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Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis.

ABSTRACT: Ulcerative colitis (UC) arises from a complex interplay between host and environmental factors, but with a largely unsolved pathophysiology. The pathophysiology was outlined by RNA-sequencing of mucosal biopsies from non-inflamed and inflamed colon of UC patients (14 and 17, respectively), and from 27 patients without intestinal inflammation. Genes differentially expressed (DE), or present in enriched gene sets, were investigated using statistical text analysis of functional protein information. Compared with controls, inflamed and non-inflamed UC mucosa displayed 9360 and 52 DE genes, respectively. Seventy-three non-pseudogenes were DE relative to both gender and inflammation. Mitochondrial processes were downregulated in inflamed and upregulated in non-inflamed UC mucosa, whereas angiogenesis and endoplasmic reticulum (ER) stress were upregulated in both tissue states. Immune responses were upregulated in inflamed mucosa, whereas the non-inflamed UC mucosa presented both up- and downregulated gene sets. DE and enriched genes overlapped with genes present in inflammatory bowel disease genome-wide associated loci (p = 1.43 × 10^-18), especially regarding immune responses, respiratory chain, angiogenesis, ER stress, and steroid hormone metabolism. Apart from confirming established pathophysiological mechanisms of immune cells, our study provides evidence for involvement of less described pathways (e.g., respiratory chain, ER stress, fatty-acid oxidation, steroid hormone metabolism and angiogenesis).

SUBMITTER: Soderman J

PROVIDER: S-EPMC9266769 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and aims: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls (HC), taken from macroscopically non-inflamed tissue from the terminal ileum and three colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. Methods: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 UC, 26 HC and 14 patients with CrohnM-bM-^@M-^Ys disease. Differential gene expression analysis was performed at each tissue location separately and results were then meta-analysed using FisherM-bM-^@M-^Ys method. Significantly differentially expressed genes were validated using qPCR. Gene location within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. Results: Seven probes were abnormally expressed throughout the colon in UC patients with Family with sequence similarity member 5 C (FAM5C) being the most significantly underexpressed. Attenuated expression of FAM5C in UC was independent of inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy approximately 23 months later. FAM5C is localised to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. Conclusion: Genome-wide expression analysis of non-inflamed mucosal biopsies from UC patients identified FAM5C as significantly under-expressed throughout the colon in a major sub-set of patients with UC. Low levels of this gene could predispose to or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition. Total RNA was extracted from the intestinal biopsies taken from macroscopically normal mucosa in the rectum, descending colon, ascending colon and terminal ileum in clinically quiescent Ulcerative colitis and Crohn's disease patients and compared to healthy controls. Normalized data for 26,261 probes out of 47,323 only. Criteria for inclusion not specified. The non-normalized matrix contains the complete non-normalized data for all probes.

Project description:ObjectiveThe pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC.DesignDeep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.ResultsIn UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.ConclusionWe demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.

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Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis.

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