Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Gut Microbes

The gut microbiome has been identified as a key to immune and metabolic health, especially in industrialized populations1. Non-industrialized individuals harbor more diverse microbiomes and distinct bacterial lineages2, but systemic under-sampling has hindered insight into the extent and functional consequences of these differences3. Here, we performed ultra-deep metagenomic sequencing and laboratory strain isolation on fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophage, and eukaryotes, and find that 43% are novel upon aggregating with existing unified datasets4,5. Analysis of in situ growth rates, genetic pN/pS signatures, and high-resolution strain tracking reveal dynamics in the hunter-gatherer gut microbiome that are distinct from industrialized populations. Industrialized versus Hadza gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. We use phylogenomics to reveal that global spread of the spirochaete Treponema succinifaciens parallels historic human migration prior to its extinction in industrialized populations. When combined with a detailed definition of gut-resident strains that are vanishing in industrialized populations, our data demonstrate extensive perturbation in many facets of the gut microbiome brought on by the industrialized lifestyle. Recognition of work with indigenous communities Research involving indigenous communities is needed for a variety of reasons including to ensure that scientific discoveries and understanding appropriately represent all populations and do not only benefit those living in industrialized nations3,6. Special considerations must be made to ensure that this research is conducted ethically and in a non-exploitative manner. In this study we performed deep metagenomic sequencing on fecal samples that were collected from Hadza hunter-gatherers in 2013/2014 and were analyzed in previous publications using different methods2,7. A material transfer agreement with the National Institute for Medical Research in Tanzania specifies that stool samples collected are used solely for academic purposes, permission for the study was obtained from the National Institute of Medical Research (MR/53i 100/83, NIMR/HQ/R.8a/Vol.IX/1542) and the Tanzania Commission for Science and Technology, and verbal consent was obtained from the Hadza after the study’s intent and scope was described with the help of a translator. The publications that first described these samples included several scientists and Tanzanian and Nepali field-guides as co-authors for the critical roles they played in sample collection, but as no new samples were collected in this study, only scientists who contributed to the analyses described here were included as co-authors in this publication. It is currently not possible for us to travel to Tanzania and present our results to the Hadza people, however we intend to do so once the conditions of the COVID-19 pandemic allow it.