When Fasting Gets Tough, the Tough Immune Cells Get Going—or Die

Abstract

Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells, but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the drastic and complex effects of fasting and severe calorie restriction on the levels and localization of different immune cells and the mechanisms responsible for them.

Dietary restriction describes interventions ranging from a chronic but minor reduction in calorie intake (calorie restriction [CR]) to periods of water-only fasting or fasting-mimicking diets (FMDs), which can be intermittent and short term (“intermittent fasting” [IF] and “time-restricted feeding” [TRF]), lasting less than 24 h, or periodic and long term, lasting more than 48 h (“periodic fasting” [PF]) (Longo and Panda, 2016).

These approaches have in common the ability to downregulate evolutionarily conserved pathways implicated in growth and cell division, including the IGF1 and mTOR pathways, and modulate stem cell activation (Fontana et al., 2010). However, in the last few years, it has become increasingly recognized that chronic dietary restriction, short-term IF, and long-term PF can have very different effects on signaling pathways, stem cells, and immune cells. The reasons for this are that (1) calorie restriction is chronic and does not include a re-feeding phase, which appears to be important for the cellular reprogramming and regenerative effects caused by intermittent and periodic fasting in various organs, and (2) calorie restriction causes relatively minor effects on the signaling pathways involved in both cell death and stem cell activation compared to the more severe fasting interventions.

Cycles of fasting or FMDs and re-feeding have been shown to promote hematopoietic stem cell activation and regeneration of immune cells (Cheng et al., 2014), modulate gut microbiota, ameliorate pathology in various mouse autoimmunity models (Choi et al., 2016; Cignarella et al., 2018; Rangan et al., 2019), and promote the T cell-dependent killing of cancer cells (Di Biase et al., 2016; Pietrocola et al., 2016). However, the mechanisms responsible for these effects of fasting cycles on the immune system remain poorly understood.

In this issue of Cell, three new studies by Jordan et al., Collins et al., and by Nagai et al. begin to shed light on these fasting-dependent effects by investigating the role of different forms of severe dietary restriction on a range of immune cells. They show that fasting or severe CR causes a drastic reduction in the number of monocytes and lymphocytes in the blood and in peripheral organs, with both increased accumulation of lymphocytes and reduced egress of monocytes in the bone marrow. Nagai et al. focused on the gut immune response, where they showed that multiple and frequent cycles of water-only fasting attenuated the normal immune response of mice to oral immunization. In this study, the loss of a large portion of germinal center and IgA+ B cells in the Payer’s patches (PPs) is caused by apoptosis (Nagai et al., 2019). Fasting downregulates the CXCL13-CXCR5 pathway in B naive cells of the PPs and CCL2-CCR2 pathway in monocytes of the bone marrow (BM), whereas CR increases the CXCL12-CXCR4 pathway in memory T cells; these signaling pathways are restored by re-feeding, leading to major changes in cellular composition. Notably, these results are in agreement with previous findings that water-only fasting cycles can promote limited changes in the gut microbiota and result in increased leakiness (Rangan et al., 2019). Similarly, Jordan et al. found that a 48 h water-only fast reduced monocyte mobilization after Listeria infection or wound healing (Jordan et al., 2019). By contrast, Collins et al. showed enhanced protection against infections and tumors when only a 50% calorie restriction was applied instead of water-only fasting (Collins et al., 2019). These studies raise the possibility that a complete lack of nutrients, but not the partial fasting conditions, may result in some immune impairments.

The differing results of Jordan et al. and Collins et al. together demonstrate the potent but complex effects of fasting and FMDs on the levels of monocytes and of both B and T cells. For instance, Jordan et al. discovered that the liver AMPK-PPRα pathway controls the level of peripheral monocytes and that the liver secretome contains different circulating factors that modulate the level of chemokine CCL2 and control the monocyte egress from the BM. Collins et al. instead propose that the glucocorticoids levels together with the higher number of adipocytes and erythropoietic cells mediate the accumulation of memory T cells in the BM and that inhibition of the mTOR pathway promotes lymphocyte survival in response to severe calorie restriction. Some of these differences may be explained by the fasting duration and severity. In response to food deprivation, the mice may begin to reduce investment in immune cells by reducing their number at least in circulation and in secondary lymphoid organs. Notably, Jordan et al. also show a reduction of circulating monocytes in patients undergoing a relatively short 19 h fast in agreement with the reduction in total lymphocyte count in over 70% of multiple sclerosis patients undergoing a 7-day long FMD (Choi et al., 2016). However, the mouse studies indicate that at least part of the major decrease in circulating immune cells appears to be due to redistribution of these cells to the bone marrow. Thus, the three new studies demonstrate the ability of different forms of fasting, as well as different lengths of fasting, to cause potent but distinct and at times opposite effects on the levels and function of various immune cell types, thus underlining the need to replace terms like fasting, or intermittent fasting, with those that describe the type and length of the fasting method such as a 24 h alternate-day fasting (24 H ADF), a 12 h time-restricted feeding (12 H TRF), or a 5-day fasting-mimicking diet (5-day FMD). Without these more precise definitions, it will be difficult to generate sufficient data to enhance our understanding of the biology of fasting responses and begin to translate this knowledge into randomized clinical trials.

Undoubtedly, the preclinical and clinical data presented here and in earlier studies are beginning to indicate that certain forms of fasting and specific compositions of these fasting-like diets can promote potent and coordinated immunomodulatory effects with the potential to be effective alone or in combination with drugs or biologicals against autoimmune diseases, cancer, neurodegeneration, and other diseases involving the microbiota and immune system.