Human microbiome science has advanced rapidly and reached a scale at which basic biology, clinical translation and population health are increasingly integrated. It is thus now possible for public ...health researchers, practitioners and policymakers to take specific action leveraging current and future microbiome-based opportunities and best practices. Here we provide an outline of considerations for research, education, interpretation and scientific communication concerning the human microbiome and public health. This includes guidelines for population-scale microbiome study design; necessary physical platforms and analysis methods; integration into public health areas such as epidemiology, nutrition, chronic disease, and global and environmental health; entrepreneurship and technology transfer; and educational curricula. Particularly in the near future, there are both opportunities for the incorporation of microbiome-based technologies into public health practice, and a growing need for policymaking and regulation around related areas such as prebiotic and probiotic supplements, novel live-cell therapies and fecal microbiota transplants.
The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed ...shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.
Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for ...diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested >1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates.
Synopsis
MACARRoN combines ecological and epidemiological metrics to prioritize metabolic features with potential bioactivity in a phenotype of interest. Its application to inflammatory bowel disease (IBD) prioritizes both previously IBD-linked and less-explored microbiome-associated metabolites.
Metabolic features that covary among conditions tend to be closer in mass and chemically homogeneous, pointing to underlying biochemical relationships.
MACARRoN integrates metabolic feature prevalence, covariance, abundance with respect to an identified metabolite, and extent of perturbation to prioritize actionable, phenotype-associated features from untargeted metabolomics data.
MACARRoN prioritized ~1,000 chemically diverse, stool-derived features as IBD-associated, including known IBD biomarkers and several unannotated features that covary with them.
Newly IBD-linked metabolic features included microbial polyamines, nicotinamide riboside (shown here to reduce colitis in DSS-treated mice), and novel putatively microbially-derived bilirubin compounds.
MACARRoN combines ecological and epidemiological metrics to prioritize metabolic features with potential bioactivity in a phenotype of interest. Its application to inflammatory bowel disease (IBD) prioritizes both previously IBD-linked and less-explored microbiome-associated metabolites.
Trimethoprim, a preferred treatment for urinary tract infections, is becoming obsolete owing to the rapid dissemination of resistant E. coli. Although direct resistance mechanisms such as ...overexpression of a mutant FolA and dfr enzymes are well characterized, associated alterations that drive or sustain resistance are unknown. We identify the repertoire of resistance-associated perturbations by constructing and interrogating a transcriptome-integrated functional interactome. From the cross talk between perturbations in stress-response and metabolic pathways, we identify the critical dependence on serine hydroxymethyltransferase (GlyA) as an emergent vulnerability. Through its deletion, we demonstrate that GlyA is necessary to sustain high levels of resistance in both laboratory-evolved resistant E. coli and a multidrug-resistant clinical isolate. Through comparative evolution, we show that the absence of GlyA activity decelerates the acquisition of resistance in E. coli. Put together, our results identify GlyA as a promising target, providing a basis for the rational design of drug combinations.
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•TMP-resistant E. coli show cross talk between stress response and metabolic pathways•Dependence on glyA is an emergent vulnerability associated with TMP resistance•Knockout of glyA partially rescues sensitivity to TMP in E. coli
Microbiology; Multi-Drug Resistant Organisms; Transcriptomics
The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional ...alterations in severe COVID-19, defined as acute respiratory or other organ failure.
We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites.
Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or "long COVID," suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease.
Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.
Antifolates are competitive inhibitors of dihydrofolate reductase (DHFR), a conserved enzyme that is central to metabolism and widely targeted in pathogenic diseases, cancer and autoimmune disorders. ...Although most clinically used antifolates are known to be target specific, some display a fair degree of cross‐reactivity with DHFRs from other species. A method that enables identification of determinants of affinity and specificity in target DHFRs from different species and provides guidelines for the design of antifolates is currently lacking. To address this, we first captured the potential druggable space of a DHFR in a substructure called the ‘supersite’ and classified supersites of DHFRs from 56 species into 16 ‘site‐types’ based on pairwise structural similarity. Analysis of supersites across these site‐types revealed that DHFRs exhibit varying extents of dissimilarity at structurally equivalent positions in and around the binding site. We were able to explain the pattern of affinities towards chemically diverse antifolates exhibited by DHFRs of different site‐types based on these structural differences. We then generated an antifolate–DHFR network by mapping known high‐affinity antifolates to their respective supersites and used this to identify antifolates that can be repurposed based on similarity between supersites or antifolates. Thus, we identified 177 human‐specific and 458 pathogen‐specific antifolates, a large number of which are supported by available experimental data. Thus, in the light of the clinical importance of DHFR, we present a novel approach to identifying differences in the druggable space of DHFRs that can be utilized for rational design of antifolates.
Druggable space of dihydrofolate reductase is defined as a supersite. An antifolate‐DHFR network based on antifolate binding affinity and structural similarities is constructed, containing 1434 antifolates mapped onto DHFR supersites from 56 species classified into 16 site-types. This is used to facilitate rationalization of known affinities based on structural variations in site-types and repurpose antifolates among similar DHFRs.
The metabolome lies at the interface of host–microbiome crosstalk. Previous work has established links between chemically diverse microbial metabolites and a myriad of host physiological processes ...and diseases. Coupled with scalable and cost-effective technologies, metabolomics is thus gaining popularity as a tool for characterization of microbial communities, particularly when combined with metagenomics as a window into microbiome function. A systematic interrogation of microbial community metabolomes can uncover key microbial compounds, metabolic capabilities of the microbiome, and also provide critical mechanistic insights into microbiome-linked host phenotypes. In this review, we discuss methods and accompanying resources that have been developed for these purposes. The accomplishments of these methods demonstrate that metabolomes can be used to functionally characterize microbial communities, and that microbial properties can be used to identify and investigate chemical compounds.
•Microbiome-associated metabolite pools aid discovery of novel functions.•Guilt-by-association approaches identify microbial derivatives of standard metabolites.•Machine learning approaches predict metabolites from metagenomes.•Computational and in vitro tools are emerging to study chemically mediated roles of the microbiome.
For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation ...by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging to two protein superfamilies: thiolases and acyl-CoA N-acyltransferases. In vitro characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort (n = 208) found three of these microbial thiolases and one acyl-CoA N-acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine.
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