Biology subjects

Rodionov, D. A.

Publications and source records attributed to Rodionov, D. A..

9 recordsLinked to original sources

bioRxiv2026

Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth

Defining mechanisms used by gut microbiota to control anti-tumor immunity may offer novel therapeutic modalities. Here, we demonstrate that Bacteroides rodentium and closely related Bacteroides uniformis species induce anti-tumor immunity and limit melanoma development when colonized in either germ-free (GF) mice, mice with a complex microbiome, or WT mice. Enhanced CD8+ T cell infiltration seen in tumors of mice harboring B. rodentium coincided with increased expression of immune-stimulating pathways and activation of bone marrow-derived dendritic cells that were co-cultured with the B. rodentium secretome. Metabolomic analyses of cecal samples from GF mice colonized with Altered Shedlar Flora (ASF) plus B. rodentium revealed lower tryptophan levels than in ASF-colonized controls, and WT mice fed a tryptophan-deficient diet exhibited inhibition of melanoma development. In silico genomic reconstruction of metabolic pathways revealed that both B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic amino transferase (ArAT) genes, both of which function in tryptophan degradation. Administration of a B. uniformis harboring TnaA mutant failed to inhibit melanoma growth in gnotobiotic mice. Notably, administration of indoles, but not kynurenines, also effectively inhibited melanoma development, increasing immune cell infiltration into the tumors. Correspondingly, levels of bacterially encoded tryptophan-degrading enzymes were higher in cohorts of melanoma patients responding to immune checkpoint blockade. These findings highlight a novel mechanism of anti-tumor immunity and tumor growth inhibition dependent on the tryptophan degradation products, indoles, produced by intestinal Bacteroides species.

cancer biology↗

bioRxiv2025

Exploring Population Differences in the Human Gut Microbiome: from Microbial Abundance to Single Nucleotide Polymorphisms

The human gut microbiota exhibits significant diversity across populations, influenced by factors such as geography, diet, and lifestyle, particularly between the Han Chinese and non-Chinese populations. While previous studies have predominantly focused on the taxonomic abundance of the gut microbiome, the impact of single nucleotide polymorphisms (SNPs) in driving population-specific differences remains largely underexplored. In this study, we systematically investigated gut microbial differences between the Han Chinese and non-Chinese populations using the Human Gut Microbiome Reference Genome Catalog (HGMRGC). HGMRGC includes 271,480 non-redundant genomes from 5,785 prokaryotic species, which was generated by metagenomic sequencing data from 9,320 publicly available samples across 22 countries and 3,584 newly sequenced samples from Han Chinese individuals across 29 provinces and regions in China. We observed geography was the primary driver of microbial variation of abundance and SNPs. We identified 625 novel population-specific genome clusters from HGMRGC with functional differences in carbohydrate utilization and 126 species exhibiting distinct prevalence related to vitamin biosynthesis, antibiotic resistance, and carbohydrate metabolism. Beta diversity analysis highlighted significant inter-population differences in both microbial abundance and SNPs, while alpha diversity analysis revealed that non-Chinese populations exhibited higher diversity in microbial abundance, and Han Chinese populations displayed greater diversity in SNPs. These results provide valuable insights into population-specific microbial diversity, laying the groundwork for future research on its functional and health implications.

microbiology↗

bioRxiv2024

Effects of intergenerational transmission of small intestinal bacteria cultured from stunted Bangladeshi children with enteropathy

Environmental enteric dysfunction (EED), a small intestinal disorder found at a high prevalence in stunted children, is associated with gut mucosal barrier disruption and decreased absorptive capacity1-4. To test the hypothesis that intergenerational transmission of a perturbed small intestinal microbiota contributes to undernutrition by inducing EED5, we characterized two consortia of bacterial strains cultured from duodenal aspirates from stunted Bangladeshi children with EED - one of which induced local and systemic inflammation in female gnotobiotic mice. Offspring of dams colonized with the inflammatory consortium exhibited impaired prenatal and postnatal growth, as well as immunologic changes phenocopying features of EED in children. Dam-to-pup transmission of the inflammatory consortium produced, in recently weaned offspring, alterations in inter-cellular signaling pathways related to intestinal epithelial cell renewal, barrier integrity and immune function. Cohousing of mice harboring the inflammatory or non-inflammatory consortia and subsequent screening of candidate disease-promoting bacterial isolates identified Campylobacter concisus, an organism typically found in the oral microbiota, as a contributor to enteropathy. The C. concisus strain induced, in a host nitric oxide synthase (NOS)-dependent manner, pro-inflammatory cytokine signaling. Moreover, host-derived nutrients generated by NOS augmented C. concisus growth. This preclinical model should facilitate identification of small intestinal microbiota-targeted therapeutics for (intergenerational) undernutrition.

systems biology↗

bioRxiv2024

Integrative genomic reconstruction of carbohydrate utilization networks in bifidobacteria: global trends, local variability, and dietary adaptation

Bifidobacteria are among the earliest colonizers of the human gut and are widely used as probiotics for their health-promoting properties. However, individual responses to probiotic supplementation may vary with strain type(s), microbiota composition, diet, or lifestyle conditions, highlighting the need for strain-level insights into the bifidobacterial metabolism of dietary and host glycans. Here, we systematically reconstructed 68 pathways involved in the utilization of mono-, di-, oligo-, and polysaccharides by analyzing the distribution of 589 curated metabolic functional roles (catabolic enzymes, transporters, transcriptional regulators) in 3083 non-redundant cultured Bifidobacterium isolates and metagenome-assembled genomes (MAGs) of human origin. Our analysis uncovered extensive inter- and intraspecies heterogeneity, including a distinct clade within the Bifidobacterium longum species capable of metabolizing -glucans. We also identified isolates of Bangladeshi origin that harbor unique gene clusters implicated in the breakdown of xyloglucan and human milk oligosaccharides. Thirty-eight predicted carbohydrate utilization phenotypes were experimentally validated in 30 geographically diverse Bifidobacterium isolates in vitro. Our large-scale genomic compendium expands the knowledge of bifidobacterial carbohydrate metabolism and can inform the rational design of probiotic and synbiotic formulations tailored to strain-specific nutrient preferences.

microbiology↗

bioRxiv2023

Prevotella copri-linked effects of a therapeutic food for malnutrition

Preclinical and clinical studies are providing evidence that the healthy growth of infants and children reflects, in part, healthy development of their gut microbiomes1-5. This process of microbial community assembly and functional maturation is perturbed in children with acute malnutrition. Gnotobiotic animals, colonized with microbial communities from children with severe and moderate acute malnutrition, have been used to develop microbiome-directed complementary food (MDCF) formulations for repairing the microbiomes of these children during the weaning period5. Bangladeshi children with moderate acute malnutrition (MAM) participating in a previously reported 3-month-long randomized controlled clinical study of one such formulation, MDCF-2, exhibited significantly improved weight gain compared to a commonly used nutritional intervention despite the lower caloric density of the MDCF6. Characterizing the metagenome assembled genomes (MAGs) of bacterial strains present in the microbiomes of study participants revealed a significant correlation between accelerated ponderal growth and the expression by two Prevotella copri MAGs of metabolic pathways involved in processing of MDCF-2 glycans1. To provide a direct test of these relationships, we have now performed reverse translation experiments using a gnotobiotic mouse model of mother-to-offspring microbiome transmission. Mice were colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains cultured from Bangladeshi infants/children in the study population, with or without P. copri isolates resembling the MAGs. By combining analyses of microbial community assembly, gene expression and processing of glycan constituents of MDCF-2 with single nucleus RNA-Seq and mass spectrometric analyses of the intestine, we establish a principal role for P. copri in mediating metabolism of MDCF-2 glycans, characterize its interactions with other consortium members including Bifidobacterium longum subsp. infantis, and demonstrate the effects of P. copri-containing consortia in mediating weight gain and modulating the activities of metabolic pathways involved in lipid, amino acid, carbohydrate plus other facets of energy metabolism within epithelial cells positioned at different locations in intestinal crypts and villi. Together, the results provide insights into structure/function relationships between MDCF-2 and members of the gut communities of malnourished children; they also have implications for developing future prebiotic, probiotic and/or synbiotic therapeutics for microbiome restoration in children with already manifest malnutrition, or who are at risk for this pervasive health challenge.

microbiology↗

bioRxiv2023

CyuR is a Dual Regulator for L-Cysteine Dependent Antimicrobial Resistance in Escherichia coli

Hydrogen sulfide (H2S), mainly produced from L-cysteine (Cys), renders bacteria highly resistant to oxidative stress. This mitigation of oxidative stress was suggested to be an important survival mechanism to achieve antimicrobial resistance (AMR) in many pathogenic bacteria. CyuR (known as DecR or YbaO) is a recently characterized Cys-dependent transcription regulator, responsible for the activation of the cyuAP operon and generation of hydrogen sulfide from Cys. Despite its potential importance, the regulatory network of CyuR remains poorly understood. In this study, we investigated the roles of the CyuR regulon in a Cys-dependent AMR mechanism in E. coli strains. We found: 1) Cys metabolism has a significant role in AMR and its effect is conserved in many E. coli strains, including clinical isolates; 2) CyuR negatively controls the expression of mdlAB encoding a transporter that exports antibiotics such as cefazolin and vancomycin; 3) CyuR binds to a DNA sequence motif GAAwAAATTGTxGxxATTTsyCC in the absence of Cys, confirmed by an in vitro binding assay; and 4) CyuR may regulate 25 additional genes as suggested by in silico motif scanning and transcriptome sequencing. Collectively, our findings expanded the understanding of the biological roles of CyuR relevant to antibiotic resistance associated with Cys.

systems biology↗

bioRxiv2022

Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria is Governed by a Global Transcriptional Regulator NagR

Bifidobacterium longum subsp. infantis (B. infantis) is a prevalent beneficial bacterium that colonizes the human neonatal gut and is uniquely adapted to efficiently use human milk oligosaccharides (HMOs) as a carbon and energy source. Multiple studies have focused on characterizing the elements of HMO utilization machinery in B. infantis; however, the regulatory mechanisms governing the expression of these catabolic pathways remain poorly understood. A bioinformatic regulon reconstruction approach used in this study implicated NagR, a transcription factor from the ROK family, as a negative global regulator of genomic loci encoding lacto-N-biose/galacto-N-biose (LNB/GNB), lacto-N-tetraose (LNT), and lacto-N-neotetraose (LNnT) utilization pathways in B. infantis. This conjecture was corroborated by transcriptome profiling upon nagR genetic inactivation and experimental assessment of binding of recombinant NagR to predicted DNA operators. The latter approach also implicated N-acetylglucosamine (GlcNAc), a universal intermediate of LNT and LNnT catabolism, and its phosphorylated derivatives as plausible NagR transcriptional effectors. Reconstruction of NagR regulons in various Bifidobacterium lineages revealed multiple regulon expansion events, suggesting evolution from a local regulator of GlcNAc catabolism in ancestral bifidobacteria to a global regulator controlling foraging of mixtures of GlcNAc-containing host-derived glycans in mammalian gut-colonizing B. infantis and Bifidobacterium bifidum. ImportanceThe predominance of bifidobacteria in the gut of breastfed infants is attributed to the ability of these bacteria to utilize human milk oligosaccharides (HMOs). Thus, individual HMOs such as lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) are considered promising prebiotics that would stimulate the growth of bifidobacteria and confer multiple health benefits to preterm and malnourished children suffering from impaired (stunted) gut microbiota development. However, the rational selection of HMO-based prebiotics is hampered by the incomplete knowledge of regulatory mechanisms governing HMO utilization in target bifidobacteria. This study describes NagR-mediated transcriptional regulation of LNT and LNnT utilization in Bifidobacterium longum subsp. infantis. The elucidated regulatory network appears optimally adapted to simultaneous utilization of multiple HMOs, providing a rationale to add HMO mixtures (rather than individual components) into infant formulas. The study also provides insights into the evolutionary trajectories of complex regulatory networks controlling carbohydrate metabolism in bifidobacteria.

microbiology↗

bioRxiv2021

A systems approach discovers the role and characteristics of seven LysR type transcription factors in Escherichia coli

Although Escherichia coli K-12 strains represent perhaps the best known model bacteria, we do not know the identity or functions of all of their transcription factors (TFs). It is now possible to systematically discover the physiological function of TFs in E. coli BW25113 using a set of synergistic methods; including ChIP-exo, growth phenotyping, conserved gene clustering, and transcriptome analysis. Among 47 LysR-type TFs (LTFs) found on the E. coli K-12 genome, many regulate nitrogen source utilization or amino acid metabolism. However, 19 LTFs remain unknown. In this study, we elucidated the regulation of seven of these 19 LTFs: YbdO, YbeF, YgfI, YiaU, YneJ, YcaN, YbhD. We show that: 1) YbdO regulation has an effect on bacterial growth at low pH with citrate supplementation. YbdO is a repressor of the ybdNM operon and is implicated in the regulation of citrate lyase genes (citCDEFG); 2) YgfI activates the dhaKLM operon that encodes the phosphotransferase system involved in glycerol and dihydroxyacetone utilization; 3) YiaU regulates the yiaT gene encoding an outer membrane protein, and waaPSBOJYZU operon is also important in determining cell density at the stationary phase; 4) YneJ, re-named here as PtrR, directly regulates the expression of the succinate-semialdehyde dehydrogenase, Sad (also known as YneI), and is a predicted regulator of fnrS (a small RNA molecule). PtrR is important for bacterial growth in the presence of L-glutamate and putrescine as nitrogen sources; and 5) YbhD and YcaN regulate adjacent y-genes on the genome and YbeF is involved in flagella gene regulation. We have thus established the functions for four LTFs and identified the target genes for three LTFs. IMPORTANCEThe reconstruction of the transcriptional regulatory network (TRN) is important for gram-negative bacteria such as E. coli. LysR-type TFs are abundant in Enterobacteria, but many LTF functions still remain unknown. Here we report putative functions of uncharacterized TFs based on multi-omics data related to L-threonine, L-glutamate, and putrescine utilization. Amino acids (AAs) and polyamines are important sources of nitrogen for many microorganisms, but the increase in one amino acid or putrescine concentration in a minimal medium also induces stress. Although polyamine metabolism has been studied, the TRN that controls the putrescine (Ptr) and AA utilization at minimal medium conditions are still poorly understood. The function of previously uncharacterized transcriptional regulators YbdO, YgfI, and YneJ (PtrR) were identified in Escherichia coli. PtrR is important for Ptr and L-glutamate utilization, while YgfI transcriptional regulation was found to be important for growth on L-threonine and glycerol as a carbon source.

systems biology↗

bioRxiv2020

Synthesis of the novel transporter YdhC, is regulated by the YdhB transcription factor controlling adenosine and adenine uptake.

The YdhB transcriptional factor, re-named here AdnB, homologous to the allantoin regulator, AllS, was shown to regulate ydhC gene expression in Escherichia coli, which is divergently transcribed from adnB, and this gene arrangement is conserved in many Protreobacteria. The predicted consensus DNA binding sequence for YdhB is also conserved in Entrobacterial genomes. RNA-seq data confirmed the activation predicted due to the binding of AdnB as shown by Chip-Exo results. Fluorescent polarization experiments revealed binding of YdhB to the predicted binding site upstream of ydhC in the presence of 0.35 mM adenine, but not in its absence. The E. coli MG1655, strain lacking the ydhB gene, showed a lower level of ydhC mRNA in cells grown in M9-glucose supplemented with 2 mM adenosine. Adenosine and adenine are products of purine metabolism and provide sources of ammonium for many organisms. They are utilized under nitrogen starvation conditions as single nitrogen sources. Deletion of either the ydhC or the ydhB gene leads to a substantially decreased growth rate for E. coli in minimal M9 medium with glycerol as the carbon source and adenosine or adenine as the single nitrogen source. The ydhC mutant showed increased resistance to Paromomycine, Sulfathiazole and Sulfamethohazole using Biolog plates. We provide evidence that YdhB, (a novel LysR family regulator) activates expression of the ydhC gene, encoding a novel adenosine/adenine transporter in E. coli. The YdhB binding consensus for different groups of Enterobacteria was predicted.

microbiology↗