, while MSH4, MSH5, MSH6 were upregulated in mated kings. Our results suggest that mating increases the expression of immune and DNA repair genes in the termite queens and kings, and thus possibly improving their survival during reproductive span due to the omnipresent pathogens.
Bioactive compounds in Layacha brown rice (Oryza sativa L.) improve immune responses in mice via activation of transcription factor Nrf2
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Dysregulated or weak immunity is caused by ageing, chemo-radiotherapy, COVID-19, infections, steroids, pollutants and toxins. Bioactive foods are required for boosting immunity. In the present study, eight rice (Oryza sativa L.) varieties were selected from the repository of 23,250 Indian germplasm accessions. The immunomodulatory effects of these rice varieties were assessed in vitro and in vivo. Layacha-rice-methanolic-extract (Larimex) significantly enhanced innate (>20%) and adaptive (>10%) immune responses evinced from higher bacterial phagocytosis by macrophages, increased mitogen-induced T-cell proliferation (11%) and scavenged reactive oxygen species (ROS) (70–80%). Larimex activated transcription factor Nrf2 and its downstream genes NQO1, HO1 and Txnrd1 in immune cells. Larimex significantly improved immune responses (>20%) only in cells from wild type but not Nrf2 knock-out mice indicating its causal role in boosting immunity. Untargeted metabolomics of Layacha rice showed preponderance of metabolic pathways and bioactive compounds, which activate Nrf2 in mammalian cells. Layacha rice can be a suitable food for boosting immunity.
Metabolism in type 2 immune responses
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The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.
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Citation 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.
Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.

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Trends in Immunology

ReviewEnemy or ally? Fasting as an essential regulator of immune responses

Highlights

Section snippets

Diet as an immune regulator

Fasting as a crucial immunomodulatory program

The ketogenic diet as a putative treatment for chronic inflammation

βOHB can promote immune memory

Concluding remarks

Acknowledgments

Declaration of Interests

Glossary

Semin. Immunol.

Immunity

Cell Metab.

Nutrition

Cell

Cell Stem Cell

Cell Rep.

Trends Immunol.

Cell

Cell

Cell

Immunol. Allergy Clin. N. Am.

Appetite

Vet. Immunol. Immunopathol.

Cell Metab.

Immunity

Cell

Cell

Cell Metab.

Cell

Free Radic. Biol. Med.

Cell

Trends Neurosci.

Immunity

Biochim. Biophys. Acta

Cell

Cell

Cell Metab.

Cell Metab.

Cell Rep.

Exp. Mol. Med.

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

Review
Enemy or ally? Fasting as an essential regulator of immune responses