In addition to the collected metabolic findings, four studies found that IF could reduce blood pressure levels 10 , 23 , 24 , Five studies focused on the effects of IF on special populations, including individuals in special physiological states, such as during pregnancy or before or after an operation, and individuals with conditions such as polycystic ovary syndrome PCOS , multiple sclerosis MS , or chronic myelogenous leukemia CML Table 3.

Ozturk et al. conducted a study of Ramadan IF in pregnant women. Pregnancy complications and birth weights were measured but showed no significant results between the IF-treated group and the controlled group A study by Ginhoven et al.

focused on IF during the perioperative period; 30 subjects who underwent kidney donation surgery were randomly assigned into a 1-day fasting group and a four-day restriction group. Many indicators were examined including CRP, white blood cells WBCs , B cells, T cells, natural killer cells, IL, IL-6, TNF-α, and lipopolysaccharide.

After surgery, the restriction group showed lower natural killer cell counts, lower WBC counts, and lower TNF-α levels Yassin et al. conducted a retrospective study of the effects of IF in subjects with CML.

Forty-nine subjects were enrolled and tested before, during, and after fasting. BCR-ABL expression levels were measured and showed no significant difference among the three time points. Various hematological parameters, including WBC, hemoglobin, and platelet levels, showed no significant changes Metabolic parameters were also assessed, and lipid metabolism had insignificant changes, whereas fasting insulin levels and HOMA-IR decreased significantly after IF compared with their baseline levels A reduction in high-sensitivity CRP hsCRP and alanine transaminase ALT levels was observed, and insulin-like growth factor 1 IGF-1 was upregulated Fitzgerald et al.

found that IF could alter T-cell subsets and metabolic markers in subjects with multiple sclerosis. The subjects in that study lost an average of 3. Individuals in the IF group showed significant reductions in memory T cells and increased naïve cell subsets For non-obese healthy people, it is believed that the body could maintain a steady state in which lipid and glucose metabolism are effective and the immune system works well From some perspectives, IF could still benefit healthy people.

After IF, WBC subsets in two trials changed in different ways 17 , The reduction in neutrophils may have resulted from the migration to extravascular lymphoid tissues This process requires a long intervention, so another shorter trial conducted by Madeo et al.

did not show such results More studies showed that the elimination of old damaged cells would process during fasting, and more active immune cells would be generated when fasting ended In this way, IF could protect various tissues against diseases with more active immune cells by hormesis mechanisms that increase cellular stress resistance A decrease in natural killer cells is mainly linked to a decrease in IL-2 or IGF Neither of which were measured in the trial by Madeo et al.

Besides IGF-1, other measurements also show significant changes. High level of adiponectin would stimulate fatty acid oxidation in skeletal muscle and inhibit glucose production in the liver, which benefit to energy homeostasis Meanwhile, adiponectin is an anti-inflammatory agent, a reduction of inflammatory markers including CRP and TNF-α could be observed in some studies 1 , 5.

Changes in gene expression provide more information on immunomodulatory effects: Wegman et al. concluded that an increase in SIRT1 and sirtuin3 SIRT3 expression could be detected after a 3-week trial For SIRT1 , other studies have also shown an increase level SIRT1 is linked to circadian rhythms and cellular mechanisms, such as cell repair, division, metabolism, and growth It could be concluded that IF could protect bodies from cardiovascular diseases.

SIRT3 is a member of the sirtuin family of histone deacetylases, which are primary mitochondrial protein deacetylases.

Moreover, it could regulate cell metabolism, thus maintaining myocardial energy steady. SIRT3 is also believed as a protection for cardiomyocytes from oxidative stress-mediated cell damage Besides that, some animal studies showed more exciting results through SIRT3 regulation of IF.

A study by Mao et al. investigated clock genes and showed that levels of genes such as BMAL1 and PER2 were elevated in a five-week trial 21 , indicating that IF could partly modulate the immune system by improving the circadian rhythm. The reinforcement of circadian rhythm could benefit body immune through promoting system recovery and the clearance of harmful cellular element Another potential immunomodulatory effect involves microbial diversity in two studies 20 , 21 : Low gut microbial diversity is associated with metabolic disease 42 , and high diversity may be due to the high expression of SIRT1 and high levels of HDL 20 and improve body immune system, such as liver function mentioned in the study by Li et al.

Emerging evidence showed that SIRT1 could promote gut microbial population shifts by influence inflammation and circadian rhythm It has also been suggested that IF could benefit healthy people lose weight 9 , even cyclists and men who practice resistance training 9 , After the trial, it was concluded that IF could lose almost fat and maintain muscle mass with the measurement of muscle area of the thigh and arm.

Healthy individuals might already have high insulin sensitivity at baseline; thus, IF seems to have less influence on glucose metabolism in these non-obese and healthy individuals Things were similar when focusing on lipid metabolism.

A decrease in leptin was found in many studies 1 , 16 , which might suggest that IF could partly strengthen lipid metabolism in healthy individuals.

To sum up, IF could benefit immune system of healthy people through migration of immune cells, regulation of oxidative-related and circadian-related genes, increasing gut microbial diversity and improvement of muscle-fat ratio.

Trials with longer durations and more factors including anxiety degree, cognition state, microbial diversity 44—46 , key gene expression, and inflammatory markers are needed to better clarify the immunomodulatory effects of IF on healthy people. Most obese subjects would harbor inflamed adipose tissue, which could cause a persistent, low-grade, inflammatory response.

Obesity is often associated with the metabolic syndrome, because fat accumulation would cause insulin resistance And evidence accumulated that persistent inflammation of adipose tissue is a central mechanism through which obesity promotes cancer risk From the perspective of immune cells, A decrease in macrophages was observed in a study by Heilbronn et al.

Most cytokines that are produced by adipose tissue originate from nonfat cells and macrophages 29 , thus the result confirmed that IF could be beneficial for inflammation associated with obesity. Recent studies have suggested that IF inhibits the nuclear factor kappa-B signaling pathway, which is an important regulator of downstream parameters including TNF-α and IL-6 25 , which is consistent with the results that IF could partly eliminate the inflammation caused by adipose tissue, with lower CRP and TNF-α There were insignificant changes of some inflammatory markers in some studies, which might be related with short trial duration and inadequate weight loss 6.

The concentration of galectin-3, which plays various roles in humans, was measured increasingly by Horne et al. in It has been shown that galectin-3 could stimulate the expression of some antiviral genes and protect against inflammation, which may result in improvements in glucose metabolism.

Although changes in inflammatory factors were less significant in obese people compared with healthy subjects, the immunomodulatory effect of IF observed in obese people might reflect a suppression of oxidative stress found that the ketone bodies, especially β-hydroxybutyrate, which protects against lipotoxicity and stimulates lipid oxidation, was significantly elevated in obese subjects As it was regarded as an epigenetic regulator in terms of histone methylation, acetylation, IF could help to delay various age-related diseases.

A decrease in 8-isoprostane, a marker of oxidative stress in lipids, was observed in two studies 6 , Oxidative stress is a definition of the imbalance between the production and elimination of reactive oxygen species Some other studies have suggested that, though IF might have little effect on inflammation, it may greatly influence oxidative stress, which is linked to insulin resistance Interestingly, improvements in glucose metabolism were observed in two studies that reported decreased oxidative stress markers 6 , Significant changes in leptin, which is regarded as a special body weight regulating hormone, were also noted 29 , meaning that the resistance to leptin is partly improved in obese subjects.

Besides the ability to regulate metabolic syndrome, including lowering glucose and lipid synthesis 50 , leptin is one of the mediators responsible for the inflammatory state In addition to the findings about immune cells and inflammatory markers, other study conduct tests of gene expression.

found that genes related to oxidative stress were down-regulated such as SOD1 and SOD2 28 , and Mindikoglu et al. found that the expression of other genes including the tumor activators POLK , NIFK , SRGN , CAMP , and D , were downregulated 10 , which are consistent with remitting oxidative effect and lowering cancer risk by IF.

To sum up, besides the advantages of IF on obese subjects including losing body weight, regulate lipid metabolism and improve insulin resistance, which was almost suggested in all studies, IF could reduce oxidative stress and remit inflammatory state through macrophage adjustment and hormone secretion.

Moreover, although evidence is accumulating that gut microbial is involved in the etiology of obesity 52 and altered by modified IF 4 , relevant researches were still rare. Another issue waiting for more studies was the influence between IF and nervous system on obese subjects.

A study in obese rat showed that IF could prevent memory loss in comparison to ad libitum by regulating body metabolism 54 , which offering a new sight for the advantages of IF to remit neuroinflammation.

Pregnancy is a state of high oxidative stress, which contributes to preeclampsia and restriction of fetal growth Maternal IF resulted in detrimental influence on fetal development and maternal stress stage by changing the metabolite profiles in animal studies However, IF has no significant influence on the high oxidative stress and fetal development in the human study The reason could be the different circadian rhythms between rats and humans.

A case related with gestational diabetes mellitus was reported that IF is a useful intervention to reduce maternal body weight, plasma glucose, and psychological distress without any adverse effects Surgery is regarded as a shock or an acute stress, and IF is able to improve resistance to this stress.

In a study by Ginhoyen et al. Compared with subjects in the non-fasting group, subjects in the restriction group showed a more moderate postoperative inflammatory response.

For healthy people in special physiological states, such as those observed during the perioperative period, IF could reduce acute stress.

More trials are needed to identify the influence on pregnant subjects, including the fetal and maternal safety, anti-stress effect and body metabolism regulation.

It is worth nothing that study include in this review on pregnant subjects was a Ramadan IF trial, which might be less convincing as subjects in this study had experienced such interventions before.

PCOS is an endocrine condition closely linked to metabolic disorders. Because obesity is closely related to PCOS, it is not surprising that IF could provide benefits by reducing insulin resistance and easing hyperandrogenemia Whether IF could be applied in subjects with cancer remains unclear 57 , because it may also affect chemotherapy.

In a study of subjects with CML, Yassin et al. reported that fasting did not result in significant immunological effects with measurements including BCR-ACL levels and hematological parameters It was suggested that IF in some patients who have cancer could be capable of decreasing chemotherapy-related toxicity and tumor growth, however 58 , more clinical trials were needed to clarify.

MS is an autoimmune disease characterized by degeneration of the central nervous system The epidemiology of this condition includes a history of childhood obesity.

Although no significant changes in leptin or adiponectin levels have been observed in studies of IF in MS, an observed difference in T-cell subsets in intestines might explain the immunological effects of IF that have been reported in studies 33 , 60 , which was also a kind of possible therapy for MS The components of the intestinal microbiome could also raise the propensity to develop MS strongly Researches about gut microbial of the influence of IF on subjects who have MS were expected as a result of migration of intestine immune cell subsets.

As mentioned before, IF is beneficial for nervous system by cellular, metabolic and circadian mechanisms and a promising therapy for brain disorders, future research should disentangle whether positive effects of IF could be applied in clinical situations Besides IF, other types of diet, including energy-restricted fasting and ketogenic diet 62 , were also evaluated as nutrition therapy for MS More results was put forward that the improvement of this diet was related with immune system, including reducing inflammatory cytokines and immune cell migration.

However, these diets might cause deficiency of various nutrients in long term To sum up, a special diet could serve as a unique nutrition therapy for MS with disadvantages of nutrition deficiency, which was nowadays a popular and promising topic.

The different evidence levels should be taken into consideration when analyzing the results of these studies. Of the 28 selected trials, 19 were randomized, controlled, parallel, or crossover studies. Some trials were cohort studies, and the trial focusing on CML was a retrospective study; the lack of a control group in that trial may lead to inaccurate conclusions.

Trials differed in terms of baseline characteristics, study durations, meal types, and IF types. These differences may interfere with the final results. For example, Gasmi et al. studied whether young people and old people would act differently while undertaking IF 17 , Paoli et al. compared all factors in a 2-month trial and in a 1-year trial 1 , and Varady et al.

focused on whether the influence of IF would vary with different durations of eating windows 6. In the future, more studies on this topic should be conducted to provide new data. This systematic review finds substantial evidence that IF can modulate the immune system in non-obese healthy people, obese people, and subjects in other physiological or pathophysiological states and these effects were clinically relevant with cognitive improvement, lipid and metabolism regulation, and inflammatory state remission.

The mechanisms influenced and regulated to drive changes in each population differ. For example, non-obese healthy people can metabolize lipids and glucose efficiently, so the immunomodulatory effect is reflected in immune cell subset migration, lower inflammatory factors, upregulation of circadian rhythm—related gene expression, and greater microbial diversity.

Although weight reduction has also been observed in healthy people, changes in parameters of lipid and glucose metabolism remained insignificant in most cases. In obese people, IF contributes to body health by regulating macrophages, which is related to the inflammatory stage of adipose tissue.

Although many inflammatory factors did not show significant changes in obese subjects, other important factors, including 9-isoprastane, leptin, and galectin-3, had significant changes.

The gene expression of cancer activators and lipid oxidative activators provides insights into the mechanisms behind these immunomodulatory effects. In pregnant women, IF seems safe to be conducted and possibly useful to treat endocrine disorders during pregnancy.

Moreover, IF is able to improve resistance to the stress of surgery. IF can be beneficial for the immune system of individuals with PCOS by improving endocrine function. Limited trials studying the effects of IF on cancer have been conducted. For nervous system, IF is believed to be applicable to treat anxiety and cognitive disorders by cellular, metabolic and circadian mechanisms.

However, more trials are needed to better understand the effects and mechanisms by which IF modulates the immune system. Our systematic review, analyzing data from IF studies in different populations, suggests that IF could have immunomodulatory effects in healthy people, obese people, and people with special physiological and pathophysiological conditions.

Different mechanisms may contribute to these effects. IF can benefit non-obese healthy individuals by strengthening circadian rhythms, migrating immune cells, lower inflammatory factors, and enriching microbial diversity. Physiological stress by surgery and pathophysiological disorders by endocrine diseases may be partly eased with IF.

ZH, HX, HY, and YM contributed to conception and design of the study. ZH and HX organized the methodology, investigation, and data collection. ZH and CL performed the statistical analysis.

ZH wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. This work was supported by grants from CAMS Innovation Fund for Medical Sciences CIFMS No. We would like to thank Editage www.

cn and Charlesworth www. cn for English language editing. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. If anyone is interested I fast every Monday for about hours. My last meal is Sunday evening and I start eating again Tuesday lunch.

Feel free to text or email me and we can fast together! The benefits of IF on the immune system include: Reduced immunosenescence, which is aging of the immune system Lower white blood cell numbers including lymphocytes, natural killer cells, and neutrophils Lowered inflammation and fewer pro-inflammatory markers Protection against inflammatory-related conditions Now the question is, how long should you fast?

I am sure you are thinking, HOW CAN I FAST FOR 3 DAYS? That is impossible! Let me add that new information regarding intermittent fasting is coming fast as it gains popularity, but this can trigger confusion and misinterpretation.

At present, evidence indicates very positive outcomes when it comes to aging as discussed below, plus weight management, but more evidence is needed before rock-solid conclusions can be made. This helps explain some of the lost muscle mass and increased body fat with aging, especially increased fat around the midsection in both men and women.

There also is the loss of vigor. But not everyone loses HGH at the same rate as several other factors besides aging contribute to the decline. Lack of exercise, a lousy diet and poor sleep play key roles, plus a decreased testosterone production in men and decreased estrogen in women.

So, is it a good idea to undergo HGH therapy? In other words, medical experts tend to be cautious regarding artificial means of increasing HGH to combat aging.

On the other hand, there are several things you can do to increase HGH naturally, which is safe and effective. First and foremost, in order of recognized importance, is the benefit of losing body fat, especially around the middle because the more belly fat you have the lower your production of HGH.

Second, studies on fasting are very promising. In addition, intermittent fasting keeps insulin levels low because you are not bombarding your body with food, and especially sugar, every few hours.

This is a good thing because an increase in insulin caused by a surge of sugar coming into the bloodstream from the digestive tract can reduce the release of HGH. Third, exercise, and especially high-intensity exercise, has been shown to increase levels of HGH.

And fifth, follow a nutritious well-balanced diet with plenty of vegetables and fruit and high-quality protein.

Nutrients like vitamin C, vitamin D, zinc, and antioxidants are vital for maintaining an effective immune response. Nuts, seeds, beans, broccoli, spinach, Greek yogurt and ginger are all excellent foods for supporting your immune system to enjoy during your eating window.

Giving intermittent fasting a go can be a transformative step towards giving your immune system the support it needs. Coupled with a nutrient-rich diet like a Mediterranean-style diet, this practice not only supports weight management but also contributes significantly to a healthy immune system, preparing your body to effectively combat illnesses.

What is autophagy? Reducing inflammatory responses and risk of disease Another critical aspect of how intermittent fasting benefits immune health is through the reduction of chronic inflammation. The bottom line: Intermittent fasting bolsters your immune system Giving intermittent fasting a go can be a transformative step towards giving your immune system the support it needs.

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β-HB also contributes to the anti-inflammatory effects by suppressing NLRP3 inflammasome activation. The pathways depicted by black arrows and red bars represent the activation and inhibition by dietary restriction, respectively.

AMPK inhibits the activity of acetyl-coenzyme A carboxylase 1 ACC1 , which leads to a reduction of fatty acid synthesis FAS 19 Figures 1 and 2. The alteration of lipid metabolism is associated with the T-cell fate decision. Consequently, this treatment improved ischemic brain injury in a transient middle cerebral artery occlusion-induced ischemia model The development of Th17 cells, but not Treg cells, requires ACC1-mediated de novo FAS.

In addition, Th17 cells mainly utilize the glycolytic-lipogenic pathway to produce phospholipids for cellular membranes, whereas Treg cells actively take up exogenous fatty acids 21 , Furthermore, the other Teff cell subsets, such as Th1 and Th2 cells, rely on de novo FAS for their differentiation, and thus the inhibition of ACC1 can suppress their differentiation 21 , Conversely, ACC1 is dispensable for the activation of dendric cells and macrophages, even though de novo FAS is augmented upon mycobacterial infection Therefore, ACC1 has emerged as a molecular target for drug development to regulate Teff cell-dependent inflammation.

A mTORC1 inhibition enhances ketogenesis and reduces glycolysis and glutaminolysis. mTORC1 inhibition also induces autophagy in macrophage and suppresses Th1, Th17, and M1 macrophage differentiation.

Further, administration of FK ameliorated disease severity in an LPS-induced sepsis model. SIRT1 protein level increases in multiple cells and tissues in response to food deprivation and CR 31 — 33 Figure 1. SIRT1 deacetylates nuclear factor kappa-light-chain enhancer of activated B cells NF-κB , peroxisome proliferator-activated receptor γ PPARγ , and hypoxia-induced factor 1α HIF-1α to regulate both innate and adaptive immune responses.

In macrophages, deficiency in SIRT1 results in the hyperactivation of NF-κB, followed by the upregulation of pro-inflammatory cytokines such as TNF-α and IL-1β In a syncytial virus infection model, the upregulation of SIRT1 in the lung was found to be essential to elicit respiratory immune responses and alleviate tissue damage In this model, SIRT1 in dendritic cells promoted the production of Th1-inducing cytokines e.

SIRT1 also inactivates HIF-1α through its deacetylating activity Accumulating evidence has indicated the importance of HIF-1α for the Warburg-like metabolic rewiring toward aerobic glycolysis in immune cells.

Therefore, SIRT1 may suppress the proinflammatory responses by inhibiting the HIF-1α-dependent metabolic rewiring The immunoregulatory effect of CR may also be mediated by the Forkhead transcription factors O class 1 and 3 FoxO1 and FoxO3 Figures 1 and 2. Treg cells play a critical role in suppressing excessive immune responses by expressing immunosuppressive molecules e.

T-cell-specific deletion of FoxO1 attenuates the TGF-β-induced differentiation of Treg cells FoxO3 suppresses the proliferation and activation of Teff cells by inhibiting NF-κB 44 , and also induces apoptosis by upregulating Puma and Bim FoxO3-deficient mice showed spontaneous lymphoproliferation, associated with inflammation of the lung, kidney, and salivary gland Such inflammation was found to correlate with the presence of hyperactivated Th1 and Th2 cells.

In addition, mice carrying T cells deficient in FoxO1 and FoxO3 develop severe systemic autoimmune diseases mainly because of a defect in Treg cells and the activation of Teff cells FoxO3 also suppresses the production of IL-6 from dendritic cells, which also contributes to the inhibition of Teff cells FoxO1 activation in macrophages exacerbates inflammatory responses.

Exogenous expression of a constitutively active form of Foxo1 in RAW Interestingly, FoxO1-induced TLR2 and TLR4 signals induced Akt phosphorylation leading to FoxO1 inactivation. This negative feedback may constrain excessive inflammatory responses in macrophages and induce resolution of inflammation.

Besides their immunomodulatory functions, FoxOs prevent tissue damage by suppressing oxidative stress and accelerating wound healing 50 — This raises the possibility that CR-dependent activation of FoxOs may also promote wound healing, although further investigations are required to prove this.

In addition to anti-inflammatory effects, CR may consolidate immunological memory in response to vaccination. These effects by CR may be attributable to the inactivation of mTOR signaling that orchestrates glycolysis, glutaminolysis, and fatty acid biosynthesis Figures 1 and 2.

In support of this, low-dose treatment with an mTOR inhibitor, rapamycin, also facilitated the development and maintenance of memory T cells and conferred protection against viral infection Similarly, in vitro culture of tumor-specific memory T cells under CR conditions enhanced anti-tumor functions, accompanied by the inactivation of mTOR signaling Thus, CR is considered to strengthen the development and functionality of the memory T-cell subset by regulating multiple mechanisms.

In addition to these molecular mechanisms in specific cell types, CR or fasting affects systemic metabolism, hormone release e. Consequently, the pleiotropic effects of CR could be attributable to integration of the alterations of metabolic, endocrine, and nerve systems.

Interestingly, the efficacy of vaccines is attenuated by both malnutrition and obesity 61 — 64 , illustrating that an appropriate energy balance is a prerequisite to induce immune responses to vaccination fully. Fasting refers to completely abstaining from food intake for certain periods ranging from several hours a day to a few weeks.

Among them, TRF represents the daily restriction of food intake, usually for 12 to 20 h 65 , In IF, subjects or laboratory animals take little or no calories at least two days per week, but are allowed ad libitum feeding on the remaining days.

IF protocols include alternative day fasting ADF , in which h fasting is repeated every other day 67 , Conversely, PF represents the intake of little or no calories for several days. PF has a more pronounced impact on metabolism and immune responses than CR or short-term fasting such as TRF and ADF Fasting has been performed as a religious practice.

In Islamic tradition, abstinence from food and drink from dawn until sunset is encouraged during the month of Ramadan Like CR, fasting also has a considerable impact on immune responses.

IF during Ramadan results in significant decreases in circulating immune cells and pro-inflammatory cytokines 71 , Other studies have also demonstrated that Ramadan fasting induces the expression of antioxidant and anti-inflammatory genes in both nondiabetic obese patients and healthy subjects 73 , Fasting also reduces blood levels of glucose, insulin, insulin growth factor-1 IGF-1 , and amino acids, with the activation of AMPK and suppression of mTOR signaling.

In response to these metabolic alterations, long-term hematopoietic stem cells undergo stress resistance, self-renewal, and regeneration Fasting also induces whole-body FAO and ketogenesis in the liver to generate ketone bodies i.

In the kidney of aging-related chronic inflammation model, β-HB exerts an anti-inflammatory effect by activating FoxO1 through inhibition of Akt phosphorylation Furthermore, the refeeding phase in the fasting regimen may be necessary for cellular reprogramming and regenerative effects in various organs such as the liver, and gut In an EAE model, IF was shown to ameliorate the disease symptoms by increasing the serum levels of adiponectin, corticosterone, and β-HB Additionally, IF alters T-cell homeostasis in the gut with a decrease in Th17 cells and an increase in Treg cells.

This effect is attributed to the alteration of gut microbiota by IF, which is characterized by an overrepresentation of Bacteroidaceae, Lactobacillaceae, and Prevotellaceae. The transplantation of fecal microbiota from IF mice was also shown to recapitulate EAE amelioration by IF Autophagy significantly contributes to somatic cell reprogramming and stem cell maintenance The process of autophagy also serves as a protective factor against inflammation, infection, and neurodegenerative diseases 79 — Autophagy was initially identified in Saccharomyces cultured under low-nutrient conditions In the liver, farnesoid X receptor FXR and cAMP response element-binding protein CREB , both of which are activated in response to nutrient signals, regulate the hepatic autophagy gene network CREB was shown to promote the autophagic degradation of lipids under nutrient-deprived conditions, while FXR inhibited this response.

Moreover, the CREB pathway enhanced alternatively activated M2 macrophage polarization in WAT Furthermore, in the liver and muscle, refeeding after h fasting suppressed autophagy by activating the mTOR complex 1 mTORC1 pathway Hence, fasting-induced autophagy might also lead to therapeutic effects.

TRF may also elicit its effect independent of the reduction of total calorie intake because TRF was shown to suppress weight gain and improve hyperinsulinemia, hepatic steatosis, and inflammation in mice fed a high-fat diet HFD Notably, the total amounts of food intake were comparable between the TRF and ad libitum -fed groups.

Ad libitum feeding with HFD disrupts the normal feeding cycle, with the mice eating the diet all day Such feeding-cycle disruption is also prevalent in modern societies.

TRF coordinates the balance of CREB, mTOR, and AMPK signaling and restores the circadian oscillations. The circadian oscillations are also observed in lymphocyte trafficking. At night, noradrenalin-dependent β2-adrenergic stimuli upregulate CCR7 and CXCR4 on B and T lymphocytes to suppress cell egress from the lymph nodes in mice Additionally, the expression of sphingosinephosphate receptor 1 S1PR1 , which also facilitates egress from the lymph nodes, by lymphocytes is also under the control of a circadian clock gene, Bmal1 Expression of sphingosinephosphate S1P is upregulated during the day.

In accordance with this observation, immunization with myelin-oligodendrocyte glycoprotein MOG at daytime augments the autoantigen-specific Th17 responses compared with nighttime immunization and exacerbates CNS inflammation in an EAE model Taking these findings into account, the anti-inflammatory effect of TRF may partially be mediated by the normalization of the circadian oscillations.

Most previous studies have underscored the beneficial effects of calorie restriction and fasting on metabolic disorders and autoimmunity, where some reports showed adverse effects of such dietary interventions. The outcomes of calorie restriction and fasting are most likely dependent on feeding regimens, disease models, and the age of animals employed in each study.

For example, a TRF in juvenile mice weeks old exacerbates metabolic disorders in adult age week-old This study also manifested that TRF in juvenile mice affects sexual maturity as evidenced by retarded testicle development as well as high levels of serum GnRH, FSH, LH, and low levels of androgen and estrogen at 8-week-old.

Such an observation is analogous to our findings that repeated fasting in juvenile mice weeks old attenuated the booster effect of oral immunization This result is consistent with the observation of cohort studies that children with malnutrition fail to obtain vaccine efficacy 91 — Thus, TRF and fasting in young adulthood may cause adverse effects in the metabolic, immunological, and enteroendocrine systems.

Recent clinical studies have shown the potential of a fasting-mimic diet FMD , which is low in calories, sugars, and protein, but high in unsaturated fats, to achieve beneficial effects against aging, cancer, metabolic diseases, and cardiovascular diseases, in association with the reduction of body mass index, blood pressure and serum parameters e.

Recent studies have also shown the effect of FMT on autoimmune diseases. Periodic 3-day FMD cycles ameliorated demyelination and symptoms in an EAE model The 4-day cycles of FMD prevent the development of the dextran sodium sulfate DSS -induced colitis model by increasing the abundance of Lactobacillaceae and Bifidobacteriaceae with anti-inflammatory properties Thus, FMD may be beneficial to improve both metabolic and inflammatory disorders.

Growing evidence has suggested that amino acid restriction AAR may be at least partly responsible for the immunomodulatory effect of dietary restriction. Leucine deprivation was found to improve insulin sensitivity of the whole-body and in vitro- cultured hepatocytes In addition, a serine protein kinase, general control nonderepressible 2 GCN2 , functions as a sensor of amino acid deprivation.

Leucine deprivation activates GCN2, which in turn inhibits mTOR signaling. Deficiency of GCN2 canceled the effect of leucine deprivation on insulin tolerance.

AAR also appears to regulate the differentiation and functions of immune cell subsets. For example, GCN2-dependent activation in response to AAR diminishes mouse and human Th17 differentiation In an EAE model, GCN2-deficient mice showed severe disease symptoms even at the remission stage in association with increases in Th1 and Th17 response and a decrease in Treg cells ATF4 transactivates a gene network that facilitates the amino acid intake and mTORC1 signaling Dietary tryptophan restriction DTR was found to impair the development of encephalitogenic Th17 cells to ameliorate EAE Interestingly, GCN2 is dispensable for the effect of DTR, since GCN2-deficient mice fed a protein-free or tryptophan-free diet were reported to show resistance to EAE similar to that of WT mice.

DTR suppresses gut inflammatory responses by shaping the gut microbial community. Oxidative stress is implicated in the development of chronic inflammatory disorders including inflammatory bowel disease IBD. Therefore, DMR ameliorated the severity of DSS-induced colitis DMR also delayed the senescence-associated secretory phenotype SASP in the kidney through hydrogen sulfide H 2 S generation and AMPK pathway activation GCN2 also contributes to the regulation of various macrophage functions.

Among the major function of splenic macrophages is the clearance of apoptotic cells, leading to immune tolerance. Interestingly, tumor-associated macrophages from patients with melanoma also activate GCN2 and IL production in the tumor microenvironment In contrast, GCN2 activation in RAW Carbohydrate restriction using a ketogenic diet KD also significantly regulates immune responses.

KD is defined as a very low-carbohydrate, high-fat diet, which induces the generation of ketone bodies. A recent study revealed that KD alters gut microbiota. The KD-associated microbiota is characterized by an underrepresentation of Bifidobacterium spp.

β-HB produced by KD plays a central role in the decrease in Bifidobacterium spp. However, it remains obscure how Bifidobacterium spp.

Notably, the reduction of bifidobacteria e. longum was also evident in humans fed KD for 4 weeks. KD has been clinically used to cure intractable epilepsy, but the therapeutic mechanism behind this is largely unknown.

Hence, KD may contribute to the treatment of intractable epilepsy by shaping the T-cell responses Meanwhile, KD was found to induce the expansion of lung γδ T cells to strengthen epithelial barrier functions and antiviral resistance to influenza A virus However, KD may exert distinct immunological effects depending on the duration of the treatment.

Short-term 1-week-long KD activates adipose-tissue-resident γδ T cells to support tissue repair, whereas long-term 4-month KD suppresses this T-cell subset and exacerbates obesity in mice Additionally, β-HB suppressed the NLRP3 inflammasome and attenuated the secretion of IL-1β and IL in both mouse bone marrow-derived macrophages and human monocytes Given that poor compliance and occasional adverse effects have limited the clinical application of CR and fasting, specific nutrient restrictions may be more feasible dietary interventions to achieve beneficial effects similar to those of CR and fasting.

Epidemiological evidence has suggested that malnutrition is a risk factor for infectious diseases and impairs vaccine efficacy — Vaccine efficacy depends on the formation of immunological memory. Vaccination evokes a GC reaction to generate plasma cells and memory B cells, which contribute to antibody production and long-lasting memory function, respectively.

Anatomically, GCs are separated into the light zone LZ and the dark zone DZ. GC B cells are highly mobile, circulating between the LZ and DZ Upon antigen stimulation, naïve B cells migrate into the LZ, where the affinity-driven selection of GC B cells occurs through interaction with follicular helper T Tfh cells and follicular dendritic cells.

The positively selected GC B cells activate mTORC1, which is required for migration into the DZ and vigorous proliferation Several studies have demonstrated that the differentiation and the survival of Tfh cells and GC B cells highly depends on the mTOR signaling pathway , We also confirmed that treatment with rapamycin greatly reduces the number of GC B cells in PPs In PPs, Tfh cells highly express glucose transporter Glut1 compared with other T-cell lineages to enhance glucose uptake.

Glut1 expression in Tfh cells partly depends on mTORC1 signaling, since rapamycin treatment reduced Glut1 expression and glucose uptake. Nevertheless, GC B cells rely on FAO rather than glycolysis to fuel proliferation , ; however, the mechanisms underlying how proliferating GC B cells actively oxidize fatty acids have remained unclear.

Moreover, recent studies have indicated that several vitamins also participate in the regulation of B-cell homeostasis. Deficiency in vitamin B 1 was found to decrease the number of naïve B cells in PPs.

Vitamin B 1 -dependent maintenance of naïve B cells is required for the induction, but not effector, phase of the IgA response upon oral immunizaition 3. Vitamin A VA deficiency is currently a global concern, especially in developing countries.

Large peritoneal macrophages LPMs , one of the mouse peritoneal macrophage subsets, supports IgA class-switching of peritoneal B-1 cells.

RA-induced activation of GATA6 in LPM precursors causes their polarization and migration to the peritoneal cavity. Thus, RA facilitates the differentiation of peritoneal B-1 cells into plasma B cells induced by LPMs RA is also required for inflammatory resolution during helminth infection Therefore, deficiency in RA attenuates the immune response and raises the risk of infectious diseases.

To deal with VA deficiency, the World Health Organization has recommended high-dose VA supplementation in children 6—59 months of age in locations where VA deficiency is endemic.

Oral supplementation of VA or RA potentiated vaccine efficacy by facilitating the trafficking of vaccine-antigen-specific T lymphocytes to the gastrointestinal mucosa in mice , Moreover, the supplementation of VA or RA upregulated Stimulated by retinoic acid-6 Stra6 in the spleen, enhancing anti-tetanus toxoid antibody production Thus, VA supplementation has been considered a promising strategy to reinforce the antigen-specific immune response upon vaccination.

These findings indicate that nutritional status influences the cell dynamics of several immune cell subsets. We observed that naïve B cells migrated from PPs to the bone marrow in a CXCLdependent manner during 36 h of fasting in mice CXCL13 expression by stromal cells is essential for the formation and maintenance of lymphoid follicles in the lymphoid organs including PPs , The Cxcl13 mRNA expression was significantly downregulated in PPs during the fasting period.

In vitro study using a lymph node-derived stromal cell line suggested that cytokine stimulus i. Because treatment with a glycolysis inhibitor, 2-deoxyglucose, mitigated Cxcl13 expression by activated BLS12 cells in a dose-dependent manner, the metabolic rewiring to glycolysis plays a pivotal role in Cxcl13 expression.

The 36 h of fasting markedly lowered blood glucose levels and attenuated glycolysis, resulting in the downregulation of Cxcl13 expression. In sharp contrast, in the bone marrow, Cxcl13 expression significantly increased during fasting, which allowed naïve B cells to accumulate mainly in the vicinity of blood vessels of the bone marrow cavity.

Such a perivascular region is also known as a site for hematopoietic stem cell HSC differentiation and proliferation due to the accumulation of survival factors such as B-cell activating factor BAFF , colony-stimulating factors CSF , and stem cell factors SCF , which are most likely fundamental for the survival of B cells — Therefore, the perivascular region could serve as a transient niche for naïve B cells during fasting.

In response to refeeding, Cxcl13 expression in the bone marrow was downregulated and naïve B cells migrated back to PPs. Thus, the number of naïve B cells was gradually restored until 48 h after refeeding. As a consequence, GC B cells were eliminated from lymphoid follicles of PPs, whereas naïve B cells were restored after fasting-refeeding.

Give that a subset of GC B cells differentiates into memory B cells, the elimination of GC B cells from PPs in fasted mice may lead to the loss of immune memory for oral antigens.

Indeed, fasted mice failed to generate antigen-specific IgA, IgM, and IgG upon repeated oral immunization with ovalbumin. Figure 3 Bone marrow serves as a reservoir for several immune cell subsets in response to calorie restriction CR or fasting. Fasting lowers CXCL13 levels in PPs and reciprocally increases the expression in the bone marrow.

This leads to the migration of naïve B cells from PPs to the bone marrow. Consequently, the egress of monocytes from the bone marrow is suppressed. Jordan et al. Fasting-induced accumulation of monocytes in the bone marrow was independent of fibroblast growth factor 21 FGF21 and ketone body production.

Transcriptome analysis demonstrated that monocytes were in a quiescent state during fasting. Notably, upon infection with Listeria monocytogenes , monocytes normally migrated from the bone marrow into the bloodstream and eliminated the pathogen without causing inflammation.

Collins et al. Under CR conditions, the concentration of glucocorticoid is increased in the blood but decreased in the bone marrow.

Furthermore, dietary restriction led to the differentiation of adipocytes that generate fatty acids. These recent studies revealed the function of the bone marrow as a shelter for several immune cell subsets during metabolic adversity.

Such a multiorgan-trafficking of immune cells may occur even under normal nutritional conditions. In support of this notion, we observed that naive B cells show circadian oscillation between the bone marrow and PPs.

The number of naive B cells in the bone marrow increased during the daytime when mice usually take little food, whereas the number decreased during nighttime in response to food intake.

Furthermore, FoxO1, which is upregulated during CR, regulates naïve T cell migration to the secondary lymphoid tissues by increasing the expression of CCR7 and L-selectin. We are only beginning to learn about the multiorgan-trafficking of immune cells as a fasting response.

Further investigation will clarify the underlying mechanisms in this emerging field. In addition to dietary interventions, drugs targeting key nutrient signaling pathways e.

Rapamycin is best characterized as an inhibitor of mTORC1, and its chronic administration also inhibits mTORC2 in some tissues. Rapamycin has been clinically used as an immunosuppressant to prevent post-transplantation rejection.

Animal studies have also corroborated that rapamycin-dependent mTOR inhibition is effective for various diseases, including ischemic stroke, rheumatoid arthritis, and EAE — Table 1. The anti-inflammatory effect of rapamycin treatment is associated with the attenuation of Thcell differentiation as well as the promotion of Treg-cell development , Moreover, the coadministration of rapamycin with FMS-like tyrosine kinase 3 FLT-3 ligand was shown to facilitate the plasmacytoid dendritic cell-dependent induction of Treg cells, thereby enhancing immune tolerance Rapamycin was also reported to alleviate the development of a murine atherosclerosis model.

During the initial phase of atherosclerosis, peritoneal macrophages transform into foam cells that elicit plaque formation inside the arterial vessels Rapamycin was found to induce autophagy in macrophages to prevent foam cell development However, rapamycin and everolimus, a derivative of rapamycin, possess only a narrow therapeutic index because of their pleiotropic effects, which potentially cause adverse effects.

Metformin, the first-line drug for type 2 diabetes, has the potential to regulate immune responses through inducing metabolic rewiring in immune cells such as T cells Table 1. It inhibits mitochondrial complex I and restrains hepatic gluconeogenesis, with an increase in glucose utilization in peripheral tissues A low concentration 0.

Similar to dietary interventions, metformin and a complex I inhibitor, rotenone, were reported to suppress mitochondrial ROS generation and NLRP3-dependent inflammasome formation in animal and human studies — Accordingly, metformin treatment decreased IL-1β production while increasing IL in response to LPS Metformin treatment also suppressed the development of Th17 cells by inhibiting mTOR and STAT3 signaling, whereas it induced Treg cells by enhancing AMPK signaling These studies demonstrate that metformin has a therapeutic effect on inflammation-related diseases, including IBD, EAE, rheumatoid arthritis, and psoriasis — These observations also raise the possibility that a combination of dietary intervention and metformin may induce synergy on the anti-inflammatory responses.

In a preliminary clinical trial, a combination of a dietary restriction with metformin on obese people enforced protective effects on insulin resistance Metformin also diminished tumor-resident Treg cells that counteract anti-tumor immunity Although Treg metabolism largely depends on OXPHOS through FAO, metformin-treated Treg cells undergo glycolysis.

These facts indicate that low-dose metformin augments anti-tumor immunity by inducing metabolic rewiring. Halofuginone HF , a derivative of the plant alkaloid Dichroa febrifuga is a pharmacological mimic of AAR.

HF competitively inhibited prolyl-tRNA synthetase, enhancing the intracellular pool of uncharged tRNA that phosphorylates and activates GCN2 HF treatment selectively constrained Th17 differentiation, but not Th1, and protected the development of EAE The administration of HF also inhibited IL-1β production by LPS-stimulated macrophages and ameliorated the severity of DSS-induced colitis Additionally, HF promoted GC formation and memory B cell formation in the draining lymph nodes in mice received vaccination Based on these observations, the pharmacological mimic of AAR responses may be a promising strategy to dampen inflammatory response and consolidate immunological memory for vaccine antigens Table 1.

Other drugs targeting the metabolic system have also become key options for immune modulation. Dimethyl fumarate DMF , a derivative of the Krebs cycle intermediate fumarate DMF inactivated a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase GAPDH and inhibited aerobic glycolysis in activated, but not resting, macrophages Table 1.

Innate immune cells also develop long-term memory upon stimulation with bacterial products like β-glucan. This phenomenon is termed as trained immunity A metabolic shift from OXPHOS to aerobic glycolysis, namely, Warburg-like effect, is vital for β-glucan-induced trained immunity.

Such a metabolic alteration is caused by the activation of mTOR-HIF-1 pathway The induction of trained immunity is also dependent on mevalonate, a metabolite of cholesterol synthesis.

Mevalonate not only active the mTOR-HIF-1 pathway but also cause epigenetic alternations characterized by enrichment of H3K4me3 on the promoter region of IL6 and TNFA gene loci Inhibition of mevalonate synthesis by fluvastatin canceled the increment of cytokine production as well as epigenetic alternations induced by either β-glucan or oxidized low-density lipoprotein in monocytes.

Thus, cholesterol biosynthetic pathways are considered as a drug target to interrupt innate immune memory Table 1. Dietary interventions have profound effects on immune responses through metabolic rewiring.

Fasting has been shown to enhance immune memory and suppress inflammation. TRF was shown to recover the appropriate circadian rhythm, improving metabolic disorders and optimizing immune responses. Moreover, accumulating studies have demonstrated the molecular mechanisms underlying these findings.

Thus, drugs targeting the metabolic system may become a critical option for immune modulation. Meanwhile, dietary interventions of different types, durations, and timings can have opposite effects on health and disease.

The benefits of dietary interventions can vary from patient to patient when we apply such interventions in a clinical setting. Experimental protocols have been performed to treat various immune-related disorders with dietary interventions.

Looking ahead, we need to develop evidence-based, optimized protocols to avoid adverse effects. New therapeutic approaches against type 2 diabetes and cardiovascular disease are currently being discussed and applied — It is reasonable to use the same approach to treat inflammatory diseases and enhance vaccine efficacy.

In addition to local responses, an integrated immunometabolic response is required for host survival in a state of energy deficit. Recent studies have revealed the function of the bone marrow as a shelter for immune cells during dietary deficiency.

It is clear that metabolic rewiring impacts immune cell dynamics, inducing inter-organ fasting responses in the body. A deeper understanding of this field could lead to the identification of novel drug targets.

TO and MN wrote the manuscript. TO prepared the figures. KH critically revised the manuscript and obtained funding. All authors contributed to the article and approved the submitted version. This study was supported by grants from the Japan Society for the Promotion of Science 20H to KH and AMED-Crest 20gmh and 20gmh and to KH.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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