Bacterial Translocation as Inflammatory Driver in Crohn’s Disease

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.

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T300A GENETIC POLYMORPHISM: a susceptibility factor for Crohn’s disease?

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032014000200005 ◽

2014 ◽

Vol 51 (2) ◽

pp. 97-101 ◽

Cited By ~ 5

Author(s):

Bruno Lorenzo SCOLARO ◽

Emily dos SANTOS ◽

Leslie Ecker FERREIRA ◽

Paulo Henrique Condeixa de FRANÇA ◽

Harry KLEINUBING ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Fragment Length Polymorphism ◽

Control Group ◽

Polymorphism Analysis ◽

Inflammatory Disorder ◽

Increased Risk ◽

Polymerase Chain ◽

Increased Susceptibility

ContextCrohn’s disease is characterized by a chronic and debilitating inflammatory disorder of the gastrointestinal tract. Several factors may contribute to its development. From extensive studies of the human genome, the polymorphism T300A of the gene ATG16L1 (autophagy-related 16-like 1) has been related to increased risk of developing this disease.ObjectivesAnalyze the role of polymorphism T300A (rs2241880) in patients with Crohn’s disease.Methods238 samples from (control group) and 106 samples from patients with Crohn’s disease recruited at five Southern Brazilian reference centers were evaluated. The genotyping consisted of the amplification via Polymerase Chain Reaction of the genomic segment encompassing T300A, followed by Restriction Fragment Length Polymorphism analysis. The amplicons and fragments were separated by agarose gel electrophoresis and confirmed under ultraviolet light.ResultsThe genotype AG was more prevalent among patients and controls (50% vs 44.8%), followed by genotypes AA (26.4% vs 35.1%) and GG (23.6% vs 20.1%). The frequency of the allele G of the polymorphism T300A was higher in the group of patients with Crohn’s disease (48.6%) than in controls (42.4%), although not reaching statistical significance.ConclusionsIt was not possible to confirm the increased susceptibility on development of Crohn’s disease conferred by polymorphism T300A.

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Journey through Crohn’s Disease Complication: From Fistula Formation to Future Therapies

Journal of Clinical Medicine ◽

10.3390/jcm10235548 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5548

Author(s):

Federica Rubbino ◽

Luana Greco ◽

Alessio di Cristofaro ◽

Federica Gaiani ◽

Stefania Vetrano ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Perianal Fistula ◽

Fistula Formation ◽

Surgical Approaches ◽

Molecular Characteristics ◽

Inflammatory Disorder ◽

Mesenchymal Transition ◽

Chronic Inflammatory Disorder ◽

Increased Risk

Crohn’s Disease (CD) is a chronic inflammatory disorder in which up to 50% of patients develop fistula within 20 years after the initial diagnosis, and half of these patients suffer perianal fistulizing disease. The etiopathogenesis of CD-related perianal fistula is still unclear, and its phenotypical and molecular characteristics are even more indefinite. A better understanding would be crucial to develop targeted and more effective therapeutic strategies. At present, the most accredited theory for the formation of CD-related fistula identifies the epithelial-to-mesenchymal transition (EMT) as the driving force. It has been well recognized that CD carries an increased risk of malignancy, particularly mucinous adenocarcinoma is often associated with long-standing fistula in CD patients. Despite the availability of multiple treatment options, perianal fistulizing CD represents a therapeutic challenge and is associated with an important impact on patients’ quality of life. To date, the most effective management is multidisciplinary with the cooperation of gastroenterologists, surgeons, radiologists, and nutritionists and the best recommended treatment is a combination of medical and surgical approaches.

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P001 Succinate, a gut microbiota-derived metabolite, modulates the inflammatory status of the creeping fat in Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.130 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S123-S123

Author(s):

C Serena ◽

D Monfort-Ferre ◽

M Bautista ◽

M Menacho ◽

M Martí ◽

...

Keyword(s):

Adipose Tissue ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Response ◽

Intestinal Barrier ◽

Fine Tuning ◽

Clinical Activity ◽

Faecal Calprotectin ◽

Inflammatory Status ◽

Adipose Tissue Dysfunction

Abstract Background Crohn’s disease [CD] is characterized by severe transmural inflammation with subsequent destruction of the intestinal barrier. Recent works suggest that bacterial infiltration across this leaky gut facilitates access to the mesenteric fat and the development of a subsequent inflammatory reaction in the surrounding adipose tissue named creeping fat [CF]. Dysbiosis in CD patients has been associated with an increase in succinate-producing bacteria and a decrease in succinate-consuming bacteria. In fact, elevated succinate levels have been found in the intestinal and faeces of CD patients. Succinate has been classically considered as a marker of hypoxia and tissue damage, assisting as a pro-inflammatory signal that triggers immune activation. However, recent observations support potential additional functions of succinate. We and others have shown that succinate plays a key role in fine-tuning of the inflammatory response, acting both as an alarmin and resolving molecule. Our hypothesis is that succinate, a microbiota-derived metabolite, is a new determinant of adipose tissue dysfunction in CD. Methods A well-characterized cohort was used to obtained mesenteric adipose tissue biopsies including a) 10 subjects with active CD that require surgery for their underlying pathology b) 10 subjects with inactive CD and c) 10 healthy controls undergoing surgery for non-acute process (herniorrhaphy, cholecystectomy for lithiasis, etc.). The groups were comparable in age, sex, and body mass index. We studied the effect of exogenous succinate in adipose tissue explants, adipose-stem cells (ASC), and adipose tissue macrophages (ATM) isolated from adipose tissue biopsies of CD patients with different clinical activity. Circulating succinate levels and inflammatory variables including hs-CRP and faecal calprotectin were also measured. Results We observed an increased expression of SUCNR1 in CF, including ASCs and ATMs, mainly in patients suffering from an active disease (figure 1A). Furthermore, succinate appears to elicit a different response in adipose tissue from CD patients, when activity status is considered. Thus, our results indicate that in an inflammatory local and systemic environment, such as occurs in CD active patients, succinate triggers a pro-inflammatory response in VAT depot, while when subjects are in a remission period, the response of VAT explants to succinate is similar to than the observed in healthy subjects, promoting an anti-inflammatory expression profile (Figure 1B). Interestingly, we found elevated circulating succinate levels in active CD patients but those decrease drastically in patients in remission of the disease (Figure 1C). Conclusion Succinate has a relevant role in adipose tissue dysfunction in CD.

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Improvement of a ‘Leaky' Intestinal Barrier

Digestive Diseases ◽

10.1159/000449078 ◽

2017 ◽

Vol 35 (1-2) ◽

pp. 21-24 ◽

Cited By ~ 4

Author(s):

Eduard F. Stange

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Intestinal Barrier ◽

Bacterial Attachment ◽

Phase Iii ◽

Colonic Disease ◽

Mucus Layer ◽

Tissue Destruction ◽

Liquid Form ◽

Mucus Production

In Crohn's disease, the mucus layer appears to be defective in terms of low defensin levels and lack of antibacterial activity. These deficiencies actually explain the Montreal phenotypes and the stable localization of disease in the terminal ileum with low α-defensins from Paneth cells and/or low β-defensins in colonic disease, respectively. Conversely, in ulcerative colitis (UC) the defensin production is normal or even induced, but the mucus layer is thinner and patchy, more in the liquid form and also chemically altered so that antibacterial peptides are not retained and lost into the luminal bacterial bulk. Therefore, both barrier problems allow slow bacterial attachment and invasion, ultimately triggering the massive response of adaptive immunity and tissue destruction. Therefore, leakiness should refer to the antibacterial barrier and not to the general barrier against small molecules, such as mannitol or lactulose, which are not antigenic. The most promising approach in UC seems to be the use of probiotics or the natural compound lecithin as a stabilizer of mucus structure to enhance the barrier. While a phase II study has yielded positive results, the results of the ongoing phase III study are eagerly awaited. It is quite possible that the protective effect of smoking in UC is related to mucus production in the colon also, but this is not an option. Another alternative would be to shift cell differentiation in the colon towards goblet cell; the relevant differentiation factors are known. In Crohn's disease, the direct oral application of defensins might be effective if release and binding to the mucus are achieved. In the experimental colitis model, this works quite well. In conclusion, in a situation where enthusiasm about so-called biologics is declining due to loss of response over time, searching for the primary defects in inflammatory bowel disease and treating them may well be worthwhile, although it is unlikely to provide rapid relief.

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Appendiceal Carcinoids In Crohn’s Disease

Canadian Journal of Gastroenterology ◽

10.1155/2003/625368 ◽

2003 ◽

Vol 17 (1) ◽

pp. 43-46 ◽

Cited By ~ 17

Author(s):

Hugh J Freeman

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Carcinoid Tumour ◽

Intestinal Resection ◽

Case Review ◽

Appendiceal Neoplasms ◽

Increased Risk ◽

Intestinal Neoplasms ◽

Resection Specimen ◽

Sporadic Cases

Earlier investigations demonstrate an increased risk for colon cancer in Crohn's disease. For other intestinal neoplasms, such as carcinoids, studies are limited. In Crohn's disease, repeated endoscopic and imaging studies along with intestinal resections may facilitate clinical recognition of neoplastic diseases, including appendiceal neoplasms. To date, however, only sporadic cases of appendiceal carcinoids have been described in Crohn's disease. In the present study, in a single clinician database of 1000 Crohn's disease patients, three of the 441 patients who had undergone intestinal resection had appendiceal carcinoids, all of which were pathologically confirmed. All were observed in female patients and were not suspected before surgical treatment. In one case, even though management was not altered, the tumour had already invaded serosal fat indicating a potential for more advanced disease. In this series, a carcinoid tumour was found in a resection specimen during a later clinical case review and another was a microcarcinoid, implying that these tumours may be overlooked in Crohn's disease. The percentage detected in the entire database (0.3%) exceeds the reported rates of detection of appendiceal carcinoids after removal of the appendix for appendicitis, as well as the rate of detection of appendiceal carcinoids in autopsy studies. This percentage would be higher if only those having an intestinal resection were considered (0.68%). Additional studies are needed to further define this risk of appendiceal carcinoids in Crohn's disease.

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391 OBESITY IS ASSOCIATED WITH INCREASED RISK OF OLDER ONSET CROHN'S DISEASE: RESULTS FROM THE DEFINE-IBD CONSORTIUM

Gastroenterology ◽

10.1016/s0016-5085(21)00938-0 ◽

2021 ◽

Vol 160 (6) ◽

pp. S-80

Author(s):

Simon Chan ◽

Ye Chen ◽

Kevin Casey ◽

Ola Olen ◽

Jonas F. Ludvigsson ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Increased Risk

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CMV pneumonitis in a patient with Crohn’s disease taking azathioprine

BMJ Case Reports ◽

10.1136/bcr-2020-241256 ◽

2021 ◽

Vol 14 (4) ◽

pp. e241256

Author(s):

Timothy Zef Hawthorne ◽

Rachel Shellien ◽

Lucy Chambers ◽

Graham Devereux

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Low Dose ◽

Antiviral Treatment ◽

Cmv Infection ◽

Rare Presentation ◽

Intravenous Ganciclovir ◽

Increased Risk ◽

Oral Valganciclovir

This case report discusses the rare presentation of cytomegalovirus (CMV) pneumonitis in a young patient with moderately severe Crohn’s disease managed with low dose azathioprine. CMV pneumonitis was initially suspected on CT chest images and confirmed by PCR for CMV. She was treated with intravenous ganciclovir and later stepped down to oral valganciclovir. Although this patient had a prolonged and complicated hospital admission, a good clinical outcome was achieved. CMV infection was raised as an early differential and antiviral treatment was started without delay. This case study, therefore, makes the case for increased awareness of the possibility of, and recognition of CMV pneumonitis among healthcare professionals as a way of preventing significant morbidity and mortality. It also raises awareness of checking for slow metabolisers of azathioprine before initiation to look for individuals who may be at increased risk of azathioprine’s adverse effects.

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GENDER-RELATED DIFFERENCES IN CLINICAL COURSE OF CROHN’S DISEASE IN AN ASIAN POPULATION: a retrospective cohort review

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032014000200004 ◽

2014 ◽

Vol 51 (2) ◽

pp. 90-96 ◽

Cited By ~ 3

Author(s):

Siu-tong LAW ◽

Kin Kong LI

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Immunosuppressive Therapy ◽

Retrospective Cohort ◽

Clinical Characteristics ◽

Positive Family History ◽

Asian Population ◽

Smoking History ◽

Phenotypic Characteristics ◽

Increased Risk

ContextData from Asian populations about gender-related differences in Crohn’s disease are few.ObjectivesThis study was to analyze the clinical characteristics between women and men affected by Crohn’s disease.MethodsThis was a retrospective cohort study to analyze consecutive Crohn’s disease patients from Jan 2000 to Dec 2012. Clinical and phenotypic characteristics and treatment outcomes were evaluated.Results79 patients (55 male and two of them with positive family history) were diagnosed with Crohn’s disease. Ileocolonic disease and inflammatory lesion was the most dominant site of involvement and disease behavior respectively in both men and women. Apart from higher frequency of nausea (45.83 vs 23.64%, P 0.024) and lower body mass index (19.44 vs 22.03 kg/m2, P 0.003) reported in women, no significant gender-related differences in clinical characteristics were observed. Women were more associated with delay use of immunosuppressive therapy (12 vs 36 months, P = 0.028), particularly for those aged less than 40 years old (85 vs 62.6%,P = 0.023). Cox proportional hazard regression analysis revealed that active smoking (HR, 4.679; 95% CI, 1.03-21.18) and delayed use of immunosuppressive therapy (HR, 4.13; 95% CI, 1.01-16.88) were only independent risk factors associated with increased risk of complications.ConclusionsThere were no significant gender-specific differences in clinical and phenotypic characteristics between male and female Crohn’s disease patients. Smoking history and delay use of immunosuppressive therapy were associated with higher risk of complications.

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Pulmonary Crohn's Disease in Down Syndrome: A Link or Linkage Problem

Case Reports in Gastroenterology ◽

10.1159/000445975 ◽

2016 ◽

Vol 10 (2) ◽

pp. 206-211

Author(s):

Danyal Thaver ◽

Mirza Beg

Keyword(s):

Down Syndrome ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Pediatric Population ◽

Pulmonary Nodules ◽

Pulmonary Involvement ◽

Lung Nodules ◽

Inflammatory Disorder ◽

Ct Guided ◽

History Of

Crohn’s disease (CD) is an autoimmune inflammatory disorder that primarily affects the gastrointestinal tract. It may have pulmonary involvement, which has been rarely reported in pediatric patients. Down syndrome (DS) has been associated with increased frequency of autoimmune diseases. However, associations between CD and DS have been rarely reported. We present the case of a 5-year-old girl with known DS and a history of chronic intermittent abdominal pain who presented with persistent pneumonia. Her workup included a chest computed tomography (CT) scan that showed multiple noncalcified pulmonary nodules. An extensive infectious workup was done that was negative. CT-guided needle biopsy of the lung nodules showed necrotizing granulomas. This raised concern for primary CD with extraintestinal pulmonary manifestation. An esophagogastroduodenoscopy and colonoscopy were performed, and colon biopsies showed scattered epithelioid granulomas. Based on this information, there was consensus that her lung nodules were secondary to CD. She was started on standard therapy for CD, and her abdominal and respiratory symptoms gradually improved. However, she continues to have mild residual lung calcification and fibrosis. To our knowledge, this is the first reported case of pulmonary CD in a child with DS. The natural history of pulmonary CD in the pediatric population is not very well studied. Furthermore, since DS has been well known to be associated with increased frequency of malignancies and autoimmune conditions due to immune dysregulation, it is difficult to predict the severity and possible complications in this patient.

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