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All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Preliminary Evidence for Sex-Specific Trends in Probiotic Modulation of Gut Saccharibacteria in Familial Mediterranean Fever Patients: Effects of Lactobacillus acidophilus INMIA 9602 Er 317/402 and Escherichia coli M-17

Candidate Phyla Radiation bacteria are emerging members of the human microbiota, particularly in oral and gut environments. Saccharibacteria were previously identified in the gut microbiota of healthy individuals and women diagnosed with familial Mediterranean fever (FMF), a monogenic autoinflammatory disorder prevalent in the eastern Mediterranean region, including Armenia. This study aimed to assess the prevalence and diversity of Saccharibacteria spp. and its basebiont Schaalia odontolytica in FMF patients, explore gender differences, and evaluate the modulation potential of two locally produced probiotics: Lactobacillus acidophilus INMIA9602 Er317/402 (Narine®, VITAMAX-E, Yerevan, Armenia) and Escherichia coli M-17 (Colibacteron®, VITAMAX-E, Yerevan, Armenia). The abundance and behavior of saccharibacteria and S. odontolytica appear to vary depending on health status and sex. Placebo administration caused both quantitative and qualitative shifts, suggesting a possible interaction between Candidatus saccharibacteria spp. and Schaalia odontolytica, though the underlying biological significance remains to be clarified. Narine administration appeared to increase the abundance of Candidatus saccharibacteria operational taxonomic units (OTUs) in FMF women and S. odontolytica OTUs in FMF men, whereas Colibacteron selectively decreased certain OTUs, predominantly in FMF women. These findings underscore the need to further investigate saccharibacteria’s role in systemic inflammation and probiotic-mediated modulation of the gut microbiota.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Severe, short-term sleep restriction reduces gut microbiota community richness but does not alter intestinal permeability in healthy young men

Sleep restriction alters gut microbiota composition and intestinal barrier function in rodents, but whether similar effects occur in humans is unclear. This study aimed to determine the effects of severe, short-term sleep restriction on gut microbiota composition and intestinal permeability in healthy adults. Fecal microbiota composition, measured by 16S rRNA sequencing, and intestinal permeability were measured in 19 healthy men (mean ± SD; BMI 24.4 ± 2.3 kg/m 2 , 20 ± 2 years) undergoing three consecutive nights of adequate sleep (AS; 7–9 h sleep/night) and restricted sleep (SR; 2 h sleep/night) in random order with controlled diet and physical activity. α-diversity measured by amplicon sequencing variant (ASV) richness was 21% lower during SR compared to AS (P = 0.03), but α-diversity measured by Shannon and Simpson indexes did not differ between conditions. Relative abundance of a single ASV within the family Ruminococcaceae was the only differentially abundant taxon (q = 0.20). No between-condition differences in intestinal permeability or β-diversity were observed. Findings indicated that severe, short-term sleep restriction reduced richness of the gut microbiota but otherwise minimally impacted community composition and did not affect intestinal permeability in healthy young men.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Associations between Frequency of Culinary Herb Use and Gut Microbiota

While evidence suggests that culinary herbs have the potential to modulate gut microbiota, much of the current research investigating the interactions between diet and the human gut microbiome either largely excludes culinary herbs or does not assess use in standard culinary settings. As such, the primary objective of this study was to evaluate how the frequency of culinary herb use is related to microbiome diversity and the abundance of certain taxa, measured at the phylum level. In this secondary data analysis of the INCLD Health cohort, we examined survey responses assessing frequency of culinary herb use and microbiome analysis of collected stool samples. We did not observe any associations between frequency of culinary herb use and Shannon Index, a measure of alpha diversity. Regarding the abundance of certain taxa, the frequency of use of polyphenol-rich herbs and herbs with certain quantities of antibacterial compounds was positively associated with Firmicutes abundance, and negatively associated with Proteobacteria abundance. Additionally, the total number of herbs used with high frequency, defined as over three times per week, was also positively associated with Firmicutes abundance, independent of adjustments, and negatively associated with Proteobacteria abundance, after adjusting for dietary factors. Frequency of culinary herb use was not associated with Bacteroidota or Actinobacteria abundance.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Microbiota functional activity biosensors for characterizing nutrient metabolism in vivo

Methods for measuring gut microbiota biochemical activities in vivo are needed to characterize its functional states in health and disease. To illustrate one approach, an arabinan-containing polysaccharide was isolated from pea fiber, its structure defined, and forward genetic and proteomic analyses used to compare its effects, versus unfractionated pea fiber and sugar beet arabinan, on a human gut bacterial strain consortium in gnotobiotic mice. We produced ‘Microbiota Functional Activity Biosensors’ (MFABs) consisting of glycans covalently linked to the surface of fluorescent paramagnetic microscopic glass beads. Three MFABs, each containing a unique glycan/fluorophore combination, were simultaneously orally gavaged into gnotobiotic mice, recovered from their intestines, and analyzed to directly quantify bacterial metabolism of structurally distinct arabinans in different human diet contexts. Colocalizing pea-fiber arabinan and another polysaccharide (glucomannan) on the bead surface enhanced in vivo degradation of glucomannan. MFABs represent a potentially versatile platform for developing new prebiotics and more nutritious foods.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Swimming and the human microbiome at the intersection of sports, clinical, and environmental sciences: A scoping review of the literature

The human microbiota is comprised of more than 10–100 trillion microbial taxa and symbiotic cells. Two major human sites that are host to microbial communities are the gut and the skin. Physical exercise has favorable effects on the structure of human microbiota and metabolite production in sedentary subjects. Recently, the concept of “athletic microbiome” has been introduced. To the best of our knowledge, there exists no review specifically addressing the potential role of microbiomics for swimmers, since each sports discipline requires a specific set of techniques, training protocols, and interactions with the athletic infrastructure/facility. Therefore, to fill in this gap, the present scoping review was undertaken. Four studies were included, three focusing on the gut microbiome, and one addressing the skin microbiome. It was found that several exercise-related variables, such as training volume/intensity, impact the athlete’s microbiome, and specifically the non-core/peripheral microbiome, in terms of its architecture/composition, richness, and diversity. Swimming-related power-/sprint- and endurance-oriented activities, acute bouts and chronic exercise, anaerobic/aerobic energy systems have a differential impact on the athlete’s microbiome. Therefore, their microbiome can be utilized for different purposes, including talent identification, monitoring the effects of training methodologies, and devising ad hoc conditioning protocols, including dietary supplementation. Microbiomics can be exploited also for clinical purposes, assessing the effects of exposure to swimming pools and developing potential pharmacological strategies to counteract the insurgence of skin infections/inflammation, including acne. In conclusion, microbiomics appears to be a promising tool, even though current research is still limited, warranting, as such, further studies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Subacute safety assessment of recombinant Lactococcus lactis on the gut microbiota of male Sprague–Dawley rats

Abstract BACKGROUND Lactococcus lactis strain pGSMT/MG1363 is a genetically modified microorganism (GMM) that constitutively expresses human metallothionein‐I fusion protein to combine with intracellular lead. Unlike traditional probiotics, pGSMT/MG1363 lacks a history of safe use in food. Administration of microorganism could influence the gut microbial community and consequently confer health benefits or cause disadvantages to the host. To date, little has been done to assess the influence of recombinant strain pGSMT/MG1363 on the stability of gut microbiota. RESULTS Liver, testis and kidney sections of male Sprague–Dawley rats orally administered pGSMT/MG1363 for 6 weeks showed normal structure and no pathological damage. There were no adverse effects on the analyzed serum biochemical parameters between the pGSMT/MG1363 group and the MG1363 group. Principal coordinate analysis showed that, compared with the MG1363 group, the 6‐week‐old fecal gut microbiota of rats fed with pGSMT/MG1363 was not significantly different (Adonis, P = 0.802). pGSMT/MG1363 treatment for 6 weeks did not significantly change the relative abundance of gut microbiota at the phylum and genus levels in comparison with MG1363 treatment. CONCLUSION Compared to the non‐GM strain MG1363 group, administration of the recombinant strain pGSMT/MG1363 for 6 weeks showed no adverse effects on the analyzed physiological parameters and gut microbial compositions of male Sprague–Dawley rats. The results suggested that, in terms of gut microbiota stability, pGSMT/MG1363 could be considered as safe as MG1363, at least for short‐term intake. Further toxicological evaluations still need to be considered before drawing a definite conclusion concerning the safe use of pGSMT/MG1363. © 2021 Society of Chemical Industry.

Chen, Guowei↗
DOE OSTI2020

The Gut Microbiome and Alcoholic Liver Disease: Ethanol Consumption Drives Consistent and Reproducible Alteration in Gut Microbiota in Mice

Phenotypic health effects, both positive and negative, have been well studied in association with the consumption of alcohol in humans as well as several other mammals including mice. Many studies have also associated these same health effects and phenotypes to specific members of gut microbiome communities. Here we utilized a chronic plus binge ethanol feed model (Gao-binge model) to explore microbiome community changes across three independent experiments performed in mice. We found significant and reproducible differences in microbiome community assemblies between ethanol-treated mice and control mice on the same diet absent of ethanol. We also identified significant differences in gut microbiota occurring temporally with ethanol treatment. Peak shift in communities was observed 4 days after the start of daily alcohol consumption. We quantitatively identified many of the bacterial genera indicative of these ethanol-induced shifts including 20 significant genera when comparing ethanol treatments with controls and 14 significant genera based on temporal investigation. Including overlap of treatment with temporal shifts, we identified 25 specific genera of interest in ethanol treatment microbiome shifts. Shifts coincide with observed presentation of fatty deposits in the liver tissue, i.e., Alcoholic Liver Disease-associated phenotype. The evidence presented herein, derived from three independent experiments, points to the existence of a common, reproducible, and characterizable “mouse ethanol gut microbiome”.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

BioTransformer 3.0 – A Web Server for Accurately Predicting Metabolic Transformation Products

BioTransformer 3.0 is a freely available web server that supports accurate, rapid and comprehensive in silico metabolism prediction. It combines machine learning approaches with a rule-based system to predict small-molecule metabolism in human tissues, the human gut as well as the external environment (soil and water microbiota). Simply stated, BioTransformer takes a molecular structure as input (SMILES or SDF) and outputs an interactively viewable/sortable table of the predicted metabolites or transformation products (SMILES, PNG images) along with the enzymes that are predicted to be responsible for those reactions and richly annotated downloadable files (CSV and JSON). The entire process typically takes a few seconds. Previous versions of BioTransformer focused exclusively on predicting the metabolism of xenobiotics (such as plant natural products, drugs, cosmetics and other synthetic compounds) using a limited number of pre-defined steps and somewhat limited rule-based methods. BioTransformer 3.0, uses much more sophisticated methods and incorporates new databases, new constraints and new prediction modules to not only more accurately predict the metabolic transformation products of exogenous xenobiotics but also the transformation products of endogenous metabolites, such as amino acids, peptides, carbohydrates, organic acids, and lipids. BioTransformer 3.0 can also support customized sequential combinations of these transformations along with multiple iterations to simulate multi-step human and/or environmental biotransformation events. Performance tests indicate that BioTransformer 3.0 is 40-50% more accurate, much less prone to combinatorial “explosions” and far more comprehensive in terms of metabolite coverage/capabilities than previous versions of BioTransformer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Presence and Persistence of Putative Lytic and Temperate Bacteriophages in Vaginal Metagenomes from South African Adolescents

The interaction between gut bacterial and viral microbiota is thought to be important in human health. While fluctuations in female genital tract (FGT) bacterial microbiota similarly determine sexual health, little is known about the presence, persistence, and function of vaginal bacteriophages. We conducted shotgun metagenome sequencing of cervicovaginal samples from South African adolescents collected longitudinally, who received no antibiotics. We annotated viral reads and circular bacteriophages, identified CRISPR loci and putative prophages, and assessed their diversity, persistence, and associations with bacterial microbiota composition. Siphoviridae was the most prevalent bacteriophage family, followed by Myoviridae, Podoviridae, Herelleviridae, and Inoviridae. Full-length siphoviruses targeting bacterial vaginosis (BV)-associated bacteria were identified, suggesting their presence in vivo. CRISPR loci and prophage-like elements were common, and genomic analysis suggested higher diversity among Gardnerella than Lactobacillus prophages. We found that some prophages were highly persistent within participants, and identical prophages were present in cervicovaginal secretions of multiple participants, suggesting that prophages, and thus bacterial strains, are shared between adolescents. The number of CRISPR loci and prophages were associated with vaginal microbiota stability and absence of BV. Our analysis suggests that (pro)phages are common in the FGT and vaginal bacteria and (pro)phages may interact.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Identification of a Novel Cobamide Remodeling Enzyme in the Beneficial Human Gut Bacterium Akkermansia muciniphila

The beneficial human gut bacterium Akkermansia muciniphila provides metabolites to other members of the gut microbiota by breaking down host mucin, but most of its other metabolic functions have not been investigated. A. muciniphila strain Muc T is known to use cobamides, the vitamin B 12 family of cofactors with structural diversity in the lower ligand. However, A. muciniphila Muc T is unable to synthesize cobamides de novo, and the specific forms that can be used by A. muciniphila have not been examined. We found that the levels of growth of A. muciniphila Muc T were nearly identical with each of seven cobamides tested, in contrast to nearly all bacteria that had been studied previously. Unexpectedly, this promiscuity is due to cobamide remodeling—the removal and replacement of the lower ligand—despite the absence of the canonical remodeling enzyme CbiZ in A. muciniphila. We identified a novel enzyme, CbiR, that is capable of initiating the remodeling process by hydrolyzing the phosphoribosyl bond in the nucleotide loop of cobamides. CbiR does not share similarity with other cobamide remodeling enzymes or B12-binding domains and is instead a member of the apurinic/apyrimidinic (AP) endonuclease 2 enzyme superfamily. We speculate that CbiR enables bacteria to repurpose cobamides that they cannot otherwise use in order to grow under cobamide-requiring conditions; this function was confirmed by heterologous expression of cbiR in Escherichia coli. Homologs of CbiR are found in over 200 microbial taxa across 22 phyla, suggesting that many bacteria may use CbiR to gain access to the diverse cobamides present in their environment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Exposing new taxonomic variation with inflammation — a murine model-specific genome database for gut microbiome researchers

The murine CBA/J mouse model widely supports immunology and enteric pathogen research. This model has illuminated Salmonella interactions with the gut microbiome since pathogen proliferation does not require disruptive pretreatment of the native microbiota, nor does it become systemic, thereby representing an analog to gastroenteritis disease progression in humans. Despite the value to broad research communities, microbiota in CBA/J mice are not represented in current murine microbiome genome catalogs. Here we present the first microbial and viral genomic catalog of the CBA/J murine gut microbiome. Using fecal microbial communities from untreated and Salmonella-infected, highly inflamed mice, we performed genomic reconstruction to determine the impacts on gut microbiome membership and functional potential. From high depth whole community sequencing (~ 42.4 Gbps/sample), we reconstructed 2281 bacterial and 4516 viral draft genomes. Salmonella challenge significantly altered gut membership in CBA/J mice, revealing 30 genera and 98 species that were conditionally rare and unsampled in non-inflamed mice. Additionally, inflamed communities were depleted in microbial genes that modulate host anti-inflammatory pathways and enriched in genes for respiratory energy generation. Our findings suggest decreases in butyrate concentrations during Salmonella infection corresponded to reductions in the relative abundance in members of the Alistipes. Strain-level comparison of CBA/J microbial genomes to prominent murine gut microbiome databases identified newly sampled lineages in this resource, while comparisons to human gut microbiomes extended the host relevance of dominant CBA/J inflammation-resistant strains. This CBA/J microbiome database provides the first genomic sampling of relevant, uncultivated microorganisms within the gut from this widely used laboratory model. Using this resource, we curated a functional, strain-resolved view on how Salmonella remodels intact murine gut communities, advancing pathobiome understanding beyond inferences from prior amplicon-based approaches. Salmonella-induced inflammation suppressed Alistipes and other dominant members, while rarer commensals like Lactobacillus and Enterococcus endure. The rare and novel species sampled across this inflammation gradient advance the utility of this microbiome resource to benefit the broad research needs of the CBA/J scientific community, and those using murine models for understanding the impact of inflammation on the gut microbiome more generally.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Roundup causes embryonic development failure and alters metabolic pathways and gut microbiota functionality in non-target species

Background: Research around the weedkiller Roundup is among the most contentious of the twenty-first century. Scientists have provided inconclusive evidence that the weedkiller causes cancer and other life-threatening diseases, while industry-paid research reports that the weedkiller has no adverse effect on humans or animals. Much of the controversial evidence on Roundup is rooted in the approach used to determine safe use of chemicals, defined by outdated toxicity tests. We apply a system biology approach to the biomedical and ecological model species Daphnia to quantify the impact of glyphosate and of its commercial formula, Roundup, on fitness, genome-wide transcription and gut microbiota, taking full advantage of clonal reproduction in Daphnia. We then apply machine learning-based statistical analysis to identify and prioritize correlations between genome-wide transcriptional and microbiota changes. Results: We demonstrate that chronic exposure to ecologically relevant concentrations of glyphosate and Roundup at the approved regulatory threshold for drinking water in the US induce embryonic developmental failure, induce significant DNA damage (genotoxicity), and interfere with signaling. Furthermore, chronic exposure to the weedkiller alters the gut microbiota functionality and composition interfering with carbon and fat metabolism, as well as homeostasis. Using the “Reactome,” we identify conserved pathways across the Tree of Life, which are potential targets for Roundup in other species, including liver metabolism, inflammation pathways, and collagen degradation, responsible for the repair of wounds and tissue remodeling. Conclusions: Our results show that chronic exposure to concentrations of Roundup and glyphosate at the approved regulatory threshold for drinking water causes embryonic development failure and alteration of key metabolic functions via direct effect on the host molecular processes and indirect effect on the gut microbiota. The ecological model species Daphnia occupies a central position in the food web of aquatic ecosystems, being the preferred food of small vertebrates and invertebrates as well as a grazer of algae and bacteria. The impact of the weedkiller on this keystone species has cascading effects on aquatic food webs, affecting their ability to deliver critical ecosystem services.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Effect of in utero and lactational exposure to antiretroviral therapy on the gut microbial composition and metabolic function in aged rat offspring

Despite the highly effective impact of antiretroviral therapy (ART) in reducing mother-to-child transmission of human immunodeficiency virus (HIV), there are concerns of long-term impacts of ART on the health of the offspring. The implications of perinatal exposure to antiviral drugs on the gut bacterial population and metabolic function in the offspring is unclear but may influence health outcomes given the various reported effects of the microbiome in human health. This study aims to gain insight into the potential effect ofin uteroand lactational exposure to ART on gut microbiota populations and short‐chain fatty acids (SCFAs) production in aged rat offspring. Pregnant rats were administered a combination of antiretroviral drugs (abacavir/dolutegravir/lamivudine) at two different dose levels during gestation and throughout lactation, and the fecal bacterial abundance and SCFA levels of the offspring were analyzed when they reached 12 months of age. Our results showed dose-dependent and sex-based differences in fecal microbial abundance at various taxonomic levels. Specifically, we found a decline inFirmicutesin males, and an increase inActinobacteriaamong males and females. Furthermore, a sex-specific distribution reorganization ofLactobacillus,Bifidobacterium, andAkkermansiawas identified. No significant difference in the concentration of prominent SCFAs and IgA levels were identified. These findings provide preliminary information indicating the need to evaluate perinatal effects of ART more comprehensively on the gut bacterial and metabolic function in future studies, and their potential role in offspring health outcomes.

Research & Experimental Medicine↗
DOE OSTI2022

Prospective Study Reveals Host Microbial Determinants of Clinical Response to Fecal Microbiota Transplant Therapy in Type 2 Diabetes Patients

Increasing evidence shows that alterations in gut microbiome (GM) contribute to the development of type 2 diabetes mellitus (T2DM), and fecal microbiota transplantation (FMT) successfully treats various human diseases. However, the benefits of FMT therapy to T2DM patients remain unknown. We enrolled 17 patients with T2DM for nonblinded, one-armed intervention trial of FMT. A total of 20 healthy individuals were recruited as the baseline control. HbA1c% and metabolic parameter change were evaluated in 17 T2DM patients 12 weeks after they received FMT from healthy donors. The GM composition was characterized by 16S rRNA gene amplicon sequencing from fecal samples prior to and 12 weeks after FMT treatment. We found that the GM of T2DM patients was reconstituted by FMT. We observed a statistically significant decrease in HbA1c% (from 7.565 ± 0.148 to 7.190 ± 0.210, p<0.01), blood glucose (from 8.483 ± 0.497 to 7.286 ± 0.454 mmol/L, p<0.01), and uric acid (from 309.4 ± 21.5 to 259.1 ± 15.8 µmol/L, p<0.01) while a significant increase in postprandial C-peptide (from 4.503 ± 0.600 to 5.471 ± 0.728 ng/ml, p<0.01) at 12 weeks after FMT. Closely evaluating the changes in these assays, we found individual variability in response to FMT treatment. Out of 17 T2DM patients, 11 were found to significantly improve T2DM symptoms. The FMT responders have significantly higher levels of the family Rikenellaceae and the genus Anaerotruncus (family Ruminococcaceae) in their pretreated fecal in comparison to nonresponders, which could predict the clinical response with an area under the curve of 0.83. Our findings suggest that certain T2DM patients can potentially benefit from FMT, and the pretreated abundance of Rikenellaceae and Anaerotruncus in the fecal of patients may serve as potential biomarkers for selecting T2DM patients to receive FMT.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Metagenomic Alterations in Gut Microbiota Precede and Predict Onset of Colitis in the IL10 Gene-Deficient Murine Model

SUMMARY. Currently, predictive markers for the development andcourse of inflammatory bowel diseases (IBD) are not available. This study supports the notion that gut microbiome metagenomic profiles could be developed into a useful tool to assess risk and manage human IBD. BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive bio-markers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts. METHODS: Using the interleukin (IL) 10 gene-deficient (IL10KO) murine model where early life dysbiosis from antibiotic (cefoperozone [CPZ]) treated dams vertically transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to even-tual clinical outcomes. RESULTS: Compared to controls, offspring acquiring maternalCPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership in both bacteriome and mycobiome that was associated with alterations in specific functional subsystems. Furthermore, among IL10 KO offspring fromCPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome. CONCLUSIONS: Our findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Antibiotic resistance and host immune system-induced metal bactericidal control are key factors for microbial persistence in the developing human preterm infant gut microbiome

The human gut microbiome, which develops and stabilizes during the early stages of infant life, plays an essential role in host health through the production of metabolic resources and the stimulation and training of the immune system. To study colonization and community functional dynamics of the microbiota based on responses to host immune processes during the normal and dysbiotic establishment of the gut, metaproteomics was conducted on 91 fecal samples collected over the first 90 days of life from 17 hospitalized premature infants. Microbial responses to antibiotic administration and host-imposed metal bactericidal control correlated with community assembly and resiliency of microbes in the developing preterm gut. Specifically, proteins related to antibiotic resistance and metal homeostasis mechanisms were predominant in persisting members in the infant gut environment over the first several weeks of life. Overall, this metaproteomics study provides a unique approach to examine the temporal expansion and resilience of microbial colonization, as it allows simultaneous examination of both host and microbial metabolic activities. Understanding the interplay between host and microbes may elucidate the microbiome’s potential immunomodulatory roles relevant to necrotizing enterocolitis and other dysbiotic conditions in preterm infants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A small molecule inhibitor prevents gut bacterial genotoxin production

Abstract The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.

Biochemistry & Molecular Biology↗
DOE OSTI2020

CeMbio - The Caenorhabditis elegans Microbiome Resource

The study of microbiomes by sequencing has revealed a plethora of correlations between microbial community composition and various life-history characteristics of the corresponding host species. However, inferring causation from correlation is often hampered by the sheer compositional complexity of microbiomes, even in simple organisms. Synthetic communities offer an effective approach to infer cause-effect relationships in host-microbiome systems. Yet the available communities suffer from several drawbacks, such as artificial (thus non-natural) choice of microbes, microbe-host mismatch (e.g., human microbes in gnotobiotic mice), or hosts lacking genetic tractability. Here we introduce CeMbio, a simplified natural Caenorhabditis elegans microbiota derived from our previous meta-analysis of the natural microbiome of this nematode. The CeMbio resource is amenable to all strengths of the C. elegans model system, strains included are readily culturable, they all colonize the worm gut individually, and comprise a robust community that distinctly affects nematode life-history. Several tools have additionally been developed for the CeMbio strains, including diagnostic PCR primers, completely sequenced genomes, and metabolic network models. With CeMbio, we provide a versatile resource and toolbox for the in-depth dissection of naturally relevant host-microbiome interactions in C. elegans.

59 BASIC BIOLOGICAL SCIENCES↗