Native Hawaiians and Pacific Islanders (NHPIs) suffer from higher prevalence of and mortality to type 2 diabetes mellitus (T2DM) than any other major race/ethnic group in Hawaii. Health inequities in this indigenous population was further exacerbated by the SARS-CoV-2 pandemic. T2DM progression and medical complications exacerbated by COVID-19 are partially regulated by the gut microbiome. However, there is limited understanding of the role of gut bacteria in the context of inflammation-related diseases of health disparities including T2DM and obesity. To address these gaps, we used a community-based research approach from a cohort enriched with NHPI residents on the island of Oahu, Hawaii (N=138). Gut microbiome profiling was achieved via 16s rDNA metagenomic sequencing analysis from stool DNA. Gut bacterial capacity for butyrate-kinase (BUK)-mediated fiber metabolism was assessed using quantitative PCR to measure the abundance of BUK DNA and RNA relative to total bacterial load per stool sample. In our cohort, age positively correlated with hemoglobin A1c (%; R=0.39; P<0.001) and body mass index (BMI; R=0.28; P<0.001). The relative abundance of major gut bacterial phyla significantly varied across age groups, including Bacteroidetes (P<0.001), Actinobacteria (P=0.007), and Proteobacteria (P=0.008). A1c was negatively correlated with the relative levels of BUK DNA copy number (R=-0.17; P=0.071) and gene expression (R=-0.33; P=0.003). Interestingly, we identified specific genera of gut bacteria potentially mediating the effects of diet on metabolic health in this cohort. Additionally, α-diversity among gut bacterial genera significantly varied across T2DM and BMI categories. Together, these results provide insight into age-related differences in gut bacteria that may influence T2DM and obesity in NHPIs. Furthermore, we observed overlapping patterns between gut bacteria and T2DM risk factors, indicating more nuanced, interdependent interactions among these factors as partial determinants of health outcomes. This study adds to the paucity of NHPI-specific data to further elucidate the biological characteristics associated with pre-existing health inequities in this racial/ethnic group that is significantly underrepresented in biomedical research.

IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.MethodsWe used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.ResultsThrough MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.ConclusionThese findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

Introduction: Native Hawaiian and other Pacific Islander (NHPI) populations experience higher rates of immunometabolic diseases compared to other racial-ethnic groups in Hawaii. As annual NHPI mortality rates for suicide and type 2 diabetes mellitus (T2DM) exceed those of the state as a whole, understanding the social and biological mechanisms underlying these disparities are urgently needed to enable preventive strategies.Methods: A community-based approach was used to investigate the immunoepigenetic-gut microbiome axis in an NHPI-enriched cohort of Oahu residents (N = 68). Self-esteem (SE) data was collected using a modified Rosenberg self-esteem (SE) assessment as a proxy measure for mental wellbeing in consideration for cultural competency. T2DM status was evaluated using point-of-care A1c (%) tests. Stool samples were collected for 16s-based metagenomic sequencing analyses. Plasma from blood samples were isolated by density-gradient centrifugation. Peripheral blood mononuclear cells (PBMCs) were collected from the same samples and enriched for monocytes using negative selection techniques. Flow-cytometry was used for immunoprofiling assays. Monocyte DNA was extracted for Illumina EPIC array-based methylation analysis.Results: Compared to individuals with normal SE (NSE), those with low SE (LSE) exhibited significantly higher plasma concentrations (pg/ml) of proinflammatory cytokines IL-8 (p = 0.051) and TNF-α (p = 0.011). Metagenomic analysis revealed that the relative abundance (%) of specific gut bacteria significantly differed between SE groups - some of which directly correlated with SE scores. Gene ontology analysis revealed that 104 significantly differentially methylated loci (DML) between SE groups were preferentially located at genes involved in immunometabolic processes. Horvath clock analyses indicated epigenetic age (Epi-Age) deceleration in individuals with LSE and acceleration in individuals with NSE (p = 0.042), yet was not reproduced by other clocks.Discussion: These data reveal novel differences in the immunoepigenetic-gut microbiome axis with respect to SE, warranting further investigation into its relationship to brain activity and mental health in NHPI. Unexpected results from Epi-Age analyses warrant further investigation into the relationship between biological age and disparate health outcomes among the NHPI population. The modifiable component of epigenetic processes and the gut microbiome makes this axis an attractive target for potential therapeutics, biomarker discovery, and novel prevention strategies.

Introduction:The incidence of type 2 diabetes mellitus (T2DM) within the Native Hawaiian population among the highest of any major ethnic group within the state of Hawaii. Modern research is beginning to mechanistically understand ancient Hawaiian concepts and practices demonstrating the importance of environment to human health. Environmental factors, such as socioeconomic status, toxicants, diet/ nutrition, etc, contribute to individual risk of T2DM, where impacts on the gut microbiome may play key roles in inflammatory and metabolic dysregulation characteristic of diabetes. In this study, we focused on understanding the relationship between the gut microbiome and T2DM risk in the Native Hawaiian population. Methods: The study enrolled a cohort of Hawaii residents (16 years or older) in a community enriched with Native Hawaiians. Microbial DNA was isolated from self-collected stool samples of all participants and used for 16S amplicon-based sequencing for metagenomic analyses and for quantifying microbial-specific butyrate kinase (BUK) gene expression levels using qPCR approaches. From each participant, anthropometric measures and blood levels of HbA1c, a diagnostic indicator of T2DM, were taken. Blood was collected by venous puncture from which plasma was isolated to measure inflammatory and metabolic biomarkers. Herein, we identified and describe significant differences between diabetic and non-diabetic microbiome composition and diversity. Results: Consistent with other studies, we observed increased levels of CRP (p, 0.01) and decreased levels of leptin (p50.04) in the plasma of diabetic compared to non-diabetic participants. Additionally, we observed that BUK levels were negatively correlated with that of HbA1c (R5-0.18, p50.04), and positively correlated with that of metabolic hormones PYY (R50.30; p50.007) and GLP-1 (R50.19; p50.04), which were largely attributed to diabetes status. Higher plasma levels of PYY and GLP-1 have previously been associated with reduced T2DM risk. Conclusion: Altogether, our data suggest a role for butyrate-producing gut bacteria in the maintenance of the homeostatic inflammatory and metabolic states that are dysregulated in the progression of T2DM and implicates novel targets for reducing T2DM risk among health disparate populations.

PURPOSE Research indicates that Native Hawaiians have the highest rates of diabetes and obesity in the state of Hawaiʻi. Understanding the way epigenetics plays a role in Type 2 Diabetes (T2DM) will help us determine how environmental factors play a role in the risk of T2DM in Native Hawaiian populations. Our objectives with this study are:(1) Understand the relationship between social context and health; (2) Learn about the mechanism through which a community‐based program impacted health/wellbeing of Native Hawaiians; (3) Consider a new model of community‐engaged research that empowers individuals and organizations to address health disparities. METHODS The study targeted individuals (16 years or older) in the state of Hawaiʻi affiliated with MAʻO organic farms or connected to their social network. Stool sample kits were distributed to participants with oral and written instructions to collect their own samples at home and store them in a freezer until they can be returned via mail or collected by a community research facilitator for analysis. Stool samples were used to metagenomics analysis. Height, weight, blood pressure, pulse and A1C were measured and recorded. RESULTS Results of this study show that main bacteria were dominant in Native Hawaiians (Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria). Actinobacteria and Proteobacteria were significantly correlated with BMI and A1c in Native Hawaiians. In the overall study population, there is a statistically significant negative correlation between A1c and the abundance of Actinobacteria (ρ= ‐0.169; CI = 90%) and Proteobacteria (ρ= ‐0.212; CI=95%). In the same group of participants, BMI is negatively correlated with the abundance of Actinobacteria (ρ= ‐0.222; CI=95%). DISCUSSION/CONCLUSION Our project integrates social and biomedical research in evaluating a holistic community‐based program on the health/wellbeing of Native Hawaiian youth and their social networks. Social networks influence individuals' choices and behaviors that either lead to unhealthy or healthy lifestyles. Recent studies suggest a link between social networks and health conditions that are likely mediated by biological mechanisms influencing glucose homeostasis and gut microbiome composition. Our project will conclude with a description of a new model of community‐engaged research that is currently being developed to facilitate the collection and sharing of social and biomedical data driven by community‐based organizations to ultimately promote Native Hawaiian health.