Summary Existing studies characterizing gut microbiome variation in the United States suffer from population ascertainment biases, with individuals of American Indian ancestry being among the most under-represented. Here, we describe the first gut microbiome diversity study of an American Indian community. We partnered with the Cheyenne & Arapaho (C&A), federally recognized American Indian Tribes in Oklahoma, and compared gut microbiome diversity and metabolic function of C&A participants to individuals of non-native ancestry in Oklahoma (NNI). While the C&A and NNI participants share microbiome features common to industrialized populations, the C&A participants had taxonomic profiles characterized by a reduced abundance of the anti-inflammatory bacterial genus Faecalibacterium, along with a fecal metabolite profile similar to dysbiotic states described for metabolic disorders. American Indians are known to be at elevated risk for metabolic disorders. While many aspects of this health disparity remain poorly understood, our results support the need to further study the microbiome as a contributing factor. As the field of microbiome research transitions to therapeutic interventions, it raises concerns that the continued exclusion and lack of participation of American Indian communities in these studies will further exacerbate health disparities. To increase momentum in fostering these much needed partnerships, it is essential that the scientific community actively engage in and recruit these vulnerable populations in basic research through a strategy that promotes mutual trust and understanding, as outlined in this study.

The C&A and NNI participants from Oklahoma have notable differences in their microbiome diversity, with a wider range of variation observed among the C&A individuals, including a higher frequency of bacteria implicated in systemic disorders. Overall, this study highlights the importance of engagement with indigenous communities, and the need for an improved understanding of human microbiome diversity among underrepresented groups and those individuals living outside of metropolitan areas.

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Conducting genetics-related research with populations that have historically experienced considerable harm and little benefit from genetics research poses unique challenges for understanding community-based perceptions of new genetic technologies. This article identifies challenges and strategies for collecting qualitative data on the perceptions of direct-toconsumer (DTC) Genetic Ancestry tests (GAT) among diverse Indigenous communities. Based on a 3-year project related to perceptions, attitudes, and values associated with genetic ancestry testing among diverse Indigenous communities in Oklahoma, the engagement process revealed specific opportunities to improve the process of qualitative data collection related to GAT, and more broadly, to conduct genetics-related research with Indigenous communities in culturally and methodologically appropriate ways. Priority areas include issues related to participant recruitment and tribal advisory boards, challenges of self-identification as a recruitment mechanism, and the necessity of including Indigenous researchers in all aspects of the research process.

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