A metabolomics pipeline enables mechanistic interrogation of the gut microbiome

Gut microbes modulate host phenotypes and are associated with numerous health effects in humans, ranging from cancer immunotherapy response to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microbes has hindered defining mechanistic connections between individual microbial strains and host phenotypes. One key way the gut microbiome influences host physiology is through the production of small molecules1-3, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites (MDMs) in diverse sample types. We report the metabolic profiles of 178 gut microbe strains using our library of 833 metabolites. Leveraging this metabolomics resource we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover novel metabolism in Bacteroides, and employ comparative genomics-based discovery of candidate biochemical pathways. MDMs can be detected in diverse biofluids in gnotobiotic and conventional mice and traced back to corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microbe and microbe-host interactions.

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Interspecies comparative metagenomics reveals correlated gut microbiome functional capacities among vertebrates

10.1101/2020.06.15.153320 ◽

2020 ◽

Author(s):

Christopher A. Gaulke ◽

Courtney R. Armour ◽

Ian R. Humphreys ◽

Laura M. Beaver ◽

Carrie L. Barton ◽

...

Keyword(s):

Animal Models ◽

Gut Microbiota ◽

Gut Microbiome ◽

Evolutionary History ◽

Species Variation ◽

Human Gut ◽

Gut Microbes ◽

Comparative Metagenomics ◽

Biochemical Pathways ◽

History Of

AbstractWhile 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.

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Bioactive small molecules produced by the human gut microbiome modulate Vibrio cholerae sessile and planktonic lifestyles

Gut Microbes ◽

10.1080/19490976.2021.1918993 ◽

2021 ◽

Vol 13 (1) ◽

pp. 1-19

Author(s):

Heidi Pauer ◽

Felipe Lopes Teixeira ◽

Avery V. Robinson ◽

Thiago E. Parente ◽

Marília A. F. De Melo ◽

...

Keyword(s):

Small Molecules ◽

Vibrio Cholerae ◽

Gut Microbiome ◽

Human Gut ◽

Human Gut Microbiome

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Infection with novel Bacteroides phage BV01 alters host transcriptome and bile acid metabolism in a common human gut microbe

10.1101/2020.04.06.028910 ◽

2020 ◽

Author(s):

Danielle E. Campbell ◽

Lindsey K. Ly ◽

Jason M. Ridlon ◽

Ansel Hsiao ◽

Rachel J. Whitaker ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Community Dynamics ◽

Bile Acid Metabolism ◽

Dependent Manner ◽

Human Gut ◽

Healthy Human ◽

Transcriptomic Response ◽

Gut Microbes ◽

Host Interactions

ABSTRACTThe bacterial genus Bacteroides is among the most abundant and common taxa in the human gut, yet little is known about the phages infecting the group. Bacteroides phage BV01 (BV01) was identified as a prophage integrated on the chromosome of its host, Bacteroides vulgatus ATCC 8482. Phage BV01 is actively produced, and infects susceptible B. vulgatus hosts in the mouse gut. Infection with BV01 causes a generalized repression of the B. vulgatus transcriptome, downregulating 103 transcripts and upregulating only 12. Integration of BV01 disrupts the promoter sequence of a downstream gene encoding a putative tryptophan-rich sensory protein (tspO). Deletion of tspO and subsequent RNAseq analysis revealed that more than half of the differentially-regulated transcripts are shared with the BV01 lysogen, suggesting the transcriptomic response to BV01 is linked to tspO. Among these differentially-regulated transcripts are two encoding bile salt hydrolases. Bile acid deconjugation assays show that BV01 represses its host’s ability to hydrolyze bile acids in a tspO-dependent manner. Analysis of 256 published healthy human gut metagenomes suggests that phage integration adjacent to B. vulgatus-like tspO genes is rare within an individual, but common among humans. Finally, this work proposes a novel phage family that includes BV01, the Salyersviridae, whose host range spans the Bacteroides and is detectable in human-associated samples. Together, these findings highlight the importance of phage-host interactions to our understanding of how gut microbes sense and interact with their environment.IMPORTANCEThe links between human disease and the gut microbiome are numerous. Most mechanisms by which most gut microbes and their activities change and impact human health remain elusive. Phages, viruses that infect bacteria, are hypothesized to play a central role in modulating both community dynamics and functional activities. Here we have characterized an active prophage, BV01, which infects a pervasive and abundant human gut-associated species. BV01 infection alters its host’s transcriptional profile including its metabolism of bile acids, molecules implicated in mediating health and disease states in the gut. This highlights that prophages and other components of the variable genome should not be overlooked in bacterial genomes because they may dramatically alter host phenotypes. Furthermore, BV01 represents a new family of phages infecting human gut symbionts, providing a foundation for future investigations of phage-host interactions in these clinically-relevant but underexplored hosts.

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Taxonomic and predicted metabolic profiles of the human gut microbiome in pre-Columbian mummies

FEMS Microbiology Ecology ◽

10.1093/femsec/fiw182 ◽

2016 ◽

Vol 92 (11) ◽

pp. fiw182 ◽

Cited By ~ 9

Author(s):

Tasha M. Santiago-Rodriguez ◽

Gino Fornaciari ◽

Stefania Luciani ◽

Scot E. Dowd ◽

Gary A. Toranzos ◽

...

Keyword(s):

Gut Microbiome ◽

Metabolic Profiles ◽

Human Gut ◽

Human Gut Microbiome

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Systematic mapping of drug metabolism by the human gut microbiome

10.1101/538215 ◽

2019 ◽

Cited By ~ 7

Author(s):

Pranatchareeya Chankhamjon ◽

Bahar Javdan ◽

Jaime Lopez ◽

Raphaella Hull ◽

Seema Chatterjee ◽

...

Keyword(s):

Drug Metabolism ◽

Small Molecules ◽

Gut Microbiome ◽

Bacterial Species ◽

Drug Bioavailability ◽

Oral Drugs ◽

Human Gut ◽

Human Gut Microbiome ◽

Comprehensive Framework

ABSTRACTThe human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities, making it one of nature’s highest density, highest diversity bioreactors. Several drugs have been previously shown to be directly metabolized by the gut microbiome, but the extent of this phenomenon has not been systematically explored. Here, we develop a systematic screen for mapping the ability of the complex human gut microbiome to biochemically transform small molecules (MDM-Screen), and apply it to a library of 575 clinically used oral drugs. We show that 13% of the analyzed drugs, spanning 28 pharmacological classes, are metabolized by a single microbiome sample. In a proof-of-principle example, we show that microbiome-derived metabolism occursin vivo, identify the genes responsible for it, and provide a possible link between its consequences and clinically observed features of drug bioavailability and toxicity. Our findings reveal a previously underappreciated role for the gut microbiome in drug metabolism, and provide a comprehensive framework for characterizing this important class of drug-microbiome interactions.

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The human gut microbiome and health inequities

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017947118 ◽

2021 ◽

Vol 118 (25) ◽

pp. e2017947118

Author(s):

Katherine R. Amato ◽

Marie-Claire Arrieta ◽

Meghan B. Azad ◽

Michael T. Bailey ◽

Josiane L. Broussard ◽

...

Keyword(s):

Socioeconomic Status ◽

Gut Microbiome ◽

Health Inequities ◽

Biological Processes ◽

Human Gut ◽

Economic Forces ◽

Gut Microbe ◽

Important Pathway ◽

Microbe Interactions ◽

Neuroendocrine Functions

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host–gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

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Mapping of the benzoate metabolism by human gut microbiome indicates food-derived metagenome evolution

Scientific Reports ◽

10.1038/s41598-021-84964-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Monika Yadav ◽

Avinash Lomash ◽

Seema Kapoor ◽

Rajesh Pandey ◽

Nar Singh Chauhan

Keyword(s):

Gut Microbiome ◽

Human Gut ◽

Food Preservatives ◽

Multiple Features ◽

Human Organ ◽

Gut Microbes ◽

Human Gut Microbiome ◽

Metabolism Analysis ◽

Aerobic And Anaerobic

AbstractSodium benzoate is one of the widely used food preservatives and its metabolism in the human body has been studied only with the host perspective. Despite the human gut microbiome being considered as a virtual human organ, its role in benzoate metabolism is yet to be elucidated. The current study uses a multi-omic approach to rationalize the role of human gut microbes in benzoate metabolism. Microbial diversity analysis with multiple features synchronously indicates the dominance of Bacteroidetes followed by Firmicutes, Actinobacteria, and Proteobacteria. Metagenomic exploration highlights the presence of benzoate catabolic protein features. These features were mapped on to the aerobic and anaerobic pathways of benzoate catabolism. Benzoate catabolism assays identified statistically significant metabolites (P < 0.05) associated with the protocatechuate branch of the beta-ketoadipate pathway of the benzoate metabolism. Analysis of the 201 human gut metagenomic datasets across diverse populations indicates the omnipresence of these features. Enrichment of the benzoate catabolic protein features in human gut microbes rationalizes their role in benzoate catabolism, as well as indicates food-derived microbiome evolution.

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The capacity to produce hydrogen sulfide (H2S) via cysteine degradation is ubiquitous in the human gut microbiome

10.1101/2021.03.24.436781 ◽

2021 ◽

Author(s):

Domenick J Braccia ◽

Xiaofang Jiang ◽

Mihai Pop ◽

Brantley Hall

Keyword(s):

Hydrogen Sulfide ◽

Gut Microbiome ◽

Bacterial Species ◽

Therapeutic Interventions ◽

Metagenomic Data ◽

Human Gut ◽

Gut Microbes ◽

Human Gut Microbiome ◽

Degrading Bacteria ◽

H2s Production

As one of the three mammalian gasotransmitters, hydrogen sulfide (H2S) plays a major role in maintaining physiological homeostasis. Endogenously produced H2S plays numerous beneficial roles including mediating vasodilation and conferring neuroprotection. Due to its high membrane permeability, exogenously produced H2S originating from the gut microbiota can also influence human physiology and is implicated in reducing intestinal mucosal integrity and potentiating genotoxicity and is therefore a potential target for therapeutic interventions. Gut microbial H2S production is often attributed to dissimilatory sulfate reducers such as Desulfovibrio and Bilophila species. However, an alternative source for H2S production, cysteine degradation, is present in gut microbes, but the genes responsible for cysteine degradation have not been systematically annotated in gut microbes. To better understand the potential for H2S production via cysteine degradation by the human gut microbiome, we performed a comprehensive search for genes encoding cysteine-degrading genes in 4,644 bacterial genomes from the Unified Human Gastrointestinal Genome (UHGG) catalogue. We identified 407 gut bacterial species as putative cysteine degrading bacteria, 328 of which have not been previously implicated in H2S production. We identified the presence of at least one putative cysteine degrading bacteria in metagenomic data of 100% of 6,644 healthy subjects and the expression of cysteine-degrading genes in metatranscriptomics data of 100% of 59 samples. Additionally, putative cysteine-degrading bacteria are more abundant than sulfate reducing bacteria (p<2.2e-16). Overall, this study improves our understanding of the capacity for H2S production by the human gut microbiome and may help to inform interventions to therapeutically modulate gut microbial H2S production.

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