Comparative genomic analysis of bacteria species

National Library Of Medicine

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Abstract

In the past decade, the amount of microbiome data has grown considerably. These enormous datasets present new challenges and opportunities to understand, and even manipulate, the human microbiome for human health. One of the key challenges is that while metagenomic sequence data can be used to identify correlations between microbiome composition and disease states, they should be analyzed in conjunction with microbiology experiments to reveal the underlying mechanism for the causal relationship. However, microbiologists have generally focused on model species or a few pathogens when they study a function. Therefore, many functions are known in only one or a few species. In this project, we used straightforward comparative genomics to identify these functions across a broad range of species of the gut microbiome. We focused on disease-relevant functions in gut bacteria. We have identified a list of features including presence of certain genes and operons or pathways for investigation. We curated a database of human gut metagenomes by manually examining phenotype information and associated all possible related metadata to the metagenomic sequence data. One of the functions we characterized in gut bacteria is histamine-secretion. Histamine is a biogenic amine that plays an essential physiological role in vascular permeability, mucus secretion, neurotransmission, and allergic response. However, the understanding of exogenous histamine is limited to foodborne poisoning. In this project, we conducted a systematic search for putative histidine-secreting species in 36,554 genomes and then analyzed the relative abundance of histamine-secreting species in the gut microbiome colorectal cancer and inflammatory bowel disease patients. We identified 97 histamine-secreting bacteria that are sporadically distributed across 6 bacterial phyla, 25 % of which are strain specific in histamine-secreting function. Additionally, histamine-secreting bacteria were significantly enriched in the gut microbiome of inflammatory bowel disease patients but not colorectal cancer patients compared to health controls. This work provides a comprehensive understanding of histamine-secreting bacteria in the human gut and advances in potential therapeutic methods/targets toward histamine-related inflammatory and immunological diseases. We continue to characterize the genomic basis of phase-variable antibiotic resistance. Invertible promoter regulating antibiotic resistance genes is a new mechanism for antibiotic-resistant bacteria to mitigate the fitness cost of encoding antibiotic resistance genes in the human gut microbiome. To assess the threat posed by phase-variable antibiotic resistance, we performed a systematic search for invertible promoter regulating antibiotic resistance genes in the human gut microbiome. We identified three classes of invertible promoters regulating antibiotic resistance genes and categorized them into three classes. We found that invertible promoter regulating antibiotic resistance genes are exclusively distributed in Bacteroidales species. They have convergently originated from insertions of antibiotic resistance genes into phase-variable capsule polysaccharide biosynthesis loci at least three times. All three classes of phase-variable ARGs have mobilized via integrative and conjugative elements, which facilitates the dissemination of antibiotic resistance genes and explains their wide taxonomic distribution across Bacteroidales species. Additionally, we have continued our collaboration with Dr. Hall (University of Maryland) and Dr. Gisela Storz (NICHD/DIR). In the project with Dr. Hall, we narrowed down genes of interest by comparative analysis of metagenomic samples with differential metabolite abundance. His lab is working on testing the results in vitro. In the project with Dr. Gisela Storz, we additionally characterized the Rpn gene and found it was frequently associated with selfish genetic elements and predicted the potential function and interaction between different domains of the Rpn gene, providing insight into how the toxin and antitoxin pairs function together.