Biology subjects

Van Treuren, W.

Publications and source records attributed to Van Treuren, W..

9 recordsLinked to original sources

bioRxiv2022

Single-strain behavior predicts responses to environmental pH and osmolality in the gut microbiota.

Changes to gut environmental factors such as pH and osmolality due to disease or drugs correlate with major shifts in microbiome composition; however, we currently cannot predict which species can tolerate such changes or how the community will be affected. Here, we assessed the growth of 92 representative human gut bacterial strains spanning 28 families across multiple pH values and osmolalities in vitro. The ability to grow in extreme pH or osmolality conditions correlated with the availability of known stress response genes in many cases, but not all, indicating that novel pathways may participate in protecting against acid or osmotic stresses. Machine learning analysis uncovered genes or subsystems that are predictive of differential tolerance in either acid or osmotic stress. For osmotic stress, we corroborated the increased abundance of these genes in vivo during osmotic perturbation. The growth of specific taxa in limiting conditions in isolation in vitro correlated with survival in complex communities in vitro and in an in vivo mouse model of diet-induced intestinal acidification. Our data show that in vitro stress tolerance results are generalizable and that physical parameters may supersede interspecies interactions in determining the relative abundance of community members. Importantly, we provide an extensive resource for predicting shifts in microbial composition and gene abundance in complex perturbations. Furthermore, this work highlights the physical environment as a major driver of bacterial composition and the importance of performing physical measurements in animal and clinical studies to elucidate the drivers of shifts in microbiota abundance. Significance StatementChanges in pH and particle concentration (osmolality) commonly result from gut disease or the ingestion of common drugs, causing changes in bacterial growth and microbiota composition within the intestine. Thus far, the effects of physical parameters on the growth of intestinal bacterial taxa have not been well documented in the context of predicting microbiota community composition. To address this gap, we examined the growth of 92 bacterial species under varying pH and osmolality conditions. We found that physical parameters are key predictors of bacterial abundance in individual-strain cultures and in complex bacterial communities. Moreover, our results identified specific genes and pathways that are predictive of growth in specific environments. Together, these findings can aid in determining the effectiveness of microbiota therapies in gut environments subjected to various perturbations.

microbiology↗

bioRxiv2022

Butyrate differentiates permissiveness to Clostridioides difficile infection and influences growth of diverse C. difficile isolates

A disrupted "dysbiotic" gut microbiome engenders susceptibility to the diarrheal pathogen Clostridioides difficile by impacting the metabolic milieu of the gut. Diet, in particular the microbiota accessible carbohydrates (MACs) found in dietary fiber, is one of the most powerful ways to affect the composition and metabolic output of the gut microbiome. As such, diet is a powerful tool for understanding the biology of C. difficile and for developing alternative approaches for coping with this pathogen. One prominent class of metabolites produced by the gut microbiome are short chain fatty acids (SCFAs), the major metabolic end products of MAC metabolism. SCFAs are known decrease the fitness of C. difficile in vitro and that high intestinal SCFA concentrations are associated with reduced fitness of C. difficile in animal models of C. difficile infection (CDI). Here, we use controlled dietary conditions (8 diets that differ only by MAC composition) to show that C. difficile fitness is most consistently impacted by butyrate, rather than the other two prominent SCFAs (acetate and propionate), during murine model CDI. We similarly show that butyrate concentrations are lower in fecal samples from humans with CDI relative to healthy controls. Finally, we demonstrate that butyrate impacts growth in diverse C. difficile isolates. These findings provide a foundation for future work which will dissect how butyrate directly impacts C. difficile fitness and will lead to the development of diverse approaches distinct from antibiotics or fecal transplant, such as dietary interventions, for mitigating CDI in at-risk human populations. IMPORTANCEClostridioides difficile is a leading cause of infectious diarrhea in humans and it imposes a tremendous burden on the healthcare system. Current treatments for C. difficile infection (CDI) include antibiotics and fecal microbiota transplant, which contribute to recurrent CDIs and face major regulatory hurdles, respectively. Therefore, there is an ongoing need to develop new ways to cope with CDI. Notably, a disrupted "dysbiotic" gut microbiota is the primary risk factor for CDI but we incompletely understand how a healthy microbiota resists CDI. Here, we show that a specific molecule produced by the gut microbiota, butyrate, is negatively associated with C. difficile burdens in humans and in a mouse model of CDI and that butyrate impedes the growth of diverse C. difficile strains in pure culture. These findings help to build a foundation for designing alternative, possibly diet-based, strategies for mitigating CDI in humans.

microbiology↗

bioRxiv2021

Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes

Metabolism of dietary compounds by the gut microbiota generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS) and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDMs generation; however, it is unclear if interindividual differences in diet or gut microbiome dominantly contribute to MDM variance. Here we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. Notably, the coefficient of variation in three uMDMs of interest, PAG, PCS, and IS (primary outcome), did not significantly decrease. The majority of circulating MDMs maintained variation despite identical diets. These results highlight the highly personalized profile of MDMs and limited contribution of short-term dietary heterogeneity, suggesting that dietary modification may need to be paired with microbial therapies to control MDM profiles.

microbiology↗

bioRxiv2021

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.

microbiology↗

bioRxiv2020

Bacteroides thetaiotaomicron-infecting bacteriophage isolates inform sequence-based host range prediction

Our emerging view of the gut microbiome largely focuses on bacteria and less is known about other microbial components such as of bacteriophages (phages). Though phages are abundant in the gut, very few phages have been isolated from this ecosystem. Here, we report the genomes of 27 phages from the United States and Bangladesh that infect the prevalent human gut bacterium Bacteroides thetaiotaomicron. These phages are mostly distinct from previously sequenced phages with the exception of two, which are crAss-like phages. We compare these isolates to existing human gut metagenomes, revealing similarities to previously inferred phages and additional unexplored phage diversity. Finally, we use host tropisms of these phages to identify alleles of phage structural genes associated with infectivity. This work provides a detailed view of the guts "viral dark matter" and a framework for future efforts to further integrate isolation- and sequencing-focused efforts to understand gut-resident phages.

microbiology↗

bioRxiv2019

Electron transfer complexes in the gut dictate high abundance circulating metabolites

It has long been known that proteolytic Clostridia obtain their energy by coupling oxidative and reductive pathways for amino acid metabolism - the Stickland reaction1. The oxidation of one amino acid is coupled with reduction of another, yielding energy in the former step and re-achieving redox balance with the latter. Here, we find that the gut bacterium, Clostridium sporogenes metabolizes amino acids through reductive pathways to produce metabolites that circulate within the host. Measurements in vitro indicate that reductive Stickland pathways are coupled to ATP formation, revealing their role in energy capture by gut bacteria. By probing the genetics of C. sporogenes, we find that the Rnf complex is involved in reductive amino acid metabolism. Rnf complex mutants are attenuated for growth in the mouse gut, demonstrating the importance of energy capture during reductive metabolism for gut colonization. Our findings reveal that the production of high-abundance molecules by a commensal bacterium within the host gut is linked to an energy yielding redox process.

microbiology↗

bioRxiv2018

Live imaging of Aiptasia larvae, a model system for studying coral bleaching, using a simple microfluidic device

Coral reefs, and their associated diverse ecosystems, are of enormous ecological importance. In recent years, coral health has been severely impacted by environmental stressors brought on by human activity and climate change, threatening the extinction of several major reef ecosystems. Reef damage is mediated by a process called coral bleaching where corals, sea anemones, and other cnidarians lose their photosynthetic algal symbionts (genus Symbiodinium) upon stress induction, resulting in drastically decreased host energy harvest and, ultimately, coral death. The mechanism by which this critical cnidarian-algal symbiosis is lost remains poorly understood. Here, we report Traptasia, a simple microfluidic device with multiple traps designed to isolate and image individual live larvae of Aiptasia, a sea anemone model organism, and their algal symbionts over extended time courses. Aiptasia larvae are ~100 m in length, deformable, and highly motile, posing particular challenges for long-term imaging. Using a trap design optimized via fluid flow simulations and polymer bead loading tests, we trapped Aiptasia larvae containing algal symbionts and demonstrated stable imaging for >10 hours. We visualized algal migration within Aiptasia larvae and observed algal expulsion under an environmental stressor. To our knowledge, this device is the first to enable live imaging of cnidarian larvae and their algal symbionts and, in further implementation, could provide important insights into the cellular mechanisms of coral bleaching under different environmental stressors. The device is simple to use, requires minimal external equipment and no specialized training to operate, and can easily be adapted to study a variety of large, motile organisms.

ecology↗

bioRxiv2018

Links between environment, diet, and the hunter-gatherer microbiome

The study of traditional populations provides a view of human-associated microbes unperturbed by industrialization, as well as a window into the microbiota that co-evolved with humans. Here we discuss our recent work characterizing the microbiota from the Hadza hunter-gatherers of Tanzania. We found seasonal shifts in bacterial taxa, diversity, and carbohydrate utilization by the microbiota. When compared to the microbiota composition from other populations around the world, the Hadza microbiota shares bacterial families with other traditional societies that are rare or absent from microbiotas of industrialized nations. We present additional observations from the Hadza microbiota and their lifestyle and environment, including microbes detected on hands, water, and animal sources, how the microbiota varies with sex and age, and the shortterm effects of introducing agricultural products into the diet. In the context of our previously published findings and of these additional observations, we discuss a path forward for future work.

microbiology↗

bioRxiv2018

Microbiota Accessible Carbohydrates Facilitate Clearance of Clostridium difficile

Clostridium difficile (Cd) is an opportunistic diarrheal pathogen and Cd infection (CDI) represents a major healthcare concern, causing an estimated 15,000 deaths per year in the United States alone1. Several enteric pathogens, including Cd, leverage inflammation and the accompanying microbial dysbiosis to thrive in the distal gut2. Although diet is among the most powerful available tools for affecting the health of humans and their relationship with their microbiota, investigation into the effects of diet on CDI has been limited. Here, we show in mice that the consumption of microbiota accessible carbohydrates (MACs) found in dietary plant polysaccharides has a significant impact on CDI. Specifically, using a model of antibiotic-induced CDI that typically resolves within 12 days of infection, we demonstrate that MAC-deficient diets perpetuate CDI. We show that Cd burdens are suppressed through ...

microbiology↗