Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, β-hydroxybutyrate (βHB) or acetoacetate (AcAc), offer an alternative approach. While βHB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.

Introduction: Infants have an immature immune system, making them more susceptible to infectious diseases, including otitis media (OM). Breastfeeding is known to reduce OM risk. Although cytokines in breast milk regulate immune functions, their association with OM incidence is underexplored. This study investigated the breast milk cytokines associated with OM in infancy. Methods: A case-control study was conducted using mother-child pairs from the Chiba Study of Mother and Child Health (16 cases, 53 controls) with a history of OM. Breast milk samples were collected at three time points (colostrum, 1 month, and 4 months postpartum), and cytokine concentrations were measured. We compared cytokine levels between cases and controls and analyzed differences between primiparous and multiparous mothers, including subgroup analysis for multiparous mothers. Results: Children in the case group were more likely to have multiparous mothers. Cytokine concentrations were highest in colostrum and decreased over time, except for interleukin-7 (IL-7), which increased at 1 month postpartum. However, among multiparous mothers, IL-7 concentration was higher in the control group at 1 month postpartum (66.3 [45.7, 84.7] versus 14.1 [0.00, 42.5] pg/mL). Conclusions: IL-7 in mature breast milk significantly prevents OM, potentially in infants born to multiparous mothers. Trial Registration: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (trial registration number: UMIN000046221, registration date: 29/11/2021).

Depression rates have been rising globally, making it a significant public health concern. Increasing evidence suggests that exposure to natural environments has positive effects on mental health. However, most studies on the restorative effects of nature have focused on healthy individuals, with limited data available on vulnerable populations, such as patients with depression. This study examined the physiological and psychological relaxation effects of viewing a small urban green space (biotope) on outpatients with depression. Conducted in an urban clinical setting, this crossover study involved 28 adult male outpatients with major depressive disorder. The experimental condition involved viewing a biotope outside the clinic, while the control condition involved viewing a building facade. Heart rate variability was used as a physiological indicator, while subjective evaluations were conducted using the modified semantic differential method and the Profile of Mood States 2nd Edition (POMS 2) short version. Results indicated that biotope viewing significantly increased parasympathetic nervous activity while decreasing sympathetic nervous activity. Subjectively, participants reported increased comfort, relaxation, and naturalness. POMS 2 assessments further revealed a significant reduction in negative affect scores and an increase in positive affect scores. This study provides empirical evidence that integrating small-scale urban greenery into clinical environments can promote relaxation and well-being in individuals with depression. Given the high levels of stress in urban populations, particularly in overcrowded cities like Tokyo, incorporating accessible green spaces in urban planning may serve as a viable intervention to mitigate environmental health disparities and improve mental health outcomes.

Adiposity rebound (AR) corresponds to the start of the second rise in the body mass index curve during infant growth. Early AR (before age 5) confers increased risk of adiposity and metabolic disorders but is less likely to occur in breastfed infants. Although lipids in breast milk are important in child growth, information is limited regarding which lipids are involved in AR. The object of this study was to explore the association between breast milk lipids and AR status in children. We designed a case-control study of 184 mother-child pairs (AR cases: n = 93; controls: n = 91) included from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Breast milk was collected 1 month postpartum and comprehensive lipid analysis was performed. Partial least square-discriminant analysis was used to explore candidate lipids, and multivariable logistic regression analysis was used to evaluate associations with the AR status of children. We detected 667 lipid molecules in 12 lipid classes in breast milk. Partial least square-discriminant analysis revealed the association of fatty acid-hydroxy fatty acid (FAHFA) and cholesterol ester (ChE) with AR status. Multivariable logistic regression analysis showed that in pairs with exclusive breastfeeding at 1 month postpartum, FAHFA (odds ratio 1.57 [95% confidence interval, 1.06-2.32]) was positively associated with early AR, and ChE (odds ratio 0.55 [95% confidence interval, 0.36-0.86]) was negatively associated. Breast milk lipids (FAHFA, ChE) associated with the AR status of children, indicating the potential to regulate a child's adiposity and possible metabolic disorders in adulthood.

Short-chain fatty acids (SCFAs) are thought to be a key factor in the health benefits of prebiotics and probiotics. This study investigated the effect of Bifidobacterium animalis subsp. lactis GCL2505 and inulin (BL+IN) on fecal SCFAs and gut microbial composition and function. A placebo-controlled, randomized, double-blind, crossover study was conducted with 120 participants. Two weeks of BL+IN intake significantly increased acetate, propionate, and butyrate concentrations and Bifidobacterium abundance compared to placebo. Functional analysis of the gut metagenome showed enrichment of genes associated with carbohydrate and amino acid metabolism, suggesting an enhanced capacity for SCFA production. A responder was defined as a participant with increased fecal SCFAs after BL+IN consumption. Responder metagenomes exhibited greater enrichment of genes involved in SCFA production and carbohydrate metabolism. In conclusion, short-term BL+IN ingestion may benefit healthy adults by increasing fecal SCFAs through influencing the composition and functional activation of SCFA-associated pathways in the gut microbiome.

Efficient energy production is essential for endurance performance, and thus it is important to promote mitochondrial ATP production. Nicotinamide mononucleotide (NMN) is converted to the coenzyme nicotinamide adenine dinucleotide (NAD+), which contributes to mitochondrial ATP production. Meanwhile, paprika xanthophyll (PX), an oil-based extract from ripe red paprika, improves the oxygen-delivery capacity of red blood cells by increasing their membrane flexibility. This study was a randomized, placebo-controlled, double-blind, parallel-group trial that investigated the effects of intake of NMN (500 mg/day), PX (9 mg/day), or their combination for 8 weeks on endurance performance. The participants were male collegiate track-and-field athletes aged 18 years or older. As endurance performance, running velocity at lactate threshold, running velocity at the onset of blood lactate accumulation, and heart rate were evaluated using the lactate curve test. The results showed that NMN did not effectively improve endurance performance after intake for 8 weeks, which was the primary endpoint of this study. However, the results after intake for 4 weeks, as well as stratified analyses by blood NAD+ levels before intake, suggested that the combination of NMN and PX might improve endurance performance. Thus, both the increase in NAD+ induced by NMN intake and sufficient oxygen delivery induced by PX intake may be beneficial for promoting mitochondrial ATP production, thereby leading to improved endurance performance.

Lactobacillus helveticus GCL1815 is a lactic acid bacterium thought to activate dendritic cells. This randomized, placebo-controlled, double-blind study aimed to evaluate the effects of L. helveticus GCL1815 on human dendritic cells and the onset of the common cold. Two hundred participants were divided into two groups and took capsules containing either six billion L. helveticus GCL1815 cells or placebo for 8 weeks. In the GCL1815 group, the cumulative incidence days of symptoms such as feverishness, fatigue, tiredness, runny nose, nasal congestion, and phlegm were significantly lower than in the placebo group. Moreover, the change in the expression of HLA-DR on plasmacytoid dendritic cells was significantly higher in the GCL1815 group than in the placebo group at 4 and 8 weeks of intake. The expression of CD86 on plasmacytoid dendritic cells was significantly increased in the GCL1815 group at 4 and 8 weeks compared with before intake. Additionally, the expression of HLA-DR on type 1 conventional dendritic cells was significantly higher in the GCL1815 group than in the placebo group at 8 weeks of intake. The expression of CD86 on type 1 conventional dendritic cells significantly decreased in the placebo group but remained statistically the same in the GCL1815 group after intake compared with before. These results suggest that GCL1815 intake may enhance the response to viruses by activating two types of dendritic cells, thereby preventing the onset of systemic and local common colds in healthy adults.

In this study, we screened 308 lactic acid bacteria strains for high immunoglobulin A (IgA) production, dendritic cell activation, and interleukin-12 (IL-12) production using human-derived cells. Among them, Lactobacillus helveticus GCL1815 demonstrated superior performance in all aspects, indicating its remarkable potential for immunomodulatory functions in both innate and adaptive immunity.