P’nG Loke

The environment shapes immune system development and the regulation of inflammatory responses, however the hematological consequences of a major environmental change, such as those experienced during migration, remain poorly understood. Here, we assess the immunological consequences in male rhesus macaques as they transitioned from an outdoor provisioned environment to an indoor laboratory facility in a process we term ‘dewilding.’ Dewilding decreased neutrophils and increased lymphocytes, skewing toward a T _H 1 response and increased T cell activation. In the gut microbiome, fungal abundance decreased while bacterial abundance increased. In the bone marrow, we observed a shift towards the less committed multipotent progenitor cells and increased erythrocyte progenitors, with upregulation of genes involved in hemoglobin control and erythropoiesis. Together, our findings illustrate how dewilding alters immune homeostasis, with implications for understanding immune adaptation in migrants from rural to urban environments and for optimizing immunization strategies during environmental change.

Gut microbiome catalogs from Indigenous Southeast Asian populations remain underrepresented. Here, we integrated metagenomic and metatranscriptomic data from Indigenous Orang Asli (OA) in Peninsular Malaysia and urban residents of Kuala Lumpur (KL), together with immune profiling, to investigate gut microbial activity and functions associated with lifestyle and helminth infection. Prevotella showed significantly higher transcriptional activity in OA, whereas Bacteroides was more active in KL, corresponding to distinct immune signatures. Microbial genome-wide association studies (mGWAS) revealed Prevotella copri_A variants were linked to lifestyle and host immunity, while Blautia strain variation was associated with helminth infection. Malaysian metagenome-assembled genomes (MAGs) uncovered 307 novel species, predominantly within Clostridia. Among these, the novel HGM13006 species were enriched with genes for starch and sucrose metabolism, and the novel Ruminococcus_D species in flagellar assembly and chemotaxis. Together, these findings provide function-level insights into gut microbiome variation associated with lifestyle and helminth infection in an indigenous population.

The mechanisms of airway allergen sensing and type 2 immune response initiation remain poorly understood. Using a mouse house dust mite (HDM)-induced allergic airway model, we identify a population of lung macrophages located close to alveolar capillaries that express Ly6G and the nuclear receptor Nr4a1/Nur77. These atypical Ly6G ⁺ Nur77 ⁺ macrophages preferentially capture airway-delivered allergens and play an important role in initiating HDM-driven T helper type 2 (Th2) responses. They sense the major HDM allergen, the cysteine protease Der p 1, via protease-activated receptor 2 (PAR2), and their activation and accumulation require both PAR2 and Nr4a1/Nur77. These Ly6G ⁺ Nur77 ⁺ macrophages regulate the migration of conventional migratory dendritic cells (mDCs) to draining mediastinal lymph nodes (mLNs) through cysteinyl leukotriene (CysLT) production, which enhances mDC migration toward CCL21 for T cell priming. Inhibiting CysLT biosynthesis reduces mDC migration and dampens Th2 allergic responses, highlighting possible therapeutic avenues in type 2 immunity.

The environment shapes immune system development and the regulation of inflammatory responses, which may affect the prevalence of immune mediated inflammatory diseases. However, the hematological consequences of a major environmental change, such as those experienced during migration, remain poorly understood. Here, we used cellular and molecular approaches to assess the immunological consequences in rhesus macaques as they transitioned from an outdoor provisioned environment to an indoor laboratory facility in a process we term ‘dewilding.’ Dewilding led to a sharp decrease in neutrophils and increased lymphocytes in the peripheral blood, a skewing toward a proinflammatory TH1 response, and increased T cell activation. Concurrently, we observed changes in the microbiome, with fungal abundance decreasing while bacterial abundance increased during dewilding. In the bone marrow, we observed increased granulopoiesis, reduced lymphocytes, and reduced hematopoietic stem cells and progenitors, with their shift toward less committed progenitor states. Single-cell nuclear RNA sequencing of the bone marrow revealed increased erythrocyte progenitors in the bone marrow during dewilding, with upregulation of genes involved in hemoglobin control and erythropoiesis. Notably, the vaccination response against measles varied based on vaccination period during the dewilding process. Together, our findings illustrate how dewilding alters immune homeostasis, with implications for understanding immune adaptation in migrants from rural to urban environments and for optimizing immunization strategies during environmental change.

Inflammatory bowel disease (IBD) is a complex, multifactorial inflammatory disorder of the gut characterized by an imbalance in host–microbiota interactions. Here, we review how early events of IBD are shaped by gene–environment interactions, especially those involving microbial perturbations. Those perturbations eventually lead to chronic inflammation and tissue damage of the gastrointestinal tract. IBD is a multi-hit process in which infectious and noninfectious agents initiate a cascade of immune activation in genetically susceptible individuals. Ultimately the process results in irreversible immunological and physical scarring. These interactions are host specific, with genetic variants influencing the threshold for immune activation and the degree of damage, thus leading to variability in disease progression and therapeutic outcomes. Finally, we discuss challenges, including addressing health disparities and potential strategies for more personalized and effective therapies that target host–microbiota interactions during the preclinical phase of IBD.

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here, we performed an in-depth examination of B cells following rewilding, the controlled release of inbred laboratory mice into an outdoor enclosure. In rewilded mice, we observed B cells in circulation with increased signs of maturation, alongside heightened germinal center responses within secondary lymphoid organs. Rewilding also expanded B cells in the gut, which was accompanied by elevated systemic levels of immunoglobulin G (IgG) and IgM antibodies reactive to the microbiota. Our findings indicate that exposing laboratory mice to a more natural environment enhances B cell development to better reflect the immune system of free-living mammals.

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

Background: Parasitic helminths influence the composition of the gut microbiome. However, the microbiomes of individuals living in helminth-endemic regions are understudied. The Orang Asli, an indigenous population in Malaysia with high burdens of the helminth Trichuris trichiura, display microbiotas enriched in Clostridiales, an order of spore-forming obligate anaerobes with immunogenic properties. We previously isolated novel Clostridiales that were enriched in these individuals and found that a subset promoted the Trichuris life cycle. In this study, we aimed to further characterize the functional properties of these bacteria. Results: Clostridiales isolates were profiled for their ability to perform 57 enzymatic reactions and produce short-chain fatty acids (SCFAs) and hydrogen sulfide, revealing that these bacteria were capable of a range of activities associated with metabolism and host response. Consistent with this finding, monocolonization of mice with individual isolates identified bacteria that were potent inducers of regulatory T-cell (Treg) differentiation in the colon. Comparisons between variables revealed by these studies identified enzymatic properties correlated with Treg induction and Trichuris egg hatching. Conclusion: We identified Clostridiales species that are sufficient to induce high levels of Tregs. We also identified a set of metabolic activities linked with Treg differentiation and Trichuris egg hatching mediated by these newly isolated bacteria. Altogether, this study provides functional insights into the microbiotas of individuals residing in a helminth-endemic region.