Biology subjects

Sharpton, T. J.

Publications and source records attributed to Sharpton, T. J..

17 recordsLinked to original sources

bioRxiv2026

Historical contingency shapes zebrafish host-microbiome responses to a subsequent biotic challenge

Environmental change exposes ecosystems, including host-associated microbiomes, to stressors that occur repeatedly and in sequence, yet it remains unclear whether prior stressor history conditions host-microbiome responses to later perturbation. We used adult zebrafish (Danio rerio) to test whether sequential exposure to antibiotics, heat stress, the intestinal nematode Pseudocapillaria tomentosa, or pairwise stressor combinations altered gut microbiome structure, intestinal host gene expression, and host health outcomes. Across eight exposure regimes, prior stressor history and parasite exposure were associated with gut microbiome composition, while increasing prior stressor history was associated with reduced gut microbial diversity and convergence in community composition. Host intestinal transcriptional responses to parasite exposure were historically contingent, with parasite-associated differential gene expression varying non-linearly across prior stressor histories. Cumulative mortality increased with prior stressor history, whereas infection prevalence among surviving hosts decreased. Integrating microbial abundance, host gene expression, mortality, and neutral-community modeling identified Cetobacterium, Culicoidibacter, Flavobacterium, and Shewanella as candidate host-linked taxa associated with host response and survival. Collectively, these findings indicate that prior environmental stressor history shapes vertebrate host-microbiome responses to future perturbation and highlight specific gut microbial members as potential biomarkers or functional targets for follow-up studies.

ecology↗

bioRxiv2026

Polycyclic aromatic hydrocarbons, gut microbiome composition, impulsivity, and attention covary in a human cohort

Polycyclic aromatic hydrocarbons (PAHs) are pervasive environmental pollutants linked to adverse neurobehavioral outcomes, yet the biological pathways coupling exposure to behavior are poorly defined. The gut microbiome is both sensitive to PAH exposure and a modulator of central nervous system function, suggesting it may mediate how PAH exposure influences neurobehavior. We tested whether PAH exposure, gut microbiome composition, and neurobehavioral function covary in a statewide sample of 34 adults stratified into high-impulsivity/poor-attention (HH) and low-impulsivity/fast-attention (LL) groups. Participants provided fecal samples for 16S rRNA profiling and wore silicone wristbands for 30 days to passively sample PAH exposure. Higher PAH exposure associated with HH group membership in a sex-dependent manner, with the largest elevations among HH males. At the community level, PAH exposure profiles correlated with microbiome dissimilarity, and HH membership associated with increased alpha-diversity and altered community composition relative to LL members. At the taxon level, 21 genera were significantly associated with 14 PAH compounds (FDR < 0.1). No individual genera were significantly associated with neurobehavioral group after multiple testing correction. Nevertheless, cross-referencing PAH-responsive genera (FDR < 0.1) against those with nominal neurobehavioral associations (p < 0.05) identified two candidate genera, Hydrogenoanaerobacterium and Methanobrevibacter, whose abundance covaries with both PAH exposure and neurobehavioral phenotype. Both have been independently linked to cognitive or neurological outcomes in prior work. These findings support a three-way relationship among environmental chemical exposure, gut microbiome composition, and neurobehavioral function, establishing an empirical foundation for testing microbiome-mediated links between PAH exposure and neurobehavioral outcomes. IMPORTANCEPAH exposure is widespread and associates with impulsivity and attention problems, but how exposure translates into neurobehavioral risk is unclear. The gut microbiome is a plausible intermediary: gut microbes biotransform environmental chemicals and produce metabolites that influence brain function. In a statewide adult cohort, we show that higher PAH exposure tracks with greater impulsivity and poorer attention in a sex-dependent manner, and that both PAH exposure and neurobehavioral phenotype associate with distinct gut microbiome features at the community and taxon levels. We identify candidate genera at the intersection of PAH exposure and neurobehavioral group whose biology independently implicates them in cognitive and neurological function. By demonstrating that all three domains covary within a single human cohort, this work moves beyond pairwise associations to identify candidate microbial intermediaries for mechanistic investigation. Defining the microbiome constituents that respond to PAH exposure and co-associate with neurobehavioral phenotypes creates opportunities to test microbiome-targeted or exposure-reduction strategies for mitigating PAH-related neurobehavioral impacts.

microbiology↗

bioRxiv2026

Guide scaffolding improves phylogenetic accuracy and enables integration across 16S amplicon regions

The growing magnitude and scale of microbiome studies now support application of meta-analytical frameworks, however the challenge of integrating microbiome sequence data across distinct studies into a unified phylogeny remains a critical barrier to progress. The 16S rDNA gene has been key to sequence-based phylogenetic microbial community analyses for over 30 years in applications ranging from human health to agricultural production efficiency. Because the full length 16S gene ([~]1500 base pairs) is longer than what short-read sequencing technologies can typically capture, researchers must target a portion of the gene, or variable region, typically [~]250 base pairs in length. Using a simulation-based approach, we show that full-length, phylogenetically diverse 16S guide sequences can serve as a scaffold to improve topological accuracy of phylogenetic trees constructed from any variable region. We also show that guide sequences can provide enough essential context to build accurate tree topologies, even in the case of disjoint amplicons, allowing for integration of microbial datasets across variable regions. We validate that our findings extend to experimental data. Our approach not only suggests that guide sequences should become a standard for building phylogenetic trees from any short-read microbial data, but also extends microbial meta-analytical methods by allowing phylogenetic integration across cohorts which have used different variable regions to assess the microbiomes association with ecosystem services. We provide an easily usable application of our method, phyloguidesR, as an open-sourced tool to enable any researcher to apply and use guide sequences easily in their microbial community of interest. IMPORTANCEIntegrating data across independent studies can uncover robust biological patterns that strengthen inference and support more generalizable conclusions. In microbiome research, such integration is constrained by the heterogeneity of how microbial communities are sequenced. May studies target different regions of the 16S rDNA gene, producing datasets that lack a shared phylogenetic framework, and are difficult to analyze together without discarding information. As a result, comparisons across studies often rely on coarse conglomeration of taxonomic summaries or exclude entire datasets to integrate results. Here, we introduce a phylogenetic scaffolding framework that produces more accurate phylogenetic trees and demonstrate that it can unify even non-overlapping 16S amplicon datasets. Such integration has the power to reveal generalizable patterns that are invisible within individual microbiome studies, where noise and region-specific amplification have long obscured biological signals. In doing so, guides set the stage for a more powerful and integrative microbiome science at scale.

microbiology↗

bioRxiv2025

Pseudocapillaria tomentosa Infections in Laboratory Larval and Adult Zebrafish (Danio rerio): Development and Advances in an In Vivo Anthelmintic Drug Discovery Model

Parasite resistance is an increasing problem in livestock and companion animals. Developing new drug discovery models may improve the identification of novel anthelmintic drugs which will reduce parasite infections. Adult zebrafish (Danio rerio) have been previously used as a model for anthelmintic drug discovery by infecting them with the gastrointestinal nematode Pseudocapillaria tomentosa. Using larval zebrafish will increase assay sensitivity and throughput because this in vivo platform evaluates host parasite interactions and is conducted in multi-well plates. To develop this assay, this study focuses on 1) evaluating infections in 5-30 days post fertilization (dpf) fish, 2) validating the assay with a known anthelmintic used in domestic animals, and 3) documenting the growth and development of P. tomentosa. 30 dpf fish had the most robust infections in multi-well plates and the best survival compared to younger larvae. Assay sensitivity was evaluated by aqueously exposing 30 dpf infected zebrafish to emamectin benzoate (a macrocyclic lactone), which successfully reduced infection intensity. In vitro larvae hatched from eggs, larval, and adult zebrafish (n=488) were used to document P. tomentosa development from 1-37 days post exposure. A change point analysis (CPA) predicted the ecdysis (molting) points as follows (mm): L1/L2 = 0.220, L2/L3 = 0.571, L3/L4 = 1.174, and L4/L5 = 1.584. Identifying the worm molts sizes enables the inclusion of developmental endpoints within trials. Overall, this study will increase the sensitivity of anthelmintic drug discovery because the validated high throughput larval zebrafish model accounts for drug interactions between the host and parasite. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/672915v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1768676org.highwire.dtl.DTLVardef@75dadcorg.highwire.dtl.DTLVardef@173dd3forg.highwire.dtl.DTLVardef@1c28722_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Modelling the zebrafish gut microbiome's resistance and sensitivity to climate change and parasite infection

As climate change increases global water temperatures, ecologists expect intestinal helminth infection ranges to expand and increase the health burden on aquatic organisms. However, the gut microbiome can interact with these parasites to influence infection outcomes, raising the possibility that its response to increasing temperatures may help buffer against increased infection burden. To evaluate this hypothesis, we sought to determine if the microbiome is resistant or resilient to the stressors of increased water temperature, helminth exposure, and their combination, and whether this variation linked to infection outcomes. We leveraged the zebrafish (Danio rerio) model organism to measure how these variables relate to the temporal dynamics of the gut microbiome. In particular, we exposed adult zebrafish to the parasitic whipworm Pseudocapillaria tomentosa across three different water temperatures (28{degrees}C, 32{degrees}C, 35{degrees}C), and analyzed fecal microbiome samples at five time points across 42 days. Our findings show that parasite exposure and water temperature independently alter gut microbiome diversity. Moreover, we find that water temperature moderates the association between parasite infection and the gut microbiome. Consistent with this observation, but at odds with current expectations, we find that increasing water temperature reduces parasitic infection in fish. Overall, our results indicate that water temperature alters the contextual landscape of the gut microbiome to impact its response to an exogenous stressor of an intestinal parasite in zebrafish. Furthermore, our findings represent the first report of the effects of elevated temperature on parasitic nematode development in a fish host. Importantly, our study demonstrates that climate change may have unanticipated and environmentally contingent impacts to vertebrate gut microbiomes and health outcomes in response to an exogenous stressor.

microbiology↗

bioRxiv2024

Clearing the air on pollutant disruptions of the gut-brain axis: Developmental exposure to Benzopyrene disturbs zebrafish behavior and the gut microbiome in adults and subsequent generations

Developmental exposure to benzo[a]pyrene (BaP), a ubiquitous environmental pollutant, has been linked to various toxic effects, including neurodegenerative disorders and, most recently, multigenerational behavioral impairment. While the specific mechanisms driving BaP neurotoxicity are not fully understood, recent work highlights two important determinants of developmental BaP neurotoxicity: (1) the aryl hydrocarbon receptor (AHR), which is responsible for inducing host metabolism of BaP, and (2) the gut microbiome, which may interact with BaP to affect its metabolism, or be perturbed directly by BaP to yield disruptions to the gut-brain axis. To explore the role of AHR, the gut microbiome, and their interaction on BaP-induced neurotoxicity, we utilized the zebrafish model. We sought to determine (1) how exposure to BaP and developmental expression of AHR2, a key gene in the zebrafish AHR pathway, link to adult zebrafish behavior, (2) how these same variables associated with the structure and function of the adult zebrafish gut metagenome, and (3) whether these associations were multigenerational. This finding revealed a reticulated axis of association between BaP exposure, developmental AHR2 expression, the zebrafish gut metagenome, and behavior. Our results also indicate that AHR2 is a key mediator of how BaP elicits neurotoxicity and microbiome dysbiosis. Additionally, this axis of association manifests inter- and transgenerationally, suggesting that exposure to BaP may yield dysbiotic and neurodevelopmental impacts on subsequent generations. These findings demonstrate the power of utilizing the zebrafish model to study pollutant-metagenome interactions and elucidate the role of specific host genes in the neurotoxicity and dysbiosis. ImportanceBenzo[a]pyrene (BaP) is a toxic chemical that is especially ubiquitous in industrialized nations, as it is produced in large quantities by burning coal, oil, and other organic compounds. Early-life and in utero exposure to this chemical can induce adverse behavior changes in model animals, like mice and zebrafish. In humans, developmental exposure is linked to symptoms of ADHD, anxiety, and depression. This study found BaP affects zebrafish behavior and the gut microbiome throughout their life and across subsequent generations. We further discovered that a host regulatory pathway called the aryl hydrocarbon receptor is a key component of how benzo[a]pyrene, the gut microbiome, and behavior interconnect. The aryl hydrocarbon receptor binds many toxicants, as well as microbial metabolites associated with maintaining gut homeostasis, and regulates the gut-brain connection. This receptor presents a new potential mechanism of how gut microbiota relate to BaP exposure and behavior for future studies to investigate.

microbiology↗

bioRxiv2024

Gut microbiota metabolically mediate intestinal helminth infection in Zebrafish

Intestinal helminth parasite (IHP) infection induces alterations in the composition of microbial communities across vertebrates, although how gut microbiota may facilitate or hinder parasite infection remains poorly defined. In this work we utilized a zebrafish model to investigate the relationship between gut microbiota, gut metabolites, and IHP infection. We found that extreme disparity in zebrafish parasite infection burden is linked to the composition of the gut microbiome, and that changes in the gut microbiome are associated with variation in a class of endogenously-produced signaling compounds, N-acylethanolamines, that are known to be involved in parasite infection. Using a statistical mediation analysis, we uncovered a set of gut microbes whose relative abundance explains the association between gut metabolites and infection outcomes. Experimental investigation of one of the compounds in this analysis reveals salicylaldehyde, which is putatively produced by the gut microbe Pelomonas, as a potent anthelmintic with activity against Pseudocapillaria tomentosa egg hatching, both in vitro and in vivo. Collectively, our findings underscore the importance of the gut microbiome as a mediating agent in parasitic infection and highlights specific gut metabolites as tools for the advancement of novel therapeutic interventions against IHP infection. ImportanceIntestinal helminth parasites (IHPs) impact human health globally and interfere with animal health and agricultural productivity. While anthelmintics are critical to controlling parasite infections, their efficacy is increasingly compromised by drug resistance. Recent investigations suggest the gut microbiome might mediate helminth infection dynamics. So, identifying how gut microbes interact with parasites could yield new therapeutic targets for infection prevention and management. We conducted a study using a zebrafish model of parasitic infection to identify routes by which gut microbes might impact helminth infection outcomes. Our research linked the gut microbiome to both parasite infection, and to metabolites in the gut to understand how microbes could alter parasite infection. We identified a metabolite in the gut, salicylaldehyde, that is putatively produced by a gut microbe and that inhibits parasitic egg growth. Our results also point to a class of compounds, N-acyl-ethanolamines, which are affected by changes in the gut microbiome and are linked to parasite infection. Collectively, our results indicate the gut microbiome may be a source of novel anthelmintics which can be harnessed to control IHPs.

microbiology↗

bioRxiv2022

Reversing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S sequences and systemic metabolic phenotypic data using a transkingdom network analysis. By incorporating cell type information from single cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reversed levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes from diet-induced obesity and metabolic syndrome. It primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in adipose tissue.

systems biology↗

bioRxiv2022

Age and micronutrient effects on the microbiome in a mouse model of zinc depletion and supplementation

Older adult populations are at risk for elevated zinc deficiency, which may predispose them to immune dysfunction and age-related chronic inflammation that drives myriad diseases and disorders. Recent work also implicates the gut microbiome in the onset and severity of age-related inflammation, indicating that dietary zinc status and the gut microbiome may interact to impact age-related host immunity. We hypothesize that age-related alterations in the gut microbiome contribute to the demonstrated zinc deficits in host zinc levels and increased inflammation. We tested this hypothesis with a multifactor two-part study design in a C57BL/6 mouse model. The two studies included young (2 month old) and aged (24 month old) mice fed either (1) a zinc adequate or zinc supplemented diet, or (2) a zinc adequate or marginal zinc deficient diet, respectively. Overall microbiome composition did not significantly change with zinc status; beta diversity was driven almost exclusively by age effects. Microbiome differences due to age are evident at all taxonomic levels, with more than half of all taxonomic units significantly different at each. Furthermore, we found 150 out of 186 genera were significantly different between the two age groups, with Bacteriodes and Parabacteroides being the primary components of young and old mice, respectively. These data suggest that modulating individual micronutrient concentrations does not lead to comprehensive microbiome shifts, but rather affects specific components of the gut microbiome. However, a phylogenetic agglomeration technique (ClaaTU) revealed phylogenetic clades of microbiota that respond to modulation of dietary zinc status in an age-dependent manner. Collectively, these results suggest that there exists a complex interplay between host age, gut microbiome composition, and dietary zinc status.

microbiology↗

bioRxiv2022

Chronic clinical signs of upper respiratory tract disease shape gut and respiratory microbiomes in cohabitating domestic felines.

Feline upper respiratory tract disease (FURTD), often caused by infections etiologies, is a multifactorial syndrome affecting feline populations worldwide. Because of its highly transmissible nature, infectious FURTD is most prevalent anywhere cats are housed in groups such as animal shelters, and is associated with negative consequences such as decreasing adoption rates, intensifying care costs, and increasing euthanasia rates. Understanding the etiology and pathophysiology of FURTD is thus essential to best mitigate the negative consequences of this disease. Clinical signs of FURTD include acute respiratory disease, with a small fraction of cats developing chronic sequelae. It is thought that nasal mucosal microbiome changes play an active role in the development of acute clinical signs, but it remains unknown if the microbiome may play a role in the development and progression of chronic clinical disease. To address the knowledge gap surrounding how microbiomes link to chronic FURTD, we asked if microbial community structure of upper respiratory and gut microbiomes differed between cats with chronic FURTD signs and clinically normal cats. We selected 8 households with at least one cat exhibiting chronic clinical FURTD, and simultaneously collected samples from cohabitating clinically normal cats. Microbial community structure was assessed via 16S rDNA sequencing of both gut and nasal microbiome communities. Using a previously described ecophylogenetic method, we identified 37 and 27 microbial lineages within gut and nasal microbiomes respectively that significantly associated with presence of active FURTD clinical signs in cats with a history of chronic signs. Overall, we find that nasal and gut microbial communities may contribute to the development of chronic clinical course, but more research is needed to confirm our observations.

microbiology↗

bioRxiv2021

Evaluation of the effects of library preparation procedure and sample characteristics on the accuracy of metagenomic profiles

Shotgun metagenomic sequencing has transformed our understanding of microbial community ecology. However, preparing metagenomic libraries for high-throughput DNA sequencing remains a costly, labor-intensive, and time-consuming procedure, which in turn limits the utility of metagenomes. Several library preparation procedures have recently been developed to offset these costs, but it is unclear how these newer procedures compare to current standards in the field. In particular, it is not clear if all such procedures perform equally well across different types of microbial communities, or if features of the biological samples being processed (e.g., DNA amount) impact the accuracy of the approach. To address these questions, we assessed how five different shotgun DNA sequence library preparation methods, including the commonly used Nextera(R) Flex kit, perform when applied to metagenomic DNA. We measured each methods ability to produce metagenomic data that accurately represents the underlying taxonomic and genetic diversity of the community. We performed these analyses across a range of microbial community types (e.g., soil, coral-associated, mouse-gut-associated) and input DNA amounts. We find that the type of community and amount of input DNA influence each methods performance, indicating that careful consideration may be needed when selecting between methods, especially for low complexity communities. However, cost-effective preparation methods we assessed are generally comparable to the current gold standard Nextera(R) DNA Flex kit for high-complexity communities. Overall, the results from this analysis will help expand and even facilitate access to metagenomic approaches in future studies. IMPORTANCEMetagenomic library preparation methods and sequencing technologies continue to advance rapidly, allowing researchers to characterize microbial communities in previously underexplored environmental samples and systems. However, widely-accepted standardized library preparation methods can be cost-prohibitive. Newly available approaches may be less expensive, but their efficacy in comparison to standardized methods remains unknown. In this study, we compared five different metagenomic library preparation methods. We evaluated each method across a range of microbial communities varying in complexity and quantity of input DNA. Our findings demonstrate the importance of considering sample properties, including community type, composition, and DNA amount, when choosing the most appropriate metagenomic library preparation method.

microbiology↗

bioRxiv2021

TXN, a Xanthohumol Derivative, Significantly Attenuates High-Fat Diet Induced Hepatic Steatosis In Vivo by Antagonizing PPARγ

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN) attenuates high-fat diet (HFD) induced obesity and metabolic syndrome in C57BL/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated TXN might antagonize lipogenic PPAR{gamma} actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A PPAR{gamma} competitive binding assay showed XN and TXN bind to PPAR{gamma} with an IC50 similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated XN and TXN bind in the PPAR{gamma} ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPAR{gamma}.

molecular biology↗

bioRxiv2020

Pseudocapillaria tomentosa, Mycoplasma spp., and intestinal lesions in experimentally infected zebrafish Danio rerio

Intestinal neoplasms and preneoplastic lesions are common in zebrafish research facilities. Previous studies have demonstrated that the neoplasms are caused by a transmissible agent, and two candidate agents have been implicated: a Mycoplasma sp. related to M. penetrans and the intestinal parasitic nematode, Pseudocapillaria tomentosa, and both agents are common in zebrafish facilities. To elucidate the role of these two agents in the occurrence and severity of the neoplasm and other intestinal lesions, we conducted two experimental inoculation studies. Exposed fish were examined at various time points over an 8 mo. period for intestinal histpathologic changes and the burden of Mycoplasma and nematodes. Fish exposed to a Mycoplasma isolate from zebrafish were associated with preneoplastic lesions. Fish exposed to the nematode alone or with the Mycoplasma isolate developed severe lesions and neoplasms. Both inflammation and neoplasm scores were associated with an increase in Mycoplasma burden. These results support the conclusions that P. tomentosa is a strong promoter of intestinal neoplasms in zebrafish, and that Mycoplasma alone can also cause intestinal lesions and accelerate cancer development in the context of nematode infection.

cancer biology↗

bioRxiv2020

Interspecies comparative metagenomics reveals correlated gut microbiome functional capacities among vertebrates

While recent research reveals that the gut microbiome drives vertebrate health, little is known about whether the mechanisms these microbes employ to interact with physiology are consistent across host species. To help close this knowledge gap, we compared gut metagenomes across 10 vertebrate species, including biomedical animal models, to define the inter-species variation in the biochemical pathways encoded by gut microbiota. Doing so revealed gut-enriched pathways conserved across vertebrates, as well as pathways that vary concordantly with host evolutionary history. Overall, the functional capacity of the non-human gut microbiome generally reflects that of humans, though a subset of the pathways encoded by human gut microbiota are not well represented in non-human microbiomes. Collectively, these results support the use of animal models to study the mechanisms through which gut microbes impact human health, but suggest that researchers should cautiously consider which model will optimally represent a specific mechanism of interest. SignificanceEfforts to understand how the gut microbiome interacts with human physiology frequently relies on the use of animal models. However, it is generally not understood if the biochemical pathways encoded in gut microbiomes of these different animal models - which define the routes of interaction between gut microbes and their hosts - reflect those found in the human gut. To address this question, we compared gut metagenomes generated 10 different vertebrate lineages. In so doing, our study revealed that non-human gut metagenomes generally encode a set of pathways that are consistent with those found in the human gut. However, some human metagenome pathways are poorly represented in non-human guts, including pathways implicated in disease. Moreover, our analysis identified pathways that appear to be conserved across vertebrates, as well as pathways that are linked to the evolutionary history of their hosts, observations that hold potential to clarify the basis for phylosymbiosis.

microbiology↗

bioRxiv2020

An integrated gene catalog of the zebrafish gut microbiome reveals significant homology with mammalian microbiomes

Gut microbiome research increasingly utilizes zebrafish (Danio rerio) given their amenability to high-throughput experimental designs. However, the utility of zebrafish for discerning translationally relevant host-microbiome interactions is constrained by a paucity of knowledge about the biological functions that zebrafish gut microbiota can execute, how these functions associate with zebrafish physiology, and the degree of homology between the genes encoded by the zebrafish and human gut microbiomes. To address this knowledge gap, we generated a foundational catalog of zebrafish gut microbiome genomic diversity consisting of 1,569,102 non-redundant genes from twenty-nine individual fish. We identified hundreds of novel microbial genes as well as dozens of biosynthetic gene clusters of potential clinical interest. The genomic diversity of the zebrafish gut microbiome varied significantly across diets and this variance associated with altered expression of intestinal genes involved in inflammation and immune activation. Zebrafish, mouse, and human fecal microbiomes shared > 50% of their total genomic diversity and the vast majority of gene family abundance for each individual metagenome ([~]99%) was accounted for by genes that comprised this shared fraction. These results indicate that the zebrafish gut houses a functionally diverse microbial community that manifests extensive homology to that of humans and mice despite substantial disparities in taxonomic composition. We anticipate that the gene catalog developed here will enable future mechanistic study of host-microbiome interactions using the zebrafish model. ImportanceZebrafish have emerged as an important model system for defining host-microbiome interactions. However, the utility of this model is blunted by limited insight into the functions that are carried by zebrafish gut microbiota, their relationship with zebrafish physiology, and their consistency with the functions carried by human gut microbiota. To address these limitations, we constructed the first genomic database of zebrafish gut microbiome diversity. We use this novel resource to demonstrate that the genomic diversity of the zebrafish gut microbiome varies with diet and this variance links with altered intestinal gene expression. We also identify substantial homology between zebrafish, human, and mouse metagenomic diversity, indicating that these microbiomes may operate similarly.

microbiology↗

bioRxiv2018

A Metagenomic Meta-Analysis Reveals Functional Signatures of Health and Disease in the Human Gut Microbiome

While recent research indicates that human health depends, in part, upon the symbiotic relationship between gut microbes and their host, the specific interactions between host and microbe that define health are poorly resolved. Metagenomic clinical studies clarify this definition by revealing gut microbial taxa and functions that stratify healthy and diseased individuals. However, the typical single-disease focus of microbiome studies limits insight into which microbiome features robustly associate with health, indicate general deviations from health, or predict specific diseases. Additionally, the focus on taxonomy may limit our understanding of how the microbiome relates to health given observations that different taxonomic members can fulfill similar functional roles. To improve our understanding of the association between the gut microbiome and health, we integrated about 2,000 gut metagenomes obtained from eight clinical studies in a statistical meta-analysis. We identify characteristics of the gut microbiome that associate generally with disease, including functional alpha-diversity, beta-diversity, and beta-dispersion. Moreover, we resolve microbiome modules that stratify diseased individuals from controls in a manner independent of study-specific effects. Many of the differentially abundant functions overlap multiple diseases suggesting a role in host health, while others are specific to a single disease and may associate with disease-specific etiologies. Our results clarify potential microbiome-mediated mechanisms of disease and reveal features of the microbiome that may be useful for the development of microbiome-based diagnostics. Ultimately, our study clarifies the definition of a healthy microbiome and how perturbations to it associate with disease.

bioinformatics↗

bioRxiv2017

Ecophylogenetics Reveals the Evolutionary Associations between Mammals and their Gut Microbiota

A tantalizing hypothesis posits that mammals coevolved with their gut microbiota. Unfortunately, the limited resolution of microbial taxonomy hinders the exploration of this hypothesis and specifically challenges the discovery of gut microbes that are linked to mammalian evolution. To address this, we developed a novel approach that groups microbes into new, more meaningful taxonomic units based on their common ancestry and ecological redundancy. Treating mammalian lineages as different ecosystems, we quantified the distribution of these microbial taxa across mammals. Our analysis discovered monophyletic clades of gut bacteria that are unexpectedly prevalent, or conserved, across all mammals, as well as conserved clades that are exclusive to particular mammalian lineages. These clades often manifest phylogenetic patterns indicating that they are subject to selection. Lineage - specific changes in clade conservation, including a human-accelerated loss of conserved clades, suggest that mammalian evolution associates with a change in the selective regimes that act on gut microbiota. Collectively, these results point to the existence of microbes that possess traits that facilitate their dispersion or survival in the mammalian gut, possibly because they are subject to host selection. Ultimately, our analysis clarifies the relationship between the diversification of the gut microbiome and mammalian evolutionary history.

microbiology↗