Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.

Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations.

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring.

Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.