F U L L T E X T S O U R C E : Cell
HIGHLIGHTS
- Fasting drastically reduces lymphocyte levels in Payer’s patches
- Naive B cells migrate to bone marrow during fasting and then back upon refeeding
- Nutritional signals are essential to maintain CXCL13 expression by stromal cells
- Fasting causes GC B cell death and attenuates antigen-specific IgA response
​
SUMMARY
Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer’s patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.
INTRODUCTION
Inappropriate calorie intake is a global health problem. In developing countries, the nutritional deficiency often compromises vaccination efficacy and increases the risk of infectious diseases. Furthermore, childhood malnutrition is a predisposing factor for environmental enteropathy characterized by intestinal dysfunction, increased intestinal permeability, and microbial dysbiosis. In industrialized countries, on the other hand, excessive food intake accompanied by a lack of exercise has augmented the incidence of obesity, which is a significant risk factor for cardiovascular disease, metabolic syndromes, and cancer. Low-grade inflammation due to obesity is significantly implicated in the development of these diseases. These observations indicate that nutritional status has a significant impact on the immune system.
The gastrointestinal mucosa is directly exposed to exogenous food ingredients and thus inevitably faces drastic changes in the nutritional status of the lumen during food uptake and fasting. We previously demonstrated that intestinal tissue is highly susceptible to deprivation of luminal nutrients, as temporal fasting arrested epithelial cell proliferation while refeeding induced hyperproliferation in the intestinal epithelium.
Given that epithelial cell turnover constitutes a robust first-line barrier to external antigens, mucosal barrier function may be more vulnerable during fasting than during feeding. Considering that fasting relieves the burden of food-borne antigens and microorganisms on the gut mucosa, it is thus reasonable to decelerate epithelial cell turnover temporarily to minimize energy expenditure under nutrient deprivation.
The gut mucosal barrier consists of not only intestinal epithelium but also an underlying immune system that establishes the second-line barrier. The gut mucosal immune response is characterized by the production of dimeric or polymeric immunoglobulin A (IgA) to the mucosal surface.
Secretory IgA (S-IgA) plays vital roles in host defense against pathogens, inhibition of microbial metabolite penetration, and regulation of the gut microbial community.
To efficiently induce S-IgA response, luminal antigens are actively taken to gut-associated lymphoid tissue, such as Peyer’s patches (PPs), that serve as an inductive site of mucosal immunity. In PPs, germinal center (GC) reactions, namely, class switch recombination to IgA as well as affinity maturation, occur continuously with the aid of follicular helper T (Tfh) cells. IgA class-switched B cells subsequently egress PPs and then home to the intestinal lamina propria via mesenteric lymph nodes (MLNs), the thoracic duct, and blood circulation, during which IgA+ B cells terminally differentiate into IgA-producing plasma cells.
Multiple lines of research have uncovered a link between immune cell function and metabolic status.
For example, upon T cell receptor (TCR) stimulation, effector T (Teff) cells enhance the uptake and utilization of glucose to promote aerobic glycolysis. Activated Teff cells also upregulate glutaminolysis. Such metabolic reprogramming is essential for Teff cells to meet the energy demand of clonal expansion and effector functions, such as the production of inflammatory cytokines.
Furthermore, IgA+ plasma cells in the intestine preferentially utilize glycolysis for energy metabolism, whereas naive B cells in PPs usually gain ATP through aerobic metabolism in mitochondria.
Stimulation with lipopolysaccharides (LPS) or B cell receptor (BCR) ligation upregulates glucose transporter 1 (Glut1) expression in B cell activating factor (BAFF)-pretreated B cells, which eventually undergo metabolic reprogramming to glycolysis.
Because B cell-specific Glut1 depletion leads to decreased B cell number and antibody production, glycolytic rewiring is critical for B cell activation. Upregulation of Glut1 expression in activated B cells is primarily mediated by activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, which in turn enhances the mechanistic target of rapamycin (mTOR) signaling. Excessive activation of the PI3K-Akt-mTOR pathway increases the frequencies of Tfh cells and GC B cells in PPs, while the opposite is true, as disruption of mTORC1 or mTORC2 diminishes GC reactions and production of S-IgA.
Given that mTOR serves as a nutrient sensor, the whole-body nutritional status in response to energy intake and starvation may considerably affect the immune response. Indeed, fasting or fasting-mimic diet exerts a protective effect on bacterial sepsis and colitis by alleviating expression of proinflammatory cytokines, whereas glucose supplementation protects against influenza viral infection.
However, the impact of nutritional signals on mucosal barriers, lymphocyte dynamics, and effector functions in the context of fasting and feeding remains unknown. Furthermore, most animal studies on calorie restriction and intermittent fasting have employed older mice, which may not adequately reflect biological responses during childhood and children susceptible to nutritional deficiency.
In the present study, we analyzed the influence of fasting-refeeding on cellular dynamics and functionality of the gut immune system mainly in juvenile mice. We observed that PP lymphocytes, particularly naive B cells, exhibit dynamic movement to the bone marrow (BM) during temporal fasting and then swiftly migrate back to PP in response to food intake. A similar oscillation of naive B cells based on the circadian rhythm was observed to a lesser extent in ad libitum-fed mice. Stromal CXCL13 expression for recruiting and retaining B cell subsets was regulated by metabolic status depending on aerobic glycolysis. The frequency of memory-like B cell subsets markedly decreased after fasting-refeeding treatment, leading to attenuation of antigen-specific IgA production and oral tolerance to a food antigen, which eventually increased susceptibility to antigen-induced diarrhea.
.../...
F O R T H E R E S T O F T H E S T U D Y , P L E A S E V I S I T T H E S O U R C E
.
