Biology subjects

Jain, S.

Publications and source records attributed to Jain, S..

At least 145 records · Page 8Linked to original sources

bioRxiv2022

A natural language fMRI dataset for voxelwise encoding models

Speech comprehension is a complex process that draws on humans abilities to extract lexical information, parse syntax, and form semantic understanding. These sub-processes have traditionally been studied using separate neuroimaging experiments that attempt to isolate specific effects of interest. More recently it has become possible to study all stages of language comprehension in a single neuroimaging experiment using narrative natural language stimuli. The resulting data are richly varied at every level, enabling analyses that can probe everything from spectral representations to high-level representations of semantic meaning. We provide a dataset containing BOLD fMRI responses recorded while 8 subjects each listened to 27 complete, natural, narrative stories (~6 hours). This dataset includes pre-processed and raw MRIs, as well as hand-constructed 3D cortical surfaces for each participant. To address the challenges of analyzing naturalistic data, this dataset is accompanied by a python library containing basic code for creating voxelwise encoding models. Altogether, this dataset provides a large and novel resource for understanding speech and language processing in the human brain.

neuroscience↗

bioRxiv2022

Transcriptional profiles of functionally distinct HLADR+CD38+ CD8 T cells subsets from acute febrile dengue patients

Previous studies showed that a discrete population of the CD8 T cells with HLADR+CD38+ phenotype expand massively during the acute febrile phase of dengue natural infection. Although about a third of these massively expanding HLADR+CD38+ CD8 T cells were of CD69high phenotype, only a small fraction of them produced IFN{gamma} upon in vitro peptide stimulation. What other cytokines/ chemokines do these peptides stimulated HLADR+CD38+ CD8 T cells express, what transcriptional profiles distinguish the CD69+IFN{gamma}+, CD69+IFN{gamma}-, and CD69-IFN{gamma}- subsets, and whether the expansion of the total HLADR+CD38+ CD8 T cells or the IFN{gamma} producing CD8 T cells differ depending on disease severity remained unclear. This study addresses these knowledge gaps. We find that the CD69+IFN{gamma}+ subset uniquely expressed key genes involved in protein translation, cellular metabolism, proliferation and dendritic cell cross talk. Both the CD69+IFN{gamma}+ and CD69+IFN{gamma}- subsets had an antigen responsive gene signature with genes involved in cytotoxic effector functions, regulation of T cell receptor signaling, signaling by MAPK, chemotaxis and T cell trafficking to inflamed tissues with the expression being more robust in the IFN{gamma}+ CD69+ subset. On the other hand, the CD69- IFN{gamma}- subset was biased towards expression of genes that both augment and dampen T cell responses. Lastly, the expansion of total HLADR+ CD38+ CD8 T cells and also the IFN{gamma} producing HLADR+ CD38+ CD8 T cells was similar in patients with different grades of disease. Taken together, this study provides valuable insights into the inherent diversity of the effector CD8 T cell response during dengue.

immunology↗

bioRxiv2022

Application of Temperature-Responsive HIS-Tag Fluorophores to Differential Scanning Fluorimetry Screening of Small Molecule Libraries

Differential scanning fluorimetry is a rapid and economical biophysical technique used to monitor perturbations to protein structure during a thermal gradient most often by detecting protein unfolding events through an environment-sensitive fluorophore. By employing an NTA-complexed fluorophore that is sensitive to nearby structural changes in 6xHIS-tagged protein, a robust and sensitive differential scanning fluorimetry (DSF) assay is established with the specificity of an affinity tag-based system. We developed, optimized, and miniaturized this histidine-tag DSF assay (HIS-DSF) into a 1536-well high-throughput biophysical platform using the Borrelial high temperature requirement A protease (BbHtrA) as a proof of concept for the workflow. A production run of the BbHtrA HIS-DSF assay showed a tight negative control group distribution of Tm values with an average coefficient of variation of 0.51% and median coefficient of variation of compound Tm of 0.26%. The HIS-DSF platform will provide an additional assay platform for future drug discovery campaigns with applications in buffer screening and optimization, target engagement screening, and other biophysical assay efforts.

biochemistry↗

bioRxiv2022

STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

cancer biology↗

bioRxiv2022

Prediction, scanning and designing of TNF-α inducing epitopes for human and mouse

Tumor Necrosis Factor alpha (TNF-) is a pleiotropic pro-inflammatory cytokine that plays a crucial role in controlling signaling pathways within the immune cells. Recent studies reported that the higher expression levels of TNF- is associated with the progression of several diseases including cancers, cytokine release syndrome in COVID-19 and autoimmune disorders. Thus, it is the need of the hour to develop immunotherapies or subunit vaccines to manage TNF- progression in various disease conditions. In the pilot study, we have proposed a host-specific in-silico tool for the prediction, designing and scanning of TNF- inducing epitopes. The prediction models were trained and validated on the experimentally validated TNF- inducing/non-inducing for human and mouse hosts. Firstly, we developed alignment free (machine learning based models using composition of peptides) methods for predicting TNF- inducing peptides and achieved maximum AUROC of 0.79 and 0.74 for human and mouse hosts, respectively. Secondly, alignment based (using BLAST) method has been used for predicting TNF- inducing epitopes. Finally, a hybrid method (combination of alignment free and alignment-based method) has been developed for predicting epitopes. Our hybrid method achieved maximum AUROC of 0.83 and 0.77 on an independent dataset for human and mouse hosts, respectively. We have also identified the potential TNF- inducing peptides in different proteins of HIV-1, HIV-2, SARS-CoV-2 and human insulin. Best models developed in this study has been incorporated in a webserver TNFepitope (https://webs.iiitd.edu.in/raghava/tnfepitope/), standalone package and GitLab (https://gitlab.com/raghavalab/tnfepitope). Key PointsO_LITNF- is a multifunctional pleiotropic pro-inflammatory cytokine. C_LIO_LIAnti-TNF- therapy used as an effective treatment in several autoimmune disorders. C_LIO_LIComposition-based features generated using Pfeature for each peptide sequence. C_LIO_LIAlignment-based and alignment-free models developed. C_LIO_LIPrediction and scanning of TNF- inducing regions in antigens. C_LIO_LITNFepitope is available as a web-server, standalone package and GitLab. C_LI

bioinformatics↗

bioRxiv2022

Artificial immune cell, AI-cell, a new tool to predict interferon production by peripheral blood monocytes in response to nucleic acid nanoparticles

Nucleic acid nanoparticles, or NANPs, are rationally designed to communicate with the human immune system and can offer innovative therapeutic strategies to overcome the limitations of traditional nucleic acid therapies. Each set of NANPs is unique in their architectural parameters and physicochemical properties, which together with the type of delivery vehicles determine the kind and the magnitude of their immune response. Currently, there are no predictive tools that would reliably guide NANPs design to the desired immunological outcome, a step crucial for the success of personalized therapies. Through a systematic approach investigating physicochemical and immunological profiles of a comprehensive panel of various NANPs, our research team has developed a computational model based on the transformer architecture able to predict the immune activities of NANPs via construction of so-called artificial immune cell, or AI-cell. The AI-cell will aid addressing in timely manner the current critical public health challenges related to overdose and safety criteria of nucleic acid therapies and promote the development of novel biomedical tools.

bioinformatics↗

bioRxiv2022

Partitioned Local Depth analysis of time course transcriptomic data reveals elaborate community structure

Transcriptome studies that provide temporal information are valuable for identifying groups of similarly-behaving transcripts, giving insight into overarching gene regulatory networks. Nevertheless, inferring transcriptional networks from time series data is challenging, in part because it is difficult to holistically consider both local relationships and global structure of these complex and overlapping transcriptional responses. To address this need, we employed the Partitioned Local Depth (PaLD) method to examine four time series transcriptomic datasets generated using the model plant Arabidopsis thaliana. Here, we provide a self-contained description of the method and demonstrate how it can be used to make predictions about gene regulatory networks based on time series data. The analysis provides a global network representation of the data from which graph partitioning methods and neighborhood analysis can reveal smaller, more well-defined groups of like-responding transcripts. These groups of transcripts that change in response to hormone treatment (e.g., auxin or ethylene) or high salinity were demonstrated to be enriched in common biological function and/or binding of transcription factors that were not identified with prior analyses of this data using other clustering and inference methodologies. These results reveal the ability of PaLD to generate predictions about gene regulatory networks using time series transcriptomic data, which can be of value to the systems biology community.

systems biology↗

bioRxiv2022

Strain dropouts reveal interactions that govern the metabolic output of the gut microbiome

The gut microbiome is complex, raising questions about the role of individual strains in the community. Here, we address this question by focusing on a functional unit within the community, the metabolic niche that controls bile acid 7-dehydroxylation. By constructing variants of a complex defined community in which we drop out strains that occupy this niche, we explore how interactions within and between niches shape community-level metabolism. Omitting both members of the niche, Clostridium scindens (Cs) and Clostridium hylemonae (Ch), eliminates secondary bile acid production and reshapes the community in a highly specific manner: eight strains go up or down in relative abundance by >100-fold, while the remaining strains are largely unaffected. In single-strain dropout communities (i.e., a strain swap within the niche), Cs and Ch reach the same relative abundance and dehydroxylate bile acids to a similar extent. However, the effect on strains in other niches differs markedly: Clostridium sporogenes increases >1000-fold in the {Delta}Cs but not {Delta}Ch dropout, reshaping the pool of microbiome-derived phenylalanine metabolites. Thus, strains that are functionally redundant within a niche can have widely varying impacts outside the niche, and a strain swap can ripple through the community in an unpredictable manner, resulting in a large impact on an unrelated community-level phenotype. Mice colonized by the {Delta}Cs{Delta}Ch community show decreased liver steatosis relative to those colonized by the {Delta}Ch community, demonstrating that a single strain from the microbiome can have a substantive impact on host physiology. Our work opens the door to the mechanistic studies of the role of an individual strain on community ecology and host physiology.

microbiology↗

bioRxiv2022

Multi-Molecular Hyperspectral PRM-SRS Imaging

Lipids play crucial roles in many biological processes under physiological and pathological conditions. Mapping spatial distribution and examining metabolic dynamics of different lipids in cells and tissues in situ are critical for understanding aging and diseases. Commonly used imaging methods, including mass spectrometry-based technologies or labeled imaging techniques, tend to disrupt the native environment of cells/tissues and have limited spatial or spectral resolution, while traditional optical imaging techniques still lack the capacity to distinguish chemical differences between lipid subtypes. To overcome these limitations, we developed a new hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. With this new approach, we directly visualized and identified multiple lipid species in cells and tissues in situ with high chemical specificity and subcellular resolution. High density lipoprotein (HDL) particles containing non-esterified cholesterol was observed in the kidney, indicating that these pools of cholesterol are ectopic deposits, or have yet to be enriched. We detected a higher Cholesterol to phosphatidylethanolamine (PE) ratio inside the granule cells of hippocampal samples in old mice, suggesting altered membrane lipid synthesis and metabolism in aging brains. PRM-SRS imaging also revealed subcellular distributions of sphingosine and cardiolipin in the human brain sample. Compared with other techniques, PRM-SRS demonstrates unique advantages, including faster data processing and direct user-defined visualization with enhanced chemical specificity for distinguishing clinically relevant lipid subtypes in different organs and species. Our method has broad applications in multiplexed cell and tissue imaging.

bioengineering↗

bioRxiv2022

A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury and matrix remodeling in patients with stone disease

Kidney stone disease causes significant morbidity and increases health care utilization. The pathogenesis of stone disease is not completely understood, due in part to the poor characterization of the cellular and molecular makeup of the kidney papilla and its alteration with disease. We deciphered the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease compared to healthy subjects using single nuclear RNA sequencing, spatial transcriptomics and high-resolution large-scale multiplexed 3D and Co-Detection by indexing (CODEX) imaging. In addition to identifying cell types important in papillary physiology, we defined subtypes of immune, stromal and principal cells enriched in the papilla, and characterized an undifferentiated epithelial cell cluster that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncovered a global injury signature involving multiple cell types within the papilla, characterized by immune activation, oxidative stress and extracellular matrix remodeling. The microenvironment of mineral deposition had features of an immune synapse with antigen presenting inflammatory macrophages interacting with T cells, and an immune repertoire ranging from inflammation to fibrosis. The expression of MMP7 and MMP9 was associated with stone disease and mineral deposition, respectively. MMP7 and MMP9 were significantly increased in the urine of patients with CaOx stone disease compared to non-stone formers, and their levels correlated with disease activity in stone formers. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla, and identify potential urinary biomarkers.

genomics↗

bioRxiv2022

Anti-COVID-19 Activity of FDA Approved Drugs through RNA G-quadruplex Binding

The COVID-19 pandemic caused by SARS-CoV-2 has caused millions of infections and deaths worldwide. Limited treatment options and the threat from emerging variants underline the need for novel and widely accessible therapeutics. G-quadruplexes (G4s) are nucleic acid secondary structures known to affect many cellular processes including viral replication and transcription. We identified heretofore not reported G4s with remarkably low mutation frequency across >5 million SARS-CoV-2 genomes. The G4 structure was targeted using FDA-approved drugs that can bind G4s - Chlorpromazine (CPZ) and Prochlorperazine (PCZ). We found significant inhibition in lung pathology and lung viral load of SARS-CoV-2 challenged hamsters when treated with CPZ, PCZ that was comparable to the widely used antiviral drug Remdesivir. In support, in vitro G4 binding, inhibition of reverse transcription from RNA isolated from COVID-infected humans, and attenuated viral replication and infectivity in Vero cell cultures were clear in case of both CPZ/PCZ. Apart from the wide accessibility of CPZ/PCZ, targeting relatively invariant nucleic acid structures poses an attractive strategy against fast mutating viruses like SARS-CoV-2.

molecular biology↗

bioRxiv2022

Small-molecule inhibitors targeting prokaryotic ClpQ protease in Plasmodium display anti-malarial efficacies against blood and liver stages

The ATP-dependent ClpQY system is a prokaryotic proteasome-like machinery in the mitochondrion of malaria parasite, Plasmodium. This protease system is identified as a validated target for malaria intervention. Here we have identified drug-like small chemical compounds, pyrimidotriazine derivatives, as specific inhibitors of P. falciparum ClpQ (PfClpQ) having effective parasiticidal efficacies on asexual and liver stages. Screening of the Malaria Box compound library, using a robust in vitro activity assay, identified a hit compound targeting the PfClpQ protease with IC50 at ~750nM. Further, Structure-Activity Relationship (SAR) analysis, using a small library of derivatives of the hit compound, identified three potential lead compounds, ICGEB-L1, ICGEB-L2 and ICGEB-L3, which inhibited enzyme activity with IC50 in 100-200nM ranges. The three lead compounds effectively inhibited in vitro asexual stage parasite growth in similar concentration ranges with ~100-fold selectivity over mammalian cell line; in addition, these compounds effectively inhibited in vitro growth and maturation of hepatocytic stage parasites with EC50 in low nano-molar ranges. These compounds were found to effectively block the development of trophozoite stages to schizont stage, concurrently arresting development and segregation of parasite mitochondria, in asexual as well as hepatocytic stages of the parasite. These morphological and developmental effects of the drugs on parasites mimic the data from genetic ablation of PfClpQ. Importantly, all three compounds showed significant in vivo anti-parasitic efficacies on blood stages of P. berghei mouse malaria model. Overall these results suggest that these PfClpQ targeting compounds are promising candidates to develop new anti-malarials.

microbiology↗

bioRxiv2022

Mapping the T cell repertoire to a complex gut bacterial community

Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response1-5. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with a complex defined community (97 or 112 bacterial strains) and profile T cell responses to each strain individually. Unexpectedly, the pattern of T cell responses suggests that many T cells in the gut repertoire recognize multiple bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all of the bacteria-specific TCRs exhibit a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that are polyspecific for 18 Firmicutes in the community. By screening three pooled bacterial genomic libraries against 13 pooled hybridomas, we discover that they share a single target: a conserved substrate-binding protein (SBP) from an ABC transport system. Treg and Th17 cells specific for an epitope from this protein are abundant in community-colonized and specific-pathogen-free mice. Our work reveals that T cell recognition of Firmicutes is focused on a widely conserved cell-surface antigen, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.

immunology↗

bioRxiv2022

A bacteriophage-based, highly efficacious, needle and adjuvant-free, mucosal COVID-19 vaccine

The authorized mRNA- and adenovirus-based SARS-CoV-2 vaccines are intramuscularly injected and effective in preventing COVID-19, but do not induce efficient mucosal immunity, or prevent viral transmission. We developed a bacteriophage T4-based, multicomponent, needle and adjuvant-free, mucosal vaccine by engineering spike trimers on capsid exterior and nucleocapsid protein in the interior. Intranasal administration of T4-COVID vaccine induced higher virus neutralization antibody titers against multiple variants, balanced Th1/Th2 antibody and cytokine responses, stronger CD4+ and CD8+ T cell immunity, and higher secretory IgA titers in sera and bronchoalveolar lavage with no effect on the gut microbiota, compared to vaccination of mice intramuscularly. The vaccine is stable at ambient temperature, induces apparent sterilizing immunity, and provides complete protection against original SARS-CoV-2 strain and its Delta variant with minimal lung histopathology. This mucosal vaccine is an excellent candidate for boosting immunity of immunized and/or as a second-generation vaccine for the unimmunized population.

microbiology↗

bioRxiv2022

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Radiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we characterize the methylomes of healthy human and mouse tissues to establish sequencing-based, cell-type specific reference DNA methylation atlases. Identified cell-type specific DNA blocks were mostly hypomethylated and located within genes intrinsic to cellular identity. Cell-free DNA fragments released from dying cells into the circulation were captured from serum samples by hybridization to CpG-rich DNA panels. The origins of the circulating DNA fragments were inferred from mapping to the established DNA methylation atlases. Thoracic radiation-induced tissue damages in a mouse model were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type specific effects of radiation and provide a quantitative measure of the biologically effective radiation dose received by healthy tissues. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/487966v3_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@129f229org.highwire.dtl.DTLVardef@d999bcorg.highwire.dtl.DTLVardef@1fc3543org.highwire.dtl.DTLVardef@10cebc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Cognitive dysfunction and anxiety resulted from synaptic downscaling, hippocampal atrophy and ventricular enlargement in i.c.v. streptozotocin injected male Wistar rats

Insulin-resistant brain state is proposed to be the early sign of Alzheimers disease(AD), which can be studied in intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, Available experimental evidence has used varying doses of STZ (<1 to 3mg/kg) and studied its effect for different study durations, ranging from 14-270 days. Though these studies suggest 3mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive. Here we sought to investigate the mechanism of action of 3mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of two weeks for two months. On 60th day, we examined layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism and mitochondrial function by histological examination. Findings suggest progressive loss of spatial, episodic, avoidance memory with increase in anxiety in a span of two month. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in dentate gyrus and imbalance in energy homeostasis was found on 60th day post injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of water maze with change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at neuronal as well as synaptic level, which is tightly associated with change in neuronal metabolism.

neuroscience↗

bioRxiv2022

Robust Variation in Infant Gut Microbiome Assembly Across a Spectrum of Lifestyles

Infant microbiome assembly is intensely studied in infants from industrialized nations, but little is known about this process in populations living non-industrialized lifestyles. In this study we deeply sequenced infant stool samples from the Hadza hunter-gatherers of Tanzania and analyzed them in a global meta-analysis. Infant microbiomes develop along lifestyle-associated trajectories, with over twenty percent of genomes detected in the Hadza infant gut representing phylogenetically diverse novel species. Industrialized infants, even those who are breastfed, have microbiomes characterized by a paucity of Bifidobacterium infantis and gene cassettes involved in human milk utilization. Strains within lifestyle-associated taxonomic groups are shared between mother-infant dyads, consistent with early-life inheritance of lifestyle-shaped microbiomes. The population-specific differences in infant microbiome composition and function underscore the importance of studying microbiomes from people outside of wealthy, industrialized nations. Recognition of work on indigenous communitiesResearch 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 nations. 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 methods (1, 2). A material transfer agreement with the National Institute for Medical Research in Tanzania ensures 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 studys intent and scope was described with the help of a translator. The publications that first described these samples included several scientists and Tanzanian 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.

microbiology↗

bioRxiv2022

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

The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 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, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.

microbiology↗