Fecal Stream Diversion Changes Intestinal Environment, Modulates Mucosal Barrier, and Attenuates Inflammatory Cells in Crohn’s Disease

Here we provide compelling evidence that inflammation in a murine model of Crohn’s disease–like inflammation is characterized by an immune reaction presumably directed at a disease-relevant microflora in a genetically susceptible host with impaired mucosal barrier function and bacterial clearance.

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DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab073.061 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S061-S062

Author(s):

P Sudhakar ◽

T Andrighetti ◽

S Verstockt ◽

C Caenepeel ◽

M Ferrante ◽

...

Keyword(s):

Gene Expression ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Molecular Mechanisms ◽

Bacterial Species ◽

Differentially Expressed ◽

Mucosal Barrier ◽

Bacterial Proteins ◽

The Impact ◽

Hub Proteins

Abstract Background Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients. Methods Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of > 2 and Q-value < 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation. Results Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively. Conclusion Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.

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Mo1637 Confocal Endomicroscopy Identifies Intestinal Mucosal Barrier Dysfunction in Macroscopically-Normal Crohn's Disease and Ulcerative Colitis

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2013.03.385 ◽

2013 ◽

Vol 77 (5) ◽

pp. AB454

Author(s):

Brendon Wong ◽

Jim Y. Chen ◽

Edmund Y. Chung ◽

Christian P. Selinger ◽

Viraj C. Kariyawasam ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Mucosal Barrier ◽

Barrier Dysfunction ◽

Intestinal Mucosal Barrier ◽

Confocal Endomicroscopy

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The role of the fecal stream in Crohn's disease: An historical and analytic review

Inflammatory Bowel Diseases ◽

10.1002/ibd.3780040107 ◽

2007 ◽

Vol 4 (1) ◽

pp. 29-39 ◽

Cited By ~ 20

Author(s):

Henry D. Janowitz ◽

Edward C. Croen ◽

David B. Sachar

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Fecal Stream ◽

Analytic Review

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Involvement of interleukin 18 in Crohn's disease: evidence from in vitro analysis of human gut inflammatory cells and from experimental colitis models

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2004.02362.x ◽

2004 ◽

Vol 135 (2) ◽

pp. 310-317 ◽

Cited By ~ 38

Author(s):

P. MAERTEN ◽

C. SHEN ◽

S. COLPAERT ◽

Z. LIU ◽

D. A. M. BULLENS ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Experimental Colitis ◽

Inflammatory Cells ◽

Interleukin 18 ◽

Human Gut ◽

Vitro Analysis ◽

In Vitro Analysis

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Regulated Spatial Distribution of Cyclooxygenases and Lipoxygenases in Crohn's Ulcer

Mediators of Inflammation ◽

10.1155/mi/2006/89581 ◽

2006 ◽

Vol 2006 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Yao Mao ◽

Jian'an Ren ◽

Jieshou Li

Keyword(s):

Arachidonic Acid ◽

Spatial Distribution ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Arachidonic Acid Metabolism ◽

Cyclooxygenase 2 ◽

Bowel Diseases ◽

Acid Pathway

Background and Aims. Arachidonic acid metabolism actively participates in the initiation, climaxing, and resolution phases of inflammation, and its close connection with inflammatory bowel diseases has been only recently discovered. We aimed to clarify the role of different arachidonic pathways and the interrelationships between them in Crohn's disease.Methods. Seventeen specimens of Crohn's disease dated between 2003/1/1 and 2005/1/1 were collected and underwent immunohistochemical analyses with cylcooxygenase 1, cyclooxygenase 2, 5-lipoxygenase, and 15-lipoxygenase-1 antibodies.Results. (1) The spatial distribution of the three leading enzymes in arachidonic acid pathway—cyclooxygenase 2, 5-lipoxygenase, and 15-lipoxygenase-1—followed sequential arrangement in Crohn's ulcer: neutrophils highly expressing 5-lipoxygenase were in the utmost surface which bordered the band of cyclooxygenase-2 expression that is located just beneath it, and in the lower layers and below the granulation region were eosinophils carrying 15-lipoxygeanse-1. (2) Cyclooxygenase-2 and 15-Lipoxygenase-1-positive cells formed two barrier-like structures that possibly inhibited neutrophil infiltration.Conclusion. The regulated distribution indicated coordinated interplay between inflammatory cells and parenchymal cells, between arachidonic acid pathways, and between innate and adaptive immunity; and the barrier-like structures indicated protective roles for cyclooxygenase 2 and 15-Lipoxygenase-1 in Crohn's disease.

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Research Advance in Intestinal Mucosal Barrier and Pathogenesis of Crohn’s Disease

Gastroenterology Research and Practice ◽

10.1155/2016/9686238 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Kuan Wang ◽

Lu-yi Wu ◽

Chuan-zi Dou ◽

Xin Guan ◽

Huan-gan Wu ◽

...

Keyword(s):

Immune Response ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Intestinal Mucosa ◽

Human Body ◽

Crucial Role ◽

Mucosal Barrier ◽

Intestinal Mucosal Barrier ◽

Environment Factors ◽

Research Advance

To date, the etiology and pathogenesis of Crohn’s disease (CD) have not been fully elucidated. It is widely accepted that genetic, immune, and environment factors are closely related to the development of CD. As an important defensive line for human body against the environment, intestinal mucosa is able to protect the homeostasis of gut bacteria and alleviate the intestinal inflammatory and immune response. It is evident that the dysfunction of intestinal mucosa barriers plays a crucial role in CD initiation and development. Yet researches are insufficient on intestinal mucosal barrier’s action in the prevention of CD onset. This article summarizes the research advances about the correlations between the disorders of intestinal mucosal barriers and CD.

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Role of Fecal Diversion in Complex Crohn's Disease

Clinics in Colon and Rectal Surgery ◽

10.1055/s-0039-1683916 ◽

2019 ◽

Vol 32 (04) ◽

pp. 273-279 ◽

Cited By ~ 3

Author(s):

John P. Burke

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Surgical Complication ◽

Fecal Diversion ◽

Fecal Stream ◽

Primary Indication ◽

Chronic Inflammatory Condition ◽

Bowel Continuity ◽

Control Disease

AbstractCrohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract resulting in progressive tissue damage, which can result in strictures, fistulae, and abscesses formation. The triggering mechanism is thought to be in the fecal stream, and diversion of this fecal stream is sometimes required to control disease when all other avenues of medical and surgical management have been exhausted. Fecal diversion can be temporary or permanent with the indications being defunctioning a high-risk anastomosis, as a result of a surgical complication, for disease control, or due to severe colonic, rectal, or perianal disease. The incidence of ostomy formation in CD has increased epidemiologically over time. The primary indication for ostomy formation is severe perianal fistulizing disease. However, while 64% of patients have an early clinical response after diversion for refractory perianal CD, restoration of bowel continuity is attempted in only 35% of patients, and is successful in only 17%. The current review discusses the indications for ostomy creation in complex CD, strategies for procedure selection, and patient outcomes.

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Evaluation of the immunoexpression of COX-1, COX-2 and p53 in Crohn's disease

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032008000400007 ◽

2008 ◽

Vol 45 (4) ◽

pp. 295-300 ◽

Cited By ~ 16

Author(s):

Mônica Romero ◽

Ricardo Artigiani ◽

Henrique Costa ◽

Celina Tizuko Fujiyama Oshima ◽

Sender Miszputen ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Cells ◽

Intraepithelial Lymphocytes ◽

Inflammatory Activity ◽

Control Group ◽

Histopathological Analysis ◽

Cyclooxygenase 1 ◽

Cox 2 ◽

Cox 1

BACKGROUND: Crohn's disease accompanied by nonspecific or idiopathic ulcerative proctocolitis corresponds to a condition called intestinal inflammatory disease. The immunoexpression of cyclooxygenase 2 (COX-2) in Crohn's disease becomes more marked with progression of the disease and the presence of wild-type p53 suppresses the transcription of COX-2. AIMS: To investigate the immunoexpression of cyclooxygenase 1 (COX-1), COX-2 and p53 in Crohn's ileocolitis and to correlated this expression with clinical and histopathological parameters. METHODS: Forty-five cases of Crohn's disease, 16 cases of actinic colitis (diseased-control group) and 11 cases without a history of intestinal disease (normal control group) were studied. Hematoxylin-eosin-stained sections were submitted to histopathological analysis and the immunohistochemical expression of COX-1, COX-2 and p53 was evaluated by the streptavidin-biotin-peroxidase method. RESULTS: Sixty percent of the Crohn's disease patients were women and 40% were men, with 75.5% whites and 25.5% non-whites. The disease involved the terminal ileum in 44.5% of cases, ileum in 33.3%, colon in 20% and duodenum-ileum in 2.2%. A significant association was observed between COX-2 immunoreactivity and age <40 years. Histopathological analysis of Crohn's disease samples showed mild or moderate crypt distortion (57.8% and 35.6% of cases), atrophy (6.6%), mild, moderate and marked chronic inflammation (46.7%, 26.7% and 20%), acute inflammatory activity (93.3%), ulceration (24.4%), mucin depletion (37.8%), Paneth's cells (24.4%), intraepithelial lymphocytes (93.3%), and subepithelial collagen (6.7%). In the CD group, COX-1 immunoreactivity in epithelial and inflammatory cells was observed in 26.7% and 22.2% of cases, respectively. COX-2 immunoreactivity was detected in epithelial cells in 68.9% of cases and in inflammatory cells in 46.7%. A marginal difference in COX-2 reactivity was observed between epithelial and inflammatory cells in association with acute inflammatory activity and increase in intraepithelial lymphocytes. Comparison of the date among the threes groups (Crohn's disease, actinic colitis and normal controls) showed a higher proportion of cases presenting COX-2 immunoreactivity in inflammatory cells in the Crohn's disease group. No p53 reactivity was observed in all cases. CONCLUSIONS: COX-2 immunoexpression is high in Crohn's disease, which suggest a possible role of the protein in the pathogenesis of the inflammation. The absence of epithelial dysplasia in all Crohn's disease samples was correlated with the lack of expression of p53.

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