Hiroshi Ohno

Analyses disentangling the role of the gut microbiome in linking lifestyle factors to health outcomes remain limited. Here, using fecal shotgun metagenomics from 6,803 adults in the Japanese 4D cohort, we identified two opposing microbiome-mediated axes linking lifestyle to health and 15 diseases. A health-associated axis enriched in microbial metabolism of dietary components was linked to plant-based, soy and dairy intake. In contrast, a disease-associated axis, enriched in oral-derived bacteria and pathobionts, was linked to refined carbohydrates and sedentary behavior. Starter culture microorganisms used to ferment foods did not show statistically significant mediation of the observed health effects. Alcohol was associated with both health- and disease-oriented mediation patterns involving microbial host-glycan utilization. Microbiome-defined health- and disease-oriented mediator axes were supported by fecal short-chain fatty acids and plasma cytokines from >1,700 individuals, revealing butyrate-associated anti-inflammatory and pro-inflammatory host profiles, respectively. Microbiome-based prediction (MADE) scores captured lifestyle-microbiome-disease mediation patterns and distinguished individual diseases across 13 independent external cohorts from the United States, China, Sweden, Russia and Australia. We identify the gut microbiome as a key mediator linking lifestyle to health and disease, providing a framework for microbiome-based assessment to guide lifestyle interventions for health promotion and disease prevention.

Background: Controlling diarrhoea in humans and livestock is a global challenge with diverse aetiologies. However, the dynamics of the microbiome for diarrhoeal remission are not sufficiently understood, and effective intervention strategies based on environmental microorganisms have not been fully explored. Methods: We investigated the metabolic structure associated with diarrhoeal remission using a combination of statistical, genomic, and proteomic approaches in a cattle model. Oral administration of the compost-derived thermophile Caldifermentibacillus hisashii significantly ameliorated persistent diarrhoea. Faecal bacterial populations and metabolites were characterised by a multi-step statistical pipeline comprising difference-in-differences (DID) analysis, Cliff's delta effect size estimation with permutation-based validation. The functional importance of the selected feature components was validated through genomic and proteomic analysis of C. hisashii N11 (AP028807.1). Results: Oral administration of C. hisashii significantly ameliorated persistent diarrhoea in calves. Although no significant differences in faecal bacterial community composition were observed, integrated analysis of faecal metabolites identified butyrate and 2-aminoisobutyrate (AIB) as the most discriminative features associated with diarrhoeal remission. Genomic and proteomic analyses of C. hisashii confirmed biosynthetic gene clusters for butyrate and AIB-containing lantibiotics, supporting the structural importance of these metabolites in diarrhoeal remission. Conclusion: These findings suggest that diarrhoeal remission observed in this study involves characteristic shifts in faecal metabolite profiles rather than marked changes in overall gut microbial community composition, highlighting a protective role of C. hisashii as an environmental probiotic against diarrhoeal dysbiosis through modulation of gut microbial metabolic output. This offers a perspective that bridges environmental microbiology and gut health within a One Health framework.

Interleukin-22 binding protein (IL-22BP) is a soluble decoy receptor that competitively inhibits IL-22 by preventing its interaction with the IL-22 receptor. Although the IL-22 receptor is primarily expressed on non-hematopoietic cells, such as airway epithelial cells, the role of IL-22BP in the pathogenesis of asthma remains uncertain. We observed that IL-22BP was upregulated in the airways of wild-type (WT) mice intranasally sensitized and challenged with house dust mite (HDM) extract. To directly elucidate the function of IL-22BP in allergic airway responses, IL-22BP-deficient (IL-22BP−/−) and WT mice were sensitized and challenged with HDM, and airway responses were systematically assessed. IL-22BP−/− mice exhibited significantly lower airway hyperresponsiveness (AHR) compared to WT mice following sensitization and challenge with HDM. In contrast, eosinophil counts in bronchoalveolar lavage (BAL) fluid did not differ significantly between the two groups. Similarly, levels of interleukin (IL)-4, IL-5, IL-6, IL-13, IL-17A, and keratinocyte chemoattractant (KC) in BAL fluid were comparable between WT and IL-22BP−/− mice. Notably, IL-22 levels in lung homogenates were significantly higher in IL-22BP−/− mice than in WT mice after sensitization and challenge with HDM. These findings suggest that inhibition of IL-22BP attenuates the development of allergen-induced AHR, an effect likely mediated through enhanced IL-22 activity rather than alterations in airway inflammation or type 2 cytokine production.

Botulinum neurotoxin (BoNT) is an etiologic agent of food poisoning caused by Clostridium botulinum . The large progenitor toxin complex (L-PTC) crosses the intestinal epithelial barrier to deliver BoNT to target neurons; however, it is not clearly understood how BoNT enters the host. Here, we identified low-density lipoprotein receptor−related protein 1 (LRP1) as a major enterocyte transcytosis receptor for the hyper-oral-toxic L-PTC serotype B-Okra (L-PTC/B ^Okra ). We found that hemagglutinin (HA), a neurotoxin-associated protein within the L-PTC/B ^Okra complex, binds to LRP1 via N -glycans. HA/B ^Okra co-localized with LRP1 within the internalized vesicles in cultured cells and enterocytes. LRP1 deletion inhibited the apical-to-basal transcytosis of L-PTC/B ^Okra in an intestinal epithelial cell line, and this effect was rescued by LRP1 re-expression. Finally, intestinal epithelial cell−specific LRP1-deficient mice displayed reduced susceptibility to toxicity caused by oral administration of L-PTC/B ^Okra . Taken together, these results indicate that N -glycosylated LRP1 mediates L-PTC/B ^Okra transcytosis via enterocytes, enabling BoNT to traverse the intestinal epithelial barrier.

Background: Malaria caused by Plasmodium parasites leads to severe complications, such as cerebral malaria; however, the influence of the gut microbiota on the pathogenesis of cerebral malaria remains unclear. Here, the effects of antibiotic-induced microbiota alteration on experimental cerebral malaria (ECM) were examined. Methods: Male C57BL/6N mice that were administered drinking water containing a four-antibiotic cocktail, ampicillin, neomycin, metronidazole and vancomycin, from 2 weeks before P. berghei ANKA (PbA) infection were used for the experiments. Disease progression, blood–brain barrier (BBB) integrity, immune responses, and gut microbiota composition were evaluated. Results: Approximately 80% of mice with modified gut microbiota avoided ECM and showed reduced BBB disruption and lymphocyte infiltration into the brain. 16S rRNA gene sequencing revealed specific bacterial species that contributed to either the protection or pathogenesis of ECM. The mono-colonization of germ-free mice revealed that distinct bacterial species could attenuate or exacerbate ECM symptoms, independent of antibiotic effects. Conclusions: The findings highlight that distinct gut microbial populations can modulate host susceptibility or resistance to ECM, underscoring the important influence of the intestinal microbiota on infectious disease outcomes. This work broadens the understanding of host‒microbe interactions and may inform new strategies for managing cerebral malaria through microbiota modulation.

Peritonitis is an inflammation of the peritoneum primarily caused by gut perforation and consequent bacterial leakage, a known cause of sepsis. Although adipose tissue is recognized as an immunologically active organ, the involvement of adipose tissue innate lymphoid cells (ILC) in regulating peritonitis remains poorly understood. Here, we employ a cecal ligation and puncture mouse model and demonstrate that circulating CD127⁻ group 1 ILC (ILC1) migrate into the mesenteric adipose tissue (MAT) during the inflammatory period of peritonitis. CD127⁻ ILC1s undergo phenotypic changes to become CD127⁺ ILC1s, resulting in an increased number of CD127⁺ ILC1s in the MAT. We also show that this population of CD127⁺ ILC1s expresses PD-L1, exhibits low IFN-γ production, and potentially acts as a negative regulator of TNF production by γδ T cells, thereby controlling acute peritonitis. Our findings suggest that MAT-CD127⁺ ILC1s play an important regulatory role in acute peritonitis and may represent a potential therapeutic target for sepsis.