Lipid nanoparticle (LNP)-mRNA vaccines robustly activate immune responses, contributing to their high efficacy and frequent adverse reactions (ARs). Here, we identified an LNP-mRNA formulation with a more favorable balanced immunogenicity-reactogenicity profile. Immune profiling in a mouse model defined the reactogenic LNP-mRNA vaccine as a potent inducer of HMGB1 release, pro-inflammatory cytokine production, and concurrent neutrophil infiltration. HMGB1 induced TNF-α secretion from monocyte subsets, yet in vivo blockade studies revealed the contribution of multiple cytokines (TNF-α, IL-1, and IL-6) to reactogenicity. Among the reactogenic cytokines, IL-1 was identified as the key mediator of vaccine-induced ARs, but was dispensable for humoral immunity. The clinical relevance was confirmed in a well-controlled vaccine cohort where IL-1 pathway activation correlated with fever severity but not with neutralizing antibody titers. We dissected early innate pathways specifically linked to vaccine reactogenicity, providing a rationale for selectively reducing ARs in next-generation vaccines.

Professor Shimon Sakaguchi received the 2025 Nobel Prize in Physiology or Medicine for his discovery and elucidation of regulatory T cells (Tregs). This review celebrates his achievement by discussing the important role of Tregs in immune responses to food. Tregs, which primarily differentiate in the thymus, are integral to suppressing immune reactions to self antigens and thus maintaining self tolerance. In addition, peripheral Tregs may differentiate in other sites, namely the intestinal immune system. Immune tolerance may be established to orally ingested antigen, termed oral tolerance, and Tregs induced in the intestinal immune system are involved. In addition, Tregs mediate immunomodulation by food, such as the alleviation of pollinosis, and may be involved in suppressing inflammation in other situations. This review also addresses the mechanisms, including those mediated by dendritic cells.

The immunomodulatory effects of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 and Streptococcus thermophilus OLS3059 were evaluated in a randomized, double-blind, placebo-controlled trial involving 140 healthy males and females. The participants ingested test yogurt or placebo daily for eight weeks. The yogurt group exhibited significantly increased CD86+ and CD80+ conventional dendritic cell (cDC) populations, CD40+ plasmacytoid DC (pDC) populations upon viral antigen stimulation, CD69 expression on CD4+ T cells, and salivary s-IgA levels compared to those in the placebo group. The onset of local (nausea) and systemic (fatigue, general malaise, and feeling somewhat unwell) cold-like symptoms was significantly reduced in the yogurt group compared to that in the placebo group. These results suggest that intake of yogurt fermented with OLL1073R-1 and OLS3059 enhances cDC and pDC activities and subsequently promotes CD4+ T cell activation and salivary s-IgA production, thereby contributing to health maintenance.

Impaired expansion, stability, and function of regulatory T cells (Tregs) are reported in patients with severe allergy. Transfer of Tregs is a potential means of treating severe food allergy; however, methods to obtain allergen-specific Tregs with stable regulatory activities are needed. To achieve our goal, we examined the characteristics of allergen-specific Tregs by comparing two mouse strains transgenic for the ovalbumin (OVA)-specific T cell receptor gene: Rag23−3 and RagD10 mice (OVA23−3 and DO11.10 crossed with Rag2 knockout mice, respectively). RagD10 is a tolerant model, whereas Rag23−3 shows severe allergy when fed egg white (EW). To examine the differentiation of CD4 + T cells into Foxp3 + Tregs (induced Tregs; iTregs), CD4 + T cells or whole cells from mesenteric lymph nodes or spleens were cultured under Treg-polarization conditions and stimulated with either a combination of anti-CD3 and anti-CD28 antibodies or OVA plus antigen-presenting cells. After stimulation with the antibodies, iTregs were induced at comparable levels from CD4 + T cells from untreated Rag23−3 and RagD10 mice. Transfer of the resultant iTregs from untreated Rag23−3 mice suppressed allergic responses in EW-fed Rag23−3 mice. In contrast, stimulation with OVA plus antigen-presenting cells prevented the differentiation of iTregs from CD4 + T cells from untreated Rag23−3 mice, suggesting that OVA-induced T-cell receptor signaling inhibits effective Treg differentiation. Furthermore, antibody-mediated differentiation afforded significantly more iTregs differentiation of naïve (CD44 lo CD62L hi ) CD4 + T cells than of effector/effector memory (CD44 hi CD62L lo ) T cells isolated from the mesenteric lymph nodes of EW-fed Rag-23–3 mice. Excessive production of interleukin-4 and interferon-gamma by CD4 + T cells from EW-fed Rag23−3 mice significantly inhibited Treg induction in RagD10 mice, suggesting the severe allergic cytokine milieu likely prevents their differentiation. However, our study showed that allergen-specific Tregs with regulatory activity can be obtained from naïve CD4 + T cells from the intestinal immune system of mice even with severe allergy.

BACKGROUND:Severe Th2 inflammatory diseases, including food allergy, are known to be associated with osteoporosis. However, while IL-4 inhibits osteoclast differentiation, detailed mechanisms of osteoporosis caused under IL-4-excessive environments remain unclear. METHODS:OVA23-3 mice are transgenic mice expressing OVA-specific T-cell receptors and develop significant IL-4-producing T-cell responses resulting in food-allergic enteropathy associated with osteoporosis when fed an egg white (EW) diet. This enteropathy is characterized by phases of inflammation and desensitization; bone loss develops during the inflammatory phase with the onset of allergic enteropathy and is maintained during the desensitization phase when the enteropathy is alleviated by immunological tolerance induction by continuous EW-feeding. We used this model to elucidate the mechanism of food antigen-induced osteoporosis, particularly in an IL-4-dominant environment. RESULTS:During the inflammatory phase, EW-feeding promoted osteoclastogenesis with increased mast cells, suppressed by administering anti-IL-4 antibody to the model. This finding suggests a critical role for IL-4 in the induction of osteoclastogenesis, which may be associated with mast cells and eosinophils over-differentiation and lead to osteoporosis. However, during the desensitization phase, the bone loss mechanism switched to high metabolic bone turnover, maintaining osteoclast activity despite amelioration of the enteropathy by continuous EW feeding. The increased number of IL-10-producing Tregs from mesenteric lymph nodes may reduce osteoclastogenesis during the desensitization phase, but did not suppress osteoporosis. CONCLUSIONS:The present study provides a new perspective on a poorly understood mechanism of osteoporosis in severe allergies, suggesting the importance of maintaining bone health in allergic patients, including food allergies.

The role of Toll-like receptor 2 (TLR2) in the central nervous system (CNS) is critical in several conditions including neurological disorders such as pain, and neurodegenerative disorders such as Parkinson’s disease. Therefore, understanding TLR2 function in the CNS is of considerable importance. In this study, we investigated neuronal responses to individual TLR2 ligands. The expression levels of cytokines increased in the culture in the presence of TLR2 ligands. Additionally, increased lactate dehydrogenase (LDH) was noted during lipoteichoic acid (LTA) stimulation. During LTA stimulation, a decrease in the peak amplitude of Ca 2 + oscillations was observed. MnTBAP, which is a reactive oxygen species (ROS) blocker, inhibited the LTA-induced cell death but had no effect on the peak amplitude of the Ca 2 + spike. Conversely, Pam3CSK4 (P3C) stimulation increased the number of Ca 2 + peaks, which was inhibited by a tumor necrosis factor alpha (TNFα) signaling inhibitor. Our study revealed that several TLR2 ligands, each with different specificities, elicited diverse responses in primary cortical cells. In conclusion, TLR1-TLR2 and TLR2-TLR6 signaling reduces the peak amplitude and induces cell death, and TLR1-TLR2 signaling enhances Ca 2 + dynamics via a TNFα pathway. Graphical Abstract

Cellular senescence refers to a state in which cells stop dividing and can no longer proliferate because of various factors, such as DNA damage and oxidative stress. It is implicated as a key driver of aging and age-related diseases. Lactiplantibacillus plantarum OLL2712 (OLL2712) is a lactic acid bacterium that alleviates chronic inflammation and improves the intestinal barrier and cognitive functions. These effects are important for preventing the changes that occur in the body with aging. In this study, we hypothesized that OLL2712 protects against intestinal barrier dysfunction associated with cellular senescence. To reveal the antiaging effect of OLL2712, we used D-galactose (D-gal) to induce cellular senescence in Caco-2 cells and investigated its effects on various phenomena occurring in senescent intestinal cells. The results showed that OLL2712 suppressed D-gal-induced cellular senescence and intestinal barrier dysfunction. Furthermore, microarray analysis showed that OLL2712 upregulated signaling involved in antioxidant effects, metabolism, and cell division, which were downregulated by cellular senescence. Overall, OLL2712 maintained intracellular homeostasis and restored intestinal barrier dysfunction associated with cellular senescence. We discovered the possibility that paraprobiotics contribute to the antiaging effects.

Immunoglobulin (Ig) G isotypes in the sera of healthy mice and humans react to commensal bacteria. We previously reported that BALB/c mice with normal gut microbiota possessed abundant B cells that produced IgG2b reactive to commensal bacteria in cecal patches (CePs), indicating a potential source of a systemic pool of commensal bacteria-reactive IgG2b. Mice housed under germ-free conditions demonstrate the importance of the gut microbiota in driving cecal IgG2b responses. However, it is unclear whether the constitutive presence of the gut microbiota and specific bacterial taxa are important for IgG2b responses in adult mice. In this study, we showed that elimination of the gut microbiota by mixed antibiotic treatment in adult mice decreased the abundance of IgG2b+ B cells, follicular helper T (Tfh) cells in CePs, and the serum levels of commensal bacteria-reactive IgG2b. Reduced IgG2b responses have also been observed in mice with an altered gut microbiota following treatment with ampicillin or vancomycin. Changes in the diversity and composition of the cecal microbiota, particularly a decrease in Lachnospiraceae, Muribaculaceae, Ruminococcaceae, and Bacteroidaceae abundance at the family level, were observed in these mice. In addition, depletion of CD4+ T cells by the injection of neutralizing antibodies in adult mice reduced IgG2b responses. Our results suggest that specific gut bacteria susceptible to ampicillin and vancomycin play roles in providing an abundance of Tfh cells to help the generation of IgG2b+ B cells in CePs in adult mice, which may contribute to the supply of systemic commensal bacteria-reactive IgG2b.

Heated eggs have often been used for oral immunotherapy of egg allergy because of their lower allergenicity than raw eggs. Furthermore, recent guidelines recommend the earlier introduction of well-cooked eggs to the diet as a supplementary food and protective measure against food allergy in infants. However, the influence of cooking with heat on the allergenicity and tolerogenicity of egg white (EW) antigen in individuals with egg allergy is not well understood. We investigated this by feeding ovalbumin (OVA)-sensitized inbred mice EW heated at 80°C for 15 min (80EW), 100°C for 5 min (100EW), or 121°C for 40 min (121EW). Only 100EW resolved enteritis, and it produced more effective tolerogenicity to OVA than EW. The state of enteritis and tolerogenicity for 80EW was almost the same as that for EW. Th1 responses to short-term feeding were observed with 121EW. We then investigated allergy recurrence after continuous feeding with the 100EW diet. Of note, however, the oral tolerance acquired with 100EW or EW was not effective against allergic recurrence in response to EW, because of residual high levels of serum OVA-specific IgE and residual infiltrated mast cells in the intestine. Furthermore, the recurrence of allergic symptoms in response to EW was more severe when oral tolerance was acquired with 100EW rather than with EW. Our results suggest that patients must be careful not to inadvertently consume EW, even if clinical tolerance to heat-treated EW has been achieved.

BACKGROUND:Maternal nutrition during critical developmental windows is crucial for offspring metabolic programming. Methionine, an essential amino acid, is crucial in pancreatic differentiation. However, the impact of a maternal methionine-deficiency (MD) diet on offspring during the critical stage of embryonic pancreatic differentiation remains unclear. METHODS:We used an in vitro human induced pluripotent stem cell (hiPSC) differentiation model and in vivo mouse and rat models to assess the impact of short-term maternal MD during pancreatic development. Offspring metabolic outcomes were evaluated under control or high-fat diet conditions. Multi-omics analyses were performed to explore mechanistic pathways, and Ruminococcus flavefaciens supplementation was used to assess microbiota-metabolite-host interactions. FINDINGS:During foetal pancreatic development in mice, a two-day maternal MD diet induced long-term metabolic perturbations in offspring. MD disrupted pancreatic progenitor differentiation in vitro and altered offspring glucose homeostasis, pancreatic function, and gut microbiota composition in vivo. Male offspring showed impaired glucose tolerance, enhanced pancreatic differentiation, and increased susceptibility to diet-induced obesity in adulthood. These metabolic impairments were evident early in life, with MD neonates displaying altered metabolic profiles and pancreatic gene expression. We identified an association between maternal MD diet, gut microbiota-dependent R. flavefaciens abundance, and elevated creatine levels in both mothers and offspring. R. flavefaciens supplementation in mice recapitulates the observed metabolic dysregulation. INTERPRETATION:Short-term maternal MD during foetal pancreatic development can induce lasting metabolic reprogramming in offspring. Gut microbiota-dependent creatine dysregulation may serve as a key mediator linking maternal diet to offspring metabolic susceptibility. These findings highlight the developmental impact of transient maternal nutrient imbalance and role of the microbiota-metabolite axis in shaping offspring health. FUNDING:See Acknowledgements.

IntroductionThe intestinal immune system plays a pivotal role in the induction of immune responses against food. In the case of T cell response, dendritic cells (DCs) are especially important. However, the regulation of immune responses to food by intestinal DCs has been poorly described. In this study, we analyzed the effect of Lactococcus lactis subsp. cremoris YRC3780, a lactic acid bacterial strain isolated from kefir, a traditional fermented milk product, on the immune responses induced by antigen presentation by intestinal DCs to T cells as well as the mechanism of action of these immunomodulatory effects. It has been shown that L. cremoris YRC3780 ameliorates the symptoms of pollinosis in both animal and human studies.MethodsCD11c+ cells from mesenteric lymph nodes (MLNs) of BALB/c mice were cultured as MLN DCs with L. cremoris YRC3780 and expression of genes inducing regulatory T cells (Tregs) was examined by qPCR. In addition, MLN DCs were cocultured with CD4+ T cells from DO11.10 transgenic mice expressing an ovalbumin (OVA)-specific TCR and the OVA antigen peptide and L. cremoris YRC3780. Induction of Tregs was examined by flow cytometry, gene expression was analyzed by DNA microarray and qPCR, and the production of cytokines was measured by ELISA. MLN DCs from TLR2-deficient mice and components of L. cremoris YRC3780 were used to examine the recognition of YRC3780 by MLN DCs.ResultsL. cremoris YRC3780 enhanced the expression of genes involved in Treg induction in MLN DCs and induced Foxp3+CD4+T cells in an MLN DC and CD4+ T-cell co-culture system. The effect on MLN DCs was likely mediated by receptors other than TLR2. Together with microarray analyses of CD4+ T cell gene expression and cytokine ELISA, it was demonstrated that L. cremoris YRC3780 promoted the induction of Th1 and Tregs, and regulated the balance of Th1/Th2 and Treg/Th17 cells involving multiple genes via the antigen-presentation of MLN DCs.DiscussionOur findings provide insights into the modulation of intestinal immune responses mediated by DCs and the antiallergic effects of lactic acid bacteria.

AIM:The ingestion of Lactiplantibacillus plantarum OLL2712 (OLL2712) cells has been shown to improve glucose metabolism by suppressing chronic inflammation in murine models and clinical studies. This study aimed to clarify the effect of OLL2712 on glycaemic control in healthy adults with prediabetes. MATERIALS AND METHODS:The study was a randomized, double-blind, placebo-controlled, parallel-group design. Adult participants with prediabetes [n = 148, glycated haemoglobin (HbA1c) range: 5.6%-6.4%, age range: 20-64 years] were assigned randomly to placebo or OLL2712 groups (n = 74/group) and administered daily for 12 weeks either conventional yogurt or yogurt containing >5 × 109 heat-treated OLL2712 cells, respectively. In addition, the participants were followed for 8 weeks after the discontinuation of either yogurt. The primary outcome was the changes in HbA1c levels at weeks 12 and 16 by analysis of covariance. RESULTS:The levels of HbA1c and glycoalbumin decreased significantly in both groups at week 12 in comparison with those at week 0, but only in the OLL2712 group at week 16. HbA1c levels decreased significantly at weeks 12 and 16 in the OLL2712 group in comparison with the placebo group (p = .014 and p = .006, respectively). No significant inter- and intragroup differences in HbA1c levels were observed at week 20. CONCLUSIONS:The ingestion of OLL2712 prevents the deterioration of glycaemic control and maintains the HbA1c levels within the normal range in adults with prediabetes; yogurt probably exhibits similar effects, which may contribute to reducing the risk of developing type 2 diabetes.

Introduction:Chronic inflammation caused by dietary obesity has been considered to induce lifestyle-related diseases and functional ingredients with anti-inflammatory effects are attracting attention. Although multiple studies on obesity had proved the anti-inflammatory effects of ingestion of lactic acid bacteria (LAB) and other functional ingredients on adipose tissue, the precise effects on the intestine, especially on the individual intestinal segments have not been made clear. In this study, we elucidated the mechanisms of Lactiplantibacillus plantarum (basonym: Lactobacillus plantarum) OLL2712 in suppressing obesity-induced inflammation using high fat diet (HFD)-fed mice obesity model.Methods:We orally administered heat-treated LAB to HFD-fed mice model, and investigated the inflammatory changes in adipose tissue and intestinal immune cells. We also analyzed gut microbiota, and evaluated the inflammation and permeability of the duodenum, jejunum, ileum and colon; four intestinal segments differing in gut bacteria composition and immune response.Results:After 3-week LAB administration, the gene expression levels of proinflammatory cytokines were downregulated in adipose tissue, colon, and Peyer's patches (PP)-derived F4/80+ cells. The LAB treatment alleviated obesity-related gut microbiota imbalance. L. plantarum OLL2712 treatment helps maintain intestinal barrier function, especially in the ileum, possibly by preventing ZO-1 and Occludin downregulation.Discussion:Our results suggest that the oral administration of the LAB strain regulated the gut microbiota, suppressed intestinal inflammation, and improved the gut barrier, which could inhibit the products of obesity-induced gut dysbiosis from translocating into the bloodstream and the adipose tissue, through which the LAB finally alleviated the inflammation caused by dietary obesity. Barrier improvement was observed, especially in the ileum, suggesting collaborative modulation of the intestinal immune responses by ingested LAB and microbiota.

Macrophages are classified into classically activated M1 macrophages and alternatively activated M2 macrophages, and the two phenotypes of macrophages are present during the development of various chronic diseases, including obesity-induced inflammation. In the present study, β-elemene, which is contained in various plant substances, is predicted to treat high-fat diet (HFD)-induced macrophage dysfunction based on the Gene Expression Omnibus (GEO) database and experimental validation. β-elemene impacts the imbalance of M1-M2 macrophages by regulating pro-inflammatory cytokines in mouse white adipose tissue both in vitro and in vivo. In addition, the RAW 264 cell line, which are macrophages from mouse ascites, is used to identify the effects of β-elemene on inhibiting bacterial endotoxin lipopolysaccharide (LPS)-induced phosphorylation of mitogen-activated protein kinase (MAPK) pathways. These pathways both induce and are activated by pro-inflammatory cytokines, and they also participate in the process of obesity-induced inflammation. The results highlight that β-elemene may represent a possible macrophage-mediated therapeutic medicine.

The biological activities of acetic acid bacteria (AAB) as Gram-negative bacteria have attracted our interests, especially in their inhibitory effects on allergic responses. To clarify the underlying mechanism that improves allergic symptoms by ingestion of the AAB Gluconacetobacter hansenii, we examined whether different extracts of heat-killed G. hansenii GK-1 could reduce the interleukin (IL)-4 production of immune cells from food-allergic model of OVA23-3, transgenic mice with ovalbumin (OVA)-specific T-cell-receptor genes. A hot-water extract fraction (FII) of G. hansenii GK-1 significantly decreased the in vitro IL-4 production of spleen cells of OVA23-3 mice compared with those stimulated with OVA alone. The IL-4 inhibitory effect was also observed for FIV (purified lipopolysaccharide (LPS) fraction), but the activity was lower than for FII or LPS from Escherichia coli. Unlike LPS from Escherichia coli, FIV significantly inhibited the LPS-induced IL-6 production of the spleen cells. The addition of FII or FIV to a Foxp3+T cell-inducing culture showed that FII significantly promoted the rate of Foxp3+CD4+T cells of OVA-stimulated mesenteric lymph node cells from recombination-activating-gene (RAG)-2-deficient food-allergic inflammatory OVA23-3 (R23-3) mice with suppression of IL-4 production, while FIV induced Foxp3+T cells from RAG-2-deficient DO11.10 non-inflammatory mice. Structure analysis showed a lack of O-antigen in FIV, which seemed to lead to the weak biological activities of FIV observed. The present study suggests that extracts of G. hansenii GK-1 to inhibit IL-4 production of immune cells and/or promote regulatory T cell differentiation synergistically play important roles in improving allergic symptoms safely as well as normal condition.

Accumulating evidence suggests that Lactococcus lactis subsp. cremoris YRC3780 isolated from kefir has the potential to alleviate allergic responses. Herein, we investigated the effect of YRC3780 on a murine model of Japanese cedar pollinosis (JCP). BALB/c mice immunized with cedar pollen extract (CPE) exhibited an increase in serum immunoglobulin E and developed nasal inflammatory responses including sneezing, nasal hyperresponsiveness, and nasal eosinophil accumulation upon intranasal allergen challenge. These responses were suppressed by the oral administration of YRC3780, although the effects on CPE-induced sneezing response and eosinophil infiltration were not statistically significant. Total fecal microbiota diversity was not affected by allergen immunization and challenge or by YRC3780 administration. However, the abundances of Bifidobacteriales, Veillonellaceae, Lactococcus, and Lactococcus lactis were larger and that of Bacteroides was smaller in YRC3780-treated mice compared with those in CPE-challenged and YRC3780-untreated mice. Our findings suggest the usefulness of YRC3780 for alleviating JCP.