New Insights into the Role of Oral Microbiota Dysbiosis in the Pathogenesis of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammatory disorders with a prolonged duration characterized by recurrent relapse and remission. The exact etiology of IBD remains poorly understood despite the identification of relevant risk factors, including individual genetic susceptibility, environmental triggers, and disruption of immune homeostasis. Dysbiosis of the gut microbiota is believed to exacerbate the progression of IBD. Recently, increasing evidence has also linked oral microbiota dysbiosis with the development of IBD. On the one hand, IBD patients show significantly unbalanced composition and function of the oral microbiota known as dysbiosis. On the other, overabundances of oral commensal bacteria with opportunistic pathogenicity have been found in the gut microbiota of IBD patients. Herein, we review the current information on the causative factors of IBD, especially recent evidence of IBD-associated oral microbiota dysbiosis, which has seldom been covered in the previous literature review, highlighting the pathogenic mechanisms of specific oral bacteria in the development of IBD. Ectopic colonization of several oral bacteria, including a subset of Porphyromonas gingivalis, Streptococcus mutans, Fusobacterium nucleatum, Campylobacter concisus, and Klebsiella pneumoniae, may lead to destruction of the intestinal epithelial barrier, excessive secretion of inflammatory cytokines, disruption of the host immune system, and dysbiosis of gut microbiota, consequently aggravating chronic intestinal inflammation. Studying oral microbiota dysbiosis may open future horizons for understanding IBD pathogenesis and provide novel biomarkers for IBD. This review also presents the current treatment and new perspectives for IBD treatment.

High-throughput sequencing provides insights into oral microbiota dysbiosis in association with inflammatory bowel disease.

Although the prevalence of inflammatory bowel disease (IBD) has been increasing worldwide, the etiology remains elusive. Investigating oral microbiota dysbiosis is essential to understanding IBD pathogenesis. Our study evaluated variations in salivary microbiota and identified potential associations with IBD. The saliva microbiota of 22 IBD patients and 8 healthy controls (HCs) was determined using 16S ribosomal RNA (rRNA) gene sequencing and analyzed using QIIME2. A distinct saliva microbiota dysbiosis in IBD, characterized by alterations in microbiota biodiversity and composition, was identified. Saccharibacteria (TM7), Absconditabacteria (SR1), Leptotrichia, Prevotella, Bulleidia, and Atopobium, some of which are oral biofilm-forming bacteria, were significantly increased. Moreover, levels of inflammatory cytokines associated with IBD were elevated and positively correlated with TM7 and SR1. Functional variations include down-regulation of genetic information processing, while up-regulation of carbohydrate metabolism and protein processing in the endoplasmic reticulum in IBD. Our data implicate salivary microbiota dysbiosis involving in IBD pathogenesis.

Clinical Features and Prognosis of Crohn's Disease with Upper Gastrointestinal Tract Phenotype in Chinese Patients.

BACKGROUND: The epidemiology of upper gastrointestinal (L4) Crohn's disease in China remains poorly characterized. AIMS: We aimed to identify the clinical characteristics of L4 disease and clarify the relationship between disease characteristics at diagnosis and early outcomes. METHODS: We retrospectively enrolled 246 patients diagnosed between 2013 and 2017 and followed up for > 1 year post-diagnosis. Primary outcomes included the 1-year rates of hospitalization and abdominal surgery according to disease location and behavior. RESULTS: Of 80 patients with L4 disease (61, 25, and 18 with esophagogastroduodenal, jejunal, and proximal ileal involvement, respectively), none had granuloma, whereas 66.7%, 50%, 46.9%, 75%, and 70% had disease-specific endoscopic lesions in the esophagus, stomach, duodenum, jejunum, and proximal ileum, respectively. Compared to non-L4 disease, L4 disease was associated with higher rates of abdominal surgery (41.3% vs. 11.4%, P < 0.001) but similar rates of hospitalization within 1 year post-diagnosis. In L4 disease, jejunal and proximal ileal involvement was associated with stricturing behavior (P = 0.034, P < 0.001) and higher abdominal surgery rate (both: P < 0.001). Risk factors for abdominal surgery within 1 year post-diagnosis included age ≥ 40 years (OR 1.920; 95% CI 1.095-3.367), L4 phenotype (OR 6.335; 95% CI 3.862-10.390), stricturing disease (OR 3.162; 95% CI 1.103-9.866), and penetrating disease (OR 11.504; 95% CI 3.409-38.825), whereas the protective factor was female sex (OR 0.214; 95% CI 0.123-0.373). CONCLUSIONS: Early outcomes are worse for L4 than for non-L4 disease. Jejunoileum involvement predicts stricturing disease and early surgery. More aggressive initial therapy is needed to improve L4-disease prognosis.

Serum Procalcitonin as a Potential Early Predictor of Short-Term Outcomes in Acute Severe Ulcerative Colitis.

BACKGROUND: Delayed colectomy can be life-threatening for patients with acute severe ulcerative colitis (ASUC). However, few biomarkers can predict the outcomes of ASUC patients before treatment. Serum procalcitonin (PCT) has been observed to be increased in ASUC patients. AIM: The aim of this study was to estimate the association between serum PCT and short-term outcomes in patients with ASUC. METHODS: A single-center observational study was conducted at a referral hospital from January 2012 to January 2018. Hospitalized ASUC patients, who were administered intravenous corticosteroids (IVCS), were enrolled and followed up for 6 months. The primary outcome was IVCS failure; the secondary outcome was colectomy. Relationships between indicators and clinical outcomes were assessed. RESULTS: Of 152 ASUC patients enrolled in this study, 81 responded to IVCS and 71 failed (62 required short-term colectomy and 9 responded to second-line rescue therapy). Serum PCT on admission was significantly higher in IVCS-failure cases and surgical cases than in medical responders. Serum PCT ≥ 0.10 µg/L (OR = 4.134, p = 0.001) predicted IVCS failure with specificity of 0.741, and the combined measurement with fecal calprotectin (FC) ≥ 1500 µg/g improved the sensitivity. Serum PCT correlated significantly with the Ulcerative Colitis Endoscopic Index of Severity (r = 0.416, p < 0.001) and FC (r = 0.384, p < 0.001). CONCLUSION: Serum PCT on admission could be a potential early non-invasive predictive biomarker for IVCS failure in ASUC patients, and a combination of PCT and FC could improve the predictive value.

Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta-analysis.

AIM: To investigate the relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) in an Asian population. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched for observational studies published up until June 2014, without language restrictions. Additional references were obtained from reviewed articles. RESULTS: Ten studies involving 1299 IBD patients and 1817 controls were included in the meta-analysis (24.9% of IBD patients had H. pylori infection vs 48.3% of the controls). The pooled risk ratio for H. pylori infection in IBD patients compared with controls was 0.48 (95%CI: 0.43-0.54; P < 0.001). There was no significant heterogeneity in the included studies (I (2) = 21%). Egger's linear regression indicated that there was no significant publication bias (P = 0.203). CONCLUSION: The H. pylori infection rate in Asian IBD patients is significantly lower than in non-IBD patients, indicating that infection protects against the development of IBD.

Unfavorable outcome of antiviral therapy in cytomegalovirus-positive ulcerative colitis may be due to inappropriate study inclusion in meta-analysis.

Some previous articles reported that antiviral treatment was effective to reduce the colectomy rate in ulcerative colitis (UC) patients with cytomegalovirus (CMV) infection. Kopylov et al recently carried out a systematic review and meta-analysis to evaluate the impact of antiviral therapy on CMV-positive UC. The results showed that patients who received antiviral treatment had a higher risk of 30-d colectomy. We found that in this meta-analysis, some studies were inappropriately included, leading to an unfavorable outcome of anti-CMV therapy in UC patients.

Confusing untypical intestinal Behcet's disease: Skip ulcers with severe lower gastrointestinal hemorrhage.

Behcet's disease (BD) is a rare and life-long disorder characterized by inflammation of blood vessels throughout the body. BD was originally described in 1937 as a syndrome involving oral and genital ulceration in addition to ocular inflammation. Intestinal BD refers to colonic ulcerative lesions documented by objective measures in patients with BD. Many studies have shown that over 40% of BD patients have gastrointestinal complaints. Symptoms include abdominal pain, diarrhea, nausea, anorexia and abdominal distension. Although gastrointestinal symptoms are common, the demonstration of gastrointestinal ulcers is rare. This so-called intestinal BD accounts for approximately 1% of cases. There is no specific test for BD, and the diagnosis is based on clinical criteria. The manifestations of intestinal BD are similar to those of other colitis conditions such as Crohn's disease or intestinal tuberculosis, thus, it is challenging for gastroenterologists to accurately diagnose intestinal BD in patients with ileo-colonic ulcers. However, giant ulcers distributed in the esophagus and ileocecal junction with gastrointestinal hemorrhage are rare in intestinal BD. Here, we present a case of untypical intestinal BD. The patient had recurrent aphthous ulceration of the oral mucosa, and esophageal and ileo-colonic ulceration, but no typical extra-intestinal symptoms. During examination, the patient had massive acute lower gastrointestinal bleeding. The patient underwent ileostomy after an emergency right hemicolectomy and partial ileectomy, and was subsequently diagnosed with incomplete-type intestinal BD by pathology. The literature on the evaluation and management of this condition is reviewed.

Involvement of 90-kuD ribosomal S6 kinase in collagen type I expression in rat hepatic fibrosis.

AIM: To investigate the relationship between 90-kuD ribosomal S6 kinase (p90RSK) and collagen type I expression during the development of hepatic fibrosis in vivo and in vitro. METHODS: Rat hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. The protein expression and cell location of p90RSK and their relationship with collagen type I were determined by co-immunofluoresence and confocal microscopy. Subsequently, RNAi strategy was employed to silence p90RSK mRNA expression in HSC-T6, an activated hepatic stellate cell (HSC) line. The expression of collagen type I in HSC-T6 cells was assessed by Western blotting and real-time polymerase chain reaction. Furthermore, HSCs were transfected with expression vectors or RNAi constructs of p90RSK to increase or decrease the p90RSK expression, then collagen type I promoter activity in the transfected HSCs was examined by reporter assay. Lastly HSC-T6 cells transfected with p90RSK siRNA was treated with or without platelet-derived growth factor (PDGF)-BB at a final concentration of 20 microg/L and the cell growth was determined by MTS conversion. RESULTS: In fibrotic liver tissues, p90RSK was over-expressed in activated HSCs and had a significant positive correlation with collagen type I levels. In HSC-T6 cells transfected with RNAi targeted to p90RSK, the expression of collagen type I was down-regulated (61.8% in mRNA, P < 0.01, 89.1% in protein, P < 0.01). However, collagen type I promoter activity was not increased with over-expression of p90RSK and not decreased with low expression either, compared with controls in the same cell line (P = 0.076). Furthermore, p90RSK siRNA exerted the inhibition of HSC proliferation, and also abolished the effect of PDGF on the HSC proliferation. CONCLUSION: p90RSK is over-expressed in activated HSCs and involved in regulating the abnormal expression of collagen type I through initiating the proliferation of HSCs.

Differential expression genes analyzed by cDNA array in the regulation of rat hepatic fibrogenesis.

PURPOSE: To analyze the gene expression pattern in rat hepatic fibrogenesis and further assess the role of some key genes during the pathological process. METHODS: Hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine or carbon tetrachloride (CCl(4)) injection subcutaneously in rats, and identification of the hepatic fibrosis related genes with cDNA microarray was performed. After some key genes up-regulated during the development of hepatic fibrosis were screened and confirmed, their effects on the function of the activated rat hepatic stellate cells (HSC) were assessed using the small interfering RNA (siRNA) technique. RESULTS: Using an Atlas rat cDNA array, a number of differentially expressed genes in fibrotic liver tissues were identified compared with non-diseased control. A total of 15 genes predominantly associated with the mitogen-activated protein kinase (MAPK) signal transduction pathway were upregulated in the fibrotic liver. Immunohistochemical study revealed that the expressions of both extracellular signal-regulated kinases (ERK) and ribosomal protein S6 kinase (RSK), two of the key genes in the MAPK pathway, were remarkably induced, which was closely correlated to that of collagen types I and III during the development of hepatic fibrosis. Transfection of siRNA targeting ERK1 mRNA (siERK1) into HSC led to a 66% and 72% reduction of ERK1 mRNA and protein expression, respectively. Furthermore, siERK1 exerted the inhibition of the proliferation of HSC, accompanied by the induction of HSC apoptosis and reduction of collagen types I and III. In addition, siERK1 abolished the effect of platelet-derived growth factor-BB on the proliferation of HSC. CONCLUSIONS: The present study provided strong evidence for the participation of the MAPK pathway in the pathogenesis of hepatic fibrosis. Selective targeting of ERK1 inhibitors to HSC might present as a novel strategy for the treatment of hepatic fibrosis.