Biology subjects

Dalal, S.

Publications and source records attributed to Dalal, S..

4 recordsLinked to original sources

bioRxiv2023

Untangling the Role of Pathobionts from Bacteroides Species in Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD) arise from a convergence of underlying genetic susceptibility, environmental factors, and shifts in gut microbiota function and membership. Although the latter may trigger and contribute to IBD, there is little consensus on a specific causative pathogen. In this study, we demonstrate that commensal Bacteroides fragilis strains from ulcerative colitis (UC) patients before and during the development of ileal pouchitis engraft and promote colitis in specific pathogen free (SPF) IL-10 deficient (IL-10-/-) mice, but not in wild type SPF mice or when mono-associated in germ free mice. The colitis in IL-10-/- mice was also associated with significant alterations in commensal microbiota potentially important for maintaining intestinal and immune homeostasis. UC pouchitis B. fragilis also engrafts in DSS-induced colitis in WT SPF mice, indicating a fitness advantage under conditions of mucosal inflammation over other commensals in the gut microbiota. These findings show that gut inflammation promotes the expansion and fitness of UC-derived Bacteroides species that is associated with changes in the SPF gut microbiota and may be promote colitis in genetically susceptible hosts. ImportanceThis study supports the notion that human inflammatory bowel diseases arise from the emergence of indigenous pathobionts in genetically-prone subjects. Colitis-promoting pathobionts are well-suited to establish themselves in the host inflammatory environment and outcompete endogenous microbiota. Once engrafted, the pathobiont can further aggravate inflammation in a genetically-susceptible host. Such complex interplay among several factors creates a vicious pro-inflammatory cycle and promotes disease development. These findings are consistent with our previous clinical observation that B. fragilis, an otherwise low-abundance commensal species, expands prior to the development of UC pouchitis. We believe these findings are relevant to the pathogenesis of UC pouchitis and possibly human inflammatory bowel diseases in general, underscoring the role of commensal to pathobiont transitions, rather than classical pathogens, in promoting and exacerbating the onset of human IBD.

microbiology↗

bioRxiv2023

Microbially-catalyzed conjugation of GABA and tyramine to bile acids

Bile acids (BAs) are cholesterol-derived molecules that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence physiology of the gut microbiota. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate BAs to other amine classes. Here, we show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis (UC) pouchitis, conjugates standard amino acids and the neuroactive amines {gamma}-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended this analysis to other human gut isolates and identified species that are competent to conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and BA-tyramine amides in human stool. A longitudinal metabolomic analysis of J-pouch contents of the patient from whom B. fragilis P207 was isolated revealed highly reduced levels of secondary bile acids and a shifting BA amide profile before, during, and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to GABA and tyramine and demonstrates that these molecules are present in the human gut. ImportanceBile acids (BAs) are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacteria isolated from the gut of human patients that conjugate the neuroactive amines, GABA and tyramine, to BAs and demonstrates that BA-GABA and BA-tyramine amides are present in the human gut. GABA and tyramine are common metabolic products of the gut microbiota and potent neuroactive molecules, and their conjugation to BAs may influence receptor-mediated regulatory mechanisms of humans and their gut microbes.

microbiology↗

bioRxiv2023

Multi-omics analysis of a Bacteroides fragilis isolate from an ulcerative colitis patient defines genetic determinants of fitness in bile

Bacteroides fragilis comprises 1-5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated a B. fragilis strain from a UC patient with pouch inflammation (i.e. pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impact B. fragilis fitness in DC and crude bile. Treatment of B. fragilis with a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems and downregulated protein synthesis genes. Using a barcoded collection of {approx}50,000 unique insertional mutants, we further defined B. fragilis genes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of a B. fragilis bile response and genetic determinants of its fitness in DC and crude bile. ImportanceThe Gram-negative bacterium, Bacteroides fragilis, is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enable B. fragilis to grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for a B. fragilis strain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, where B. fragilis often blooms. Using this resource, we uncovered pathways and processes that impact B. fragilis fitness in bile and that may contribute to population expansions during bouts of gut inflammation.

microbiology↗

bioRxiv2021

The CXCR6/CXCL16 axis links inflamm-aging to disease severity in COVID-19 patients

Advancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+ T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing the CXCR6 gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+ T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

immunology↗