Disease Severity and Immune Activity Relate to Distinct Interkingdom Gut Microbiome States in Ethnically Distinct Ulcerative Colitis Patients

Abstract

Significant gut microbiota heterogeneity exists among ulcerative colitis (UC) patients, though the clinical implications of this variance are unknown. We hypothesized that ethnically distinct UC patients exhibit discrete gut microbiotas with unique metabolic programming that differentially influence immune activity and clinical status. Using parallel 16S rRNA and internal transcribed spacer 2 sequencing of fecal samples (UC, 30; healthy, 13), we corroborated previous observations of UC-associated bacterial diversity depletion and demonstrated significant Saccharomycetales expansion as characteristic of UC gut dysbiosis. Furthermore, we identified four distinct microbial community states (MCSs) within our cohort, confirmed their existence in an independent UC cohort, and demonstrated their coassociation with both patient ethnicity and disease severity. Each MCS was uniquely enriched for specific amino acid, carbohydrate, and lipid metabolism pathways and exhibited significant luminal enrichment of the metabolic products of these pathways. Using a novel ex vivo human dendritic cell and T-cell coculture assay, we showed that exposure to fecal water from UC patients caused significant Th2 skewing in CD4+ T-cell populations compared to that of healthy participants. In addition, fecal water from patients in whom their MCS was associated with the highest level of disease severity induced the most dramatic Th2 skewing. Combined with future investigations, these observations could lead to the identification of highly resolved UC subsets based on defined microbial gradients or discrete microbial features that may be exploited for the development of novel, more effective therapies.

Predictive Metagenomic Analysis of Autoimmune Disease Identifies Robust Autoimmunity and Disease Specific Microbial Signatures

“…We were able to recapitulate major findings from all studies. For example, we identified disease-specific alterations in multiple studies in Akkermansia 39,31 24,40,39,33,20 and Streptococcus 34 (Fig. 2).…”

“…Following quality control (QC) and filtering, 20 16S rRNA studies remained for downstream analysis (Fig. 1) 19,20,[22][23][24][26][27][28]30,31,[33][34][35][36][37][38][39][40]46,47 . Notably, 8 out of the 20 studies used investigated the role of the human gut microbiome in IBD, due in part to its relatively high prevalence in 1.3% of US adults 48 .…”

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

“…The majority of these studies revealed a decrease in overall bacterial diversity in NAFLD, similar to that reported in obesity. (80) However, as for other chronic diseases, (81)(82)(83) human microbiome studies in NAFLD have not identified a unique microbial signature. The most consistent finding among studies is that higher disease severity, and in particular advanced fibrosis, is associated with enrichment of members of the Bacteroides and Escherichia genera.…”

Acetylcholinesterase Inhibitor Pyridostigmine Bromide Attenuates Gut Pathology and Bacterial Dysbiosis in a Murine Model of Ulcerative Colitis

“…UC is rarely observed in smokers, as nicotine/nicotinic receptor agonists suppress colitis [4]; however, the mechanism by which cigarette smoke/nicotine suppresses the development of UC is unclear. UC is primarily a Th2-mediated IBD associated with eosinophilic infiltration and overproduction of Th2 chemokines/cytokines including eotaxin (CCL11), IL-5, and IL-13 [5][6][7]. In animal models, activation of pulmonary nicotinic acetylcholine receptors (nAChRs) moderates eosinophilic infiltration through suppression of Th2 responses [8].…”

“…MUC2, the predominant mucin in the gut, plays a critical role in gut homeostasis, and MUC2deficient mice develop colitis spontaneously [13]; however, unlike MUC5AC in bronchial epithelial cells [14], IL-13 does not always stimulate MUC2 [15]. UC also affects gut microbiota and the integrity of the epithelial barrier in the colon [2,5,6]; thus normal fecal microbial transplantation is a promising treatment for UC [16,17]. As DSS has been found to induce UC-like conditions in a mouse model [18,19], in this study we examined whether PB attenuated DSSinduced colon pathology in C57BL/6 mice.…”