Role of Kupffer cells in tolerance induction after liver transplantation.

Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.

Patients with breath test positive are necessary to be identified from irritable bowel syndrome: a clinical trial based on microbiomics and rifaximin sensitivity.

BACKGROUND: As a non-invasive and effective diagnostic method for small intestinal bacterial overgrowth (SIBO), wild-use of breath test (BT) has demonstrated a high comorbidity rate in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and SIBO. Patients overlapping with SIBO respond better to rifaximin therapy than those with IBS-D only. Gut microbiota plays a critical role in both of these two diseases. We aimed to determine the microbial difference between IBS-D overlapping with/without SIBO, and to study the underlying mechanism of its sensitivity to rifaximin. METHODS: Patients with IBS-D were categorized as BT-negative (IBSN) and BT-positive (IBSP). Healthy volunteers (BT-negative) were enrolled as healthy control. The patients were clinically evaluated before and after rifaximin treatment (0.4 g bid, 4 weeks). Blood, intestine, and stool samples were collected for cytokine assessment and gut microbial analyses. RESULTS: Clinical complaints and microbial abundance were significantly higher in IBSP than in IBSN. In contrast, severe systemic inflammation and more active bacterial invasion function that were associated with enrichment of opportunistic pathogens were seen in IBSN. The symptoms of IBSP patients were relieved in different degrees after therapy, but the symptoms of IBSN rarely changed. We also found that the presence of IBSN-enriched genera ( Enterobacter and Enterococcus ) are unaffected by rifaximin therapy. CONCLUSIONS: IBS-D patients overlapping with SIBO showed noticeably different fecal microbial composition and function compared with IBS-D only. The better response to rifaximin in those comorbid patients might associate with their different gut microbiota, which suggests that BT is necessary before IBS-D diagnosis and use of rifaximin. REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017911.

The impact of Helicobacter pylori infection, eradication therapy, and probiotics intervention on gastric microbiota in young adults.

BACKGROUND: The impact of probiotics on non-Helicobacter pylori gastric microbiota and its role in microbial restoration after eradication were relatively unknown. We aimed to explore the effect of H. pylori eradication and probiotic intervention on gastric microbiota in young adults. METHODS: Fifty-six H. pylori-negative and 95 H. pylori-positive subjects aged 19-30 were included in this study. H. pylori-infected individuals were randomly assigned to quadruple therapy, probiotics supplemented quadruple therapy, or probiotics monotherapy group. Gastric mucosa and gastric juice samples were collected before and 2 months after treatment for 16SrRNA gene sequencing. RESULTS: The gastric microbial community structure and composition differed from H. pylori-negative subjects 2 months after successful H. pylori eradication. The α diversity of gastric mucosal microbiota significantly increased and was higher than H. pylori-negative subjects, while the α diversity of gastric juice microbiota decreased and was lower than the H. pylori-negative. After probiotics supplemented eradication treatment, Bifidobacterium was enriched in gastric mucosa, Lactobacillus was enriched in gastric juice, potentially pathogenic bacteria such as Fusobacterium and Campylobacter decreased, and the microbial diversity was closer to that of H. pylori-negative subjects compared to quadruple therapy group. Probiotics monotherapy significantly altered the diversity, community structure, and composition of gastric microbiota but showed no advantage in H. pylori inhibition and upregulating beneficial bacteria such as Bifidobacterium and Lactobacillus and related metabolism pathways. Certain potentially pathogenic bacteria such as Fusobacterium increased after probiotic monotherapy. CONCLUSION: H. pylori eradication significantly disrupted gastric microbiota in young adults and could not be restored in a short time. Probiotics supplementation partially helped restore the gastric dysbiosis caused by eradication therapy, but it might be unnecessary for H. pylori-infected young adults to take probiotics alone.

Epidemiological and clinical features of functional dyspepsia in a region with a high incidence of esophageal cancer in China.

BACKGROUND: Functional dyspepsia (FD) has rarely been investigated in areas with a high prevalence of esophageal squamous cell carcinoma (ESCC). This study aims to reveal the epidemiological and clinical features of FD and organic dyspepsia (OD) in such a population. METHODS: A middle-aged and elderly population-based study was conducted in a region with a high incidence of ESCC. All participants completed the Gastroesophageal Reflux Disease Questionnaire and Functional Gastrointestinal Disease Rome III Diagnostic Questionnaire, and they underwent gastroscopy. After exclusion of gastroesophageal reflux disease, uninvestigated dyspepsia (UID) was divided into OD and FD for further analyses. RESULTS: A total of 2916 participants were enrolled from July 2013 to March 2014 in China. We detected 166 UID cases with questionnaires, in which 17 patients with OD and 149 with FD were diagnosed via gastroscopy. OD cases presented as reflux esophagitis (RE), ESCC, and duodenal ulcer. Heartburn (52.94%) and reflux (29.41%) were common in OD, but no symptomatic differences were found between FD and OD. Male sex, low education level, and liquid food were the risk factors for OD, while frequent fresh vegetable consumption was a protective factor. FD included 56 (37.58%) cases of postprandial distress syndrome (PDS), 52 (34.89%) of epigastric pain syndrome (EPS), nine (6.04%) of PDS + EPS, and 32 (21.48%) of FD + functional esophageal disorders. The Helicobacter pylori infection rate in FD patients was not higher than that in the control group (34.23% vs. 42.26%, P = 0.240). Frequent spicy food consumption was associated with PDS (odds ratio [OR]: 2.088, 95% confidence interval [CI]: 1.028-4.243), while consumption of deep well water was protective for PDS (OR: 0.431, 95% CI: 0.251-0.741). CONCLUSIONS: The prevalence of FD was 5.11% in the studied population. Gastroscopy should be prescribed for dyspepsia patients in case that ESCC and RE would be missed in UID cases diagnosed solely by the Rome III questionnaire. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01688908; https://clinicaltrials.gov/ct2/show/record/NCT01688908.

Shared genetic susceptibilities for irritable bowel syndrome and depressive disorder in Chinese patients uncovered by pooled whole-exome sequencing.

Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorder presenting a high comorbidity with depressive disorder (DD). Many studies have confirmed that these two disease share the similar pathophysiological process, but evidence of the genetic risks is limited. This study aimed to analyze the genetic susceptibilities for IBS and DD in Chinese patients. Pooled whole-exome sequencing (pooled-WES) was performed to identify the candidate variants in the group of diarrhea predominant IBS (IBS-D) patients, DD patients, and healthy controls (HC). Then, targeted sequencing was used to validate the candidate variants in three additional cohorts of IBS-D, DD, and HC. Four variants associated with both IBS-D and DD were identified through pooled-WES, and three of them were validated in targeted sequencing. SYT8 rs3741231 G allele and SSPO rs12536873 TT genotype were associated with both IBS-D and DD. The genes of these variants are important in neurogenesis and neurotransmission. In addition, we found COL6A1 rs13051496, a unique risk variation for IBS-D. It increased the IBS-D risk and had a positive correlation with the scores of abdominal bloating and dissatisfaction of bowel habits. Through the results of this study, it provides a genetic basis for the high comorbidity of IBS-D and DD.

Increased Expression of Colonic Mucosal Melatonin in Patients with Irritable Bowel Syndrome Correlated with Gut Dysbiosis.

Dysregulation of the gut microbiota/gut hormone axis contributes to the pathogenesis of irritable bowel syndrome (IBS). Melatonin plays a beneficial role in gut motility and immunity. However, altered expression of local mucosal melatonin in IBS and its relationship with the gut microbiota remain unclear. Therefore, we aimed to detect the colonic melatonin levels and microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and explore their relationship in germ-free (GF) rats and BON-1 cells. Thirty-two IBS-D patients and twenty-eight healthy controls (HCs) were recruited. Fecal specimens from IBS-D patients and HCs were separately transplanted into GF rats by gavage. The levels of colon mucosal melatonin were assessed by immunohistochemical methods, and fecal microbiota communities were analyzed using 16S rDNA sequencing. The effect of butyrate on melatonin synthesis in BON-1 cells was evaluated by ELISA. Melatonin levels were significantly increased and negatively correlated with visceral hypersensitivity in IBS-D patients. GF rats inoculated with fecal microbiota from IBS-D patients had high colonic melatonin levels. Butyrate-producing Clostridium cluster XIVa species, such as Roseburia species and Lachnospira species, were positively related to colonic mucosal melatonin expression. Butyrate significantly increased melatonin secretion in BON-1 cells. Increased melatonin expression may be an adaptive protective mechanism in the development of IBS-D. Moreover, some Clostridium cluster XIVa species could increase melatonin expression via butyrate production. Modulation of the gut hormone/gut microbiota axis offers a promising target of interest for IBS in the future.

Effect of the interleukin 10 polymorphisms on interleukin 10 production and visceral hypersensitivity in Chinese patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS), a functional gastrointestinal disorder, is characterized by cytokine imbalance. Previously, decreased plasma interleukin 10 (IL-10) level was reported in patients with IBS, which may be due to genetic polymorphisms. However, there are no reports correlating the IL-10 polymorphisms with IL-10 production in patients with IBS. This study aimed to analyze the effect of IL-10 polymorphisms on IL-10 production and its correlation with the clinical symptoms in Chinese patients with diarrhea-predominant IBS (IBS-D). METHODS: Two IL-10 single nucleotide polymorphisms (rs1800871 and rs1800896) were detected in 120 patients with IBS-D and 144 healthy controls (HC) using SNaPshot. IBS symptom severity score, Bristol scale, hospital anxiety, and depressive scale (HADS) were used to evaluate the clinical symptoms, as well as the psychological status and visceral sensitivity of the subjects. IL-10 levels in the plasma and peripheral blood mononuclear cell (PBMC) culture supernatant were measured using enzyme-linked immunosorbent assay, while those in ileal and colonic mucosal biopsies were measured using immunohistochemistry. RESULTS: The frequency of rs1800896 C allele was significantly lower in the patients with IBS-D than that in the HC (odds ratio: 0.49, 95% confidence interval: 0.27-0.92, P = 0.0240). The IL-10 levels in the plasma (P = 0.0030) and PBMC culture supernatant (P = 0.0500) of the CT genotype subjects were significantly higher than those in the TT genotype subjects. The CT genotype subjects exhibited a higher pain threshold in the rectal distention test than the TT genotype subjects. Moreover, IL-10 rs1800871 GG genotype subjects showed an increase in the HADS score compared to other genotype subjects. CONCLUSIONS: IL-10 rs1800896 C allele is correlated with higher IL-10 levels in the plasma and the PBMC culture supernatant, which is associated with a higher pain threshold in the Chinese patients with IBS-D. This study provides an explicit relationship of IL-10 polymorphisms with IL-10 production, which might help in understanding the pathogenesis of IBS-D.

A population-based survey of gastroesophageal reflux disease in a region with high prevalence of esophageal cancer in China.

BACKGROUND: The exact relationship between gastroesophageal reflux disease (GERD) and esophageal squamous cell cancer (ESCC) is far from clarification. The aim of this study was to investigate the epidemiology of GERD in a region with high prevalence of ESCC in China. METHODS: A population-based, cross-sectional study was conducted in a high ESCC prevalent area, Anyang, Henan, China. All subjects fulfilled questionnaires and underwent gastroendoscopy with routine esophageal biopsy. The subjects were divided into GERD subtypes (reflux esophagitis [RE] and non-erosive reflux disease [NERD]) and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine risk factors for RE and NERD. RESULTS: A total of 2844 subjects were finally enrolled. The prevalence of GERD (RE + NERD) was 17.3%. Among them, 271 (9.53%) adults were diagnosed with RE. The prevalence of RE increased with age (7.09% in 45-50 years, 8.00% in 51-60 years, and 9.53% in 61-69 years, χ = 62.216, P < 0.001). Sixty-seven (2.36%) subjects were diagnosed with the silent RE. A total of 221 (7.77%) subjects were diagnosed with NERD. Frequent liquid food consumption (OR [95% CI]: 1.502 [1.076-2.095]) was independent risk factor for RE as well as age, male gender, high body mass index (BMI), ever smoking. Age was independent risk factor for NERD. For silent RE, age, male gender, and frequent liquid food consumption were risk factors. CONCLUSIONS: In the population with high prevalence of ESCC, a high prevalence of GERD and inverted proportion of RE/NERD were presented. Age was an independent risk factor for GERD. The male gender, high BMI, smoking, and frequent liquid food consumption may be risk factors for RE but not for NERD.

Similar Fecal Microbiota Signatures in Patients With Diarrhea-Predominant Irritable Bowel Syndrome and Patients With Depression.

BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) often have psychiatric comorbidities. Alterations in the intestinal microbiota have been associated with IBS and depression, but it is not clear if there is a microbial relationship between these disorders. We studied the profiles of fecal microbiota samples from patients with IBS, depression, or comorbidities of IBS and depression; we determined the relationships among these profiles and clinical and pathophysiological features of these disorders. METHODS: We used 454 pyrosequencing to analyze fecal microbiota samples from 100 subjects (40 with diarrhea-predominant IBS [IBS-D], 15 with depression, 25 with comorbidities of IBS and depression, and 20 healthy individuals [controls]), recruited at Peking University. Abdominal and psychological symptoms were evaluated with validated questionnaires. Visceral sensitivity was evaluated using a barostat. Colonic mucosal inflammation was assayed by immunohistochemical analyses of sigmoid tissue biopsy specimens. RESULTS: Fecal microbiota signatures were similar between patients with IBS-D and depression in that they were less diverse than samples from controls and had similar abundances of alterations. They were characterized by high proportions of Bacteroides (type I), Prevotella (type II), or nondominant microbiota (type III). Most patients with IBS-D or depression had type I or type II profiles (IBS-D had 85% type I and type II profiles, depression had 80% type I and type II profiles). Colon tissues from patients with type I or type II profiles had higher levels of inflammatory markers than colon tissues from patients with type III profiles. The level of colon inflammation correlated with the severity of IBS symptoms. CONCLUSIONS: Patients with IBS-D and depression have similar alterations in fecal microbiota; these might be related to the pathogenesis of these disorders. We identified 3 microbial profiles in patients that could indicate different subtypes of IBS and depression or be used as diagnostic biomarkers.

[A meta-analysis of the prevalence and risk factors of irritable bowel syndrome in Chinese community].

OBJECTIVE: To estimate the prevalence and risk factors for irritable bowel syndrome (IBS) in China. METHODS: Cross-sectional studies relevant to IBS conducted among Chinese were identified through the databases including PubMed, Web of Science, the Cochrane Library, CBM, CNKI, Wanfang data and VIP. Quality of studies was assessed according to the criteria for cross-sectional studies recommended by Agency for Healthcare Research and Quality (AHRQ). Analysis of data, publication bias and sensitivity were performed with Stata (Version 12.0). RESULTS: A total of twenty-three studies were extracted. No obvious publication bias was detected in all analysis except the effect of depression on IBS prevalence. Pooled prevalence of IBS in China was 6.5%. IBS was more common in women than in men (8.1% vs 6.8%;OR = 1.23, 95%CI 1.09-1.38) and high rate in age group between 30 to 59 years (6.9%; OR = 1.22, 95%CI 1.12-1.32) . Intestinal infection history (OR = 2.39, 95%CI 1.69-3.38), anxiety (OR = 2.95, 95%CI 1.94-4.49), depression (OR = 1.85, 95%CI 1.11-3.09), food allergy (OR = 2.80, 95%CI 2.12-3.67) and alcohol consumption (OR = 1.15, 95%CI 1.07-1.24) might increase the risk for IBS. There were no significant difference of IBS prevalence between urban and rural areas (OR = 0.97, 95%CI 0.72-1.29) , neither in different education classes (OR = 0.85, 95%CI 0.70-1.03) . Sub-group analysis showed IBS prevalence varied apparently with different diagnostic criteria: prevalence defined by Manning was 11.8% and by RomeIIand Rome III prevalence values were 4.4% and 8.9% respectively. CONCLUSIONS: Pooled prevalence of IBS in China was 6.5%. IBS is more common in age group between 30 to 59 years. Female, history of intestinal infection, anxiety, depression, food allergy and alcohol consumption were risk factors for IBS in Chinese population.

Effect of taurine on IRAK4 and NF-kappa B in Kupffer cells from rat liver grafts after ischemia-reperfusion injury.

BACKGROUND: The aim of this study was to explore the protective mechanisms of taurine pretreatment against hepatic ischemia/reperfusion injury after liver transplantation. METHODS: A Sprague-Dawley-to-Sprague-Dawley rat liver transplantation model was used in this study. At 0, 60, and 180 minutes after reperfusion, expression of interleukin-1 receptor-associated kinase-4 (IRAK-4) messenger ribonucleic acid and protein in Kupffer cells was determined by real-time polymerase chain reaction and Western blotting. The activity of nuclear factor κB in Kupffer cells was determined by electrophoretic mobility shift assay. The serum tumor necrosis factor-α level was detected by enzyme-linked immunosorbent assay. Serum transaminases, liver histology, and animal survival were also investigated. RESULTS: At 60 and 180 minutes after reperfusion, levels of IRAK-4 messenger ribonucleic acid and protein, activities of nuclear factor κB, and levels of serum transaminases and tumor necrosis factor-α were all obviously elevated. However, changes in these parameters in rats treated with taurine were remarkably attenuated at the indicated time points. CONCLUSIONS: These data suggest that taurine could protect against hepatic ischemia/reperfusion injury after liver transplantation, and the protective effects may be through downregulation of IRAK-4 and downstream nuclear factor κB and tumor necrosis factor-α expression in Kupffer cells.

Diagnosis and treatment of juxta-ampullary duodenal diverticulum.

OBJECTIVE: To summarize the diagnosis and treatment of juxta-ampullary duodenal diverticulum (JAD) in our hospital. METHODS: Of 5000 consecutive endoscopic retrograde cholangiopancreatography (ERCP) performed in our department, 225 patients were diagnosed with JAD and treated. All patients were classified based on the location of Ampullae of Vater in relation to the duodenal diverticulum. Of the 225 JAD patients, 96 patients (43%) required surgery. RESULTS: The 225 patients with JAD were divided into Type A (146 cases, 65%) or Type B (79 cases, 35%). Type A patients presented with papillae near the diverticulum or in its margin. In this type, 36 patients (25%) presented with diverticulitis, bleeding, perforation or cholelithiasis, and were treated surgically. Type B patients presented with papillae inside the diverticulum. Among them, 60 patients (76%) had complications requiring surgery. CONCLUSIONS: JAD can be divided into two types based on location of the papillae. ERCP was the primary method of diagnosing JAD and patients with severe complications required surgical intervention.