Corrigendum: Application of a multispecies probiotic reduces gastro-intestinal discomfort and induces microbial changes after colonoscopy.

[This corrects the article DOI: 10.3389/fonc.2022.1078315.].

Autoantibodies to beta tubulin in autoimmune liver diseases - relation to pANCA and clinical relevance.

There was evidence that pANCA (perinuclear antineutrophil cytoplasmic antibodies) in autoimmune liver diseases react with human beta-tubulin-5 (TBB5). Here we re-evaluate the specificity and clinical relevance of anti-TBB5 antibodies. Patients with untreated autoimmune hepatitis (AIH; n=53), AIH under immunosuppressive therapy (AIH-IS; n=125), primary sclerosing cholangitis (PSC; n=40), primary biliary cholangitis (PBC; n=250), non-autoimmune liver diseases (n=158), inflammatory bowel diseases (IBD; n=30), and healthy individuals (n=62) were tested by enzyme linked immunosorbent assay (ELISA) for IgG- and IgA-antibodies against recombinant human TBB5. pANCA were detected by immunofluorescence test. Sera were absorbed with TBB5 coupled to cyanogen bromide-activated sepharose. Prevalence and reactivity of IgG anti-TBB5 were significantly higher in patients with untreated AIH (68%; arbitrary units [AU] median:369) than in PSC (28%; AU median:84, p<0.001), other liver diseases (14%; AU median:185, p<0.0001), IBD (3%; AU median:111, p<0.0001) and healthy controls (3%; AU median:135; p<0.0001). Anti-TBB5 did not correlate with pANCA, and immunoprecipitation with TBB5 did not abolish pANCA reactivity. In untreated AIH anti-TBB5-reactivity was significantly higher than in AIH-IS. Transaminases decreased under IS preferentially in anti-TBB5 negative patients. There was no correlation between anti-TBB5-reactivity and histological stages. IgA-anti-TBB5 was mainly found in alcohol-associated liver disease (ALD; 39%). Our data do not support TBB5 as an autoantigenic target of pANCA. However, IgG-anti-TBB5 showed high specificity for (untreated) AIH. While they did not correlate with histological and laboratory parameters, their presence may indicate a poor response to IS.

[Structural, procedural, and personnel requirements for cross-sectoral provision of endoscopic gastroenterological procedures]. / Strukturelle, prozedurale und personelle Voraussetzungen für eine sektorenübergreifende Erbringung endoskopischer gastroenterologischer Leistungen.

Gastroenterology has made crucial advances in diagnostic and interventional endoscopic procedures, opening up improvements in the treatment of many patients. Thus, organ-preserving treatments are increasingly being made possible, replacing more invasive organ resecting surgical procedures. At the same time, the degree of complexity and risks varies widely between different endoscopic procedures. In many cases, simpler endoscopic procedures are now offered on an outpatient basis. Further potential for cross-sectoral performance of endoscopic procedures exists in the case of complex endoscopic procedures, which, however, require special structural, procedural and personnel requirements in order to provide quality-assured treatment, enable post-interventional monitoring and, if necessary, take measures to ensure the success of the treatment. We summarize the essential prerequisites and limitations for cross-sector performance of endoscopic procedures in gastroenterology.

Hepatobiliary manifestations in patients with ulcerative colitis: a retrospective analysis.

Background: Inflammatory bowel diseases (IBDs) are often associated with altered liver function tests (LFTs). There is little data on the relationship between abnormal LFT and IBD. Our study aimed to evaluate the prevalence and etiology of elevated LFT in patients with ulcerative colitis (UC) and to determine whether there is an association with clinical and demographic parameters. Methods: The clinical records of the Gastroenterology Outpatients Clinic at a single center were reviewed and screened for patients with UC from 2005 to 2014. In total, 263 patients were included. Patients with Crohn's disease (CD), colitis indeterminate, and colitis of other origins were excluded. Abnormal LFT and liver injuries were analyzed. Results: A cohort of 182 patients was analyzed (114 males, 68 females; mean age = 50.2 ± 16.1 years). 58 patients had already been diagnosed with a hepatobiliary disorder. Patients with a known hepatobiliary disorder suffered from UC for a significantly longer duration. Elevated LFT in patients without known hepatobiliary disorders was 69.4%. Liver injury was found in 21.8%. A transient increase in abnormal LFT was shown in 59 patients (68.6%), a persistent increase was found in 27 patients (31.4%). Treatment with thiopurines was a risk factor for persistent elevated LFT (p = 0.029), steroids had a protective impact (p = 0.037). Conclusion: This study clearly highlights the importance of screening for hepatobiliary disorders and abnormal LFT in patients with UC, as the prevalence of hepatobiliary disorders and abnormal LFT is detected very often among this patient group.

Application of a multispecies probiotic reduces gastro-intestinal discomfort and induces microbial changes after colonoscopy.

Even after decades of research and pharmaceutical development, cancer is still one of the most common causes of death in the western population and the management of cancer will remain a major challenge of medical research. One of the most common types of cancer is colorectal cancer (CRC). Prevention by detection of early-stage precursors is the most reliable method to prevent CRC development. In dependence of age, familial predisposition, and other risk factors the preventative routine screening for CRC by colonoscopy should be performed at least twice in intervals of about ten years. Although colonoscopy is a life-saving clinical examination reducing both incidence and mortality of CRC significantly, it has still a bad reputation in the population as an uncomfortable procedure with unpleasant side effects lasting sometimes over days to weeks. These effects are most likely caused by the bowel preparation before colonoscopy, which is crucial for a successful colonoscopy with high quality. Beside pain, bleeding and other rare but severe complications of colonoscopy, cleaning of the intestinal mucosa alters the gut microbiome significantly and consistently. Abdominal pain, cramps, diarrhea, nausea, bloating, and constipation are common adverse events which can continue to affect patients for days or even weeks after the procedure. In this multicenter, placebo controlled, double blind clinical trial, we investigated the effect of an intervention with a multispecies probiotic formulation for 30 days on the adverse events due to bowel preparation. We show that the treatment of participants with the multispecies probiotic formulation decreases the number of days with constipation significantly, and reduced pain, bloating, diarrhea, and general discomfort. 16S based amplicon analyses reveal recovery of administered probiotic strains from stool samples and differences in alpha diversity dynamics with higher variability in the probiotic group compared to the placebo group. In conclusion, the probiotic ameliorates the side effects after colonoscopy and might be an important supplement to increase acceptance of this life-saving preventative examination. Further, we present here for the first time that probiotic intervention of only 30 days affects alpha diversity parameters in stool samples.

[The gastroenterology during the first and second wave of corona pandemic - two surveys by the working group of the guiding gastroenterologic clinicians (ALGK)]. / Die Gastroenterologie in der ersten und zweiten Corona-Welle ­ zwei Umfragen der Arbeitsgemeinschaft Leitender Gastroenterologischer Krankenhausärzte (ALGK).

BACKGROUND: An evaluation of the non-university hospitals in Germany with regard to the actual and follow-up working condition, alterations and perspectives during the Corona-crisis is missing. The working group of the guiding gastroenterologic clinicians (ALGK) comprises more than 70% of the head physicians of gastroenterological units leading to representative informations. METHODS: The ALGK conducted two surveys among its members in 2020 during the first and 2021 during the second Corona-wave. 369 members with correct email adresses were contacted. The first survey included 17 and the second survey 21 questions. RESULTS: 58 % of the respondent represented primary and standard care hospitals, 36 % secondary care hospitals, 6 % tertiary hospitals of maximum care, 43 % communal, 38 % confessional and 18 % private hospitals. 87 % of the respondent reported about cancellation of the hospital appointments by the patients (87 %/85 %). In the second survey, appointment cancellation by the physican (58 % vs. 84 %), reduction of emergency cases (16 % vs. 29 %), postponement of diagnostic or therapeutic appointments (85 % vs. 99 %) and reduction of programmed inpatient (65 vs. 91 %) or outpatient treatment (15 % vs. 84 %) were lesser compared to the first survey. Mean reduction of endoscopic procedures per unit were 337/month to 151/month (55 %) for diagnostic endoscopy, 174/month to 84/month (52 %) for therapeutic endoscopy and 56/month to 7/month (87,5 %) for prevention colonoscopy. The comparison between hospital operators revealed more reports on staff to be under quarantine, more very strong or strong feeling of psychological stress, more fear of corona-infection and more suspicion of ambulatory maintenance in gastroenterology in private hospitals. Willingness for vaccination was very high among physicians and nursing staff (92 %/89 %) and not different between the hospital operators. 38 % of the repsondent reported on the fear of existential risk of their hospital because of the Corona-crisis. CONCLUSION: The two ALGK surveys give a reprensentative picture of the situation of non-university gastroenterological units during Corona-pandemic in Germany.

Safety of vedolizumab in the treatment of pregnant women with inflammatory bowel disease: a targeted literature review.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) commonly affect women in their childbearing years. Vedolizumab (VDZ) is approved for treatment of moderate-to-severe CD and UC, but there is a knowledge gap regarding its use during pregnancy. This targeted literature review describes available evidence on safety of VDZ in pregnant patients in order to offer physicians a detailed and balanced view on persistent data during their decision-making process for an individualized treatment concept. METHODS: The search included literature from the MEDLINE database and abstracts of five gastroenterological conferences published until November 2019. Publications were included if pregnancy outcomes in women receiving VDZ or neonatal outcomes in newborns of women previously exposed to VDZ were reported. RESULTS: Out of 196 initially identified records, 18 publications reporting results of five different studies were identified. In total, for 213 of 284 VDZ-exposed documented pregnancies the following pregnancy outcomes were reported: 167 live births (172 infants due to twin births), 1 stillbirth, 35 miscarriages, 10 elective terminations (1 due to detected Down syndrome). Furthermore, during pregnancy, the following complications were observed: seven cases of (pre) eclampsia, three cases of premature rupture of membranes and one case each of placenta previa, chorioamnionitis, pneumonia, first-trimester bleeding, cholestasis, sepsis, or neonatal intraventricular hemorrhage. Based on 172 infants, 30 preterm deliveries (17.4%), 9 cases of low birth weight (5.2%), 5 infections (2.9%), and 6 cases (3.8%) with congenital anomalies were reported. CONCLUSION: There was no evidence for safety concerns regarding pregnancy outcomes associated with VDZ therapy. Due to the limited scope of included records, further research is needed to understand the safety profile regarding the use of VDZ during pregnancy.

p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ.

OBJECTIVE: Autoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) directed against an unknown antigen of myeloid cells. METHODS AND RESULTS: Here, it is reported that p-ANCAs in autoimmune liver disorders react with beta-tubulin isotype 5 (TBB-5) as autoantigen as well as with its evolutionary bacterial precursor protein FtsZ. Both proteins were confirmed as antigens of p-ANCAs in autoimmune liver disorders by demonstrating reactivity of ANCA-positive sera with recombinant TBB-5 (72-88%) and FtsZ (64-82%) on immunoblots and antigen-specific abrogation of ANCA immunofluorescence when sera had been preabsorbed with tubulin and FtsZ. Using sera from interleukin 10-deficient mice (Il10(-)/(-)), an animal model of inflammatory bowel disease, it was also demonstrated that antibodies against TBB-5 are generated in response to intestinal microorganisms. However, unlike autoimmune liver disorders, human antibodies to FtsZ in the absence of TBB-5 antibodies were also a frequent finding in non-autoimmune liver diseases (up to 95%). Reactivity to TBB-5 without the presence of FtsZ antibodies was found in very few cases (<1%) in autoimmune liver disorders. CONCLUSIONS: Thus, p-ANCAs in autoimmune liver diseases are directed against human TBB-5 cross-reacting with the bacterial protein FtsZ, probably reflecting an abnormal immune response to intestinal microorganisms in susceptible, possibly genetically predisposed individuals.

Atypical p-ANCA in PSC and AIH: a hint toward a "leaky gut"?

Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are enigmatic chronic inflammatory diseases of the liver, which are frequently associated with chronic inflammatory bowel diseases. Both types of liver disease share various distinct autoantibodies such as atypical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and thus are considered autoimmune disorders with atypical features. The discovery that atypical p-ANCA recognize both tubulin beta isoform 5 in human neutrophils and the bacterial cell division protein FtsZ has renewed the discussion on the potential role of microorganisms in the pathogenesis of both diseases. In this paper, we review the evidence for microbial infection in PSC and AIH and discuss new concepts how cross-recognition between microbial antigens in the gut and host components by the immune system along with stimulation of pattern recognition receptors might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.

Concordance of genetic and breath tests for lactose intolerance in a tertiary referral centre.

BACKGROUND AND AIMS: Lactase non-persistence causes gastrointestinal symptoms after milk ingestion. Hydrogen breath test (BTH) and genotyping of a single nucleotide polymorphism (SNP) C >T 13,910 base pairs upstream of the lactase gene represent potential methods for diagnosis of this autosomal-recessive trait. The aim of the study was to compare the results of both tests in detecting lactose non-persistence in a tertiary referral centre. PATIENTS: A group of 58 patients admitted to a German university hospital for symptoms suggesting lactose intolerance. METHODS: BTH after lactose ingestion (50 g) and SNP -13,910C>T genotyping using single nucleotide primer extension (SNaPshot) technology (CC genotype--lactase non-persistence; TC/TT genotypes--lactase persistence). RESULTS: Overall, 17 (29%) patients had a positive and 41 (71%) had a negative BTH result; 15 (26%) patients were CC-positive and 43 (74%) were CC-negative [28 (48%) TC; 15 (26%) TT]. The genotype frequencies did not deviate from the Hardy-Weinberg equilibrium. In the CC-positive group, concordance between both tests was 100%. In contrast, in the CC-negative group concordance was 95%, and positive BTH results could be attributed to other gastrointestinal pathologies in two patients. BTH had 100% negative predictive value, 88% positive predictive value, 100% sensitivity and 95% specificity, as compared to genetic testing. CONCLUSIONS: In carriers of the CC-genotype, BTH and genotyping correlate perfectly, and the genetic test provides an unambiguous result. In BTH-positive individuals with a negative genetic test there is good reason to suspect secondary causes of lactase deficiency.

Hepatitis C-associated autoimmunity in patients coinfected with HIV.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with multiple extrahepatic manifestations. It is unclear to what extent extrahepatic manifestations occur in HIV/HCV coinfection. METHODS: We prospectively assessed cross-sectional frequencies of autoimmune manifestations in HIV/HCV-coinfected patients (n=98), HIV-mono-infected (n=45) and HCV-mono-infected patients (n=78). Diagnostic vasculitis scores, HCV and HIV loads, CD4 cell counts, thyroid-, cardiolipin-, non-organ-specific tissue antibodies (nuclear, smooth muscle, anti-liver-kidney-microsome, neutrophil-cytoplasmic) and cryoglobulins were determined. RESULTS: Synergistic effects of HCV and HIV infection were observed with respect to the prevalence of antibodies against thyroglobulin (HCV infection 15.4%, HIV infection 8.8%, HIV/HCV coinfection 30.6%; P<0.001) and cardiolipin antibodies (HCV infection 9.0%, HIV infection 31%, HIV/HCV coinfection 46%; P<0.001). Cryoglobulinemia type III, was significantly associated with HCV infection (HCV, 25.6%; HIV/HCV, 20.4%) but not with HIV infection (4.4%, P<0.05). Rheumatoid factor was commonly detected in patients with HCV infection (48%), but occurred considerably less frequently in patients with HIV infection (4.4%) or HIV/HCV coinfection (9.5%, P<0.01). CONCLUSION: HIV coinfection appears to differentially modulate the frequency of HCV-related autoimmunity. However, autoimmunity is rarely accompanied by clinical manifestations.

Role of auto-antibodies for the diagnosis of chronic cholestatic liver diseases.

Auto-antibodies are an integral part of the diagnostic armentarium in chronic cholestatic liver disorders, such as primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC),auto-immune cholangitis, or overlap syndromes among these disorders. However, care should be taken not to overestimate the diagnostic specificity. Auto-antibodies to mitochondrial antigens(AMAs) with reactivity to the E2 subunit of the pyruvate dehydrogenase complex represent the hallmark antibody for the diagnosis of PBC, whereas antinuclear antibodies (ANAs)with low disease specificity are found in up to 50% of these sera. Antibodies that recognize nuclear envelope proteins exert a similarly high diagnostic specificity as AMA in PBC but occur at a rather low prevalence. The role of auto-antibodies is less well-studied for patients with PSC, but there is growing evidence that only antineutrophil cytoplasmic antibodies(ANCAs) are of relevant diagnostic significance. In contrast, auto-antibodies-particularlyAMAs-do not contribute to the diagnosis of auto-immune cholangitis, whereas ANCAs,ANAs, smooth muscle antibodies, and AMAs are of varying significance in PBC-auto-immune hepatitis (AIH) or PSC-AIH overlap syndromes. It has been widely accepted that the course of the auto-antibody serum end point titers are not suited for the clinical management of patients with chronic cholestatic liver disorders. Additionally, auto-antibodies in these disorders usually do not contribute to the immunopathogenesis of the disease.

[Acute biliary colic. Etiology, diagnosis and therapy]. / Akute Gallenkolik. Ursachen, Diagnostik und Therapie.

Acute biliary pain represents the main symptom of gallbladder stones, less frequently of common bile duct stones or functional disorders of the biliary tract. The pain lasts at least 15 minutes, is typically localized to the epigastrium or the right upper quadrant of the abdomen and my radiate to the right shoulder. Diagnosis of biliary pain is primarily based on clinical criteria, ultrasound allows detection of causative gallstones with high sensitivity and specificity. Analgesics and laparoscopic cholecystectomy are widely accepted as standard therapy for the majority of patients.

Bleeding complications after percutaneous liver biopsy. An analysis of risk factors.

BACKGROUND AND AIMS: To assess the risk of bleeding after percutaneous liver biopsy, we retrospectively analyzed 629 procedures with particular respect to patients with an increased a priori bleeding risk. METHODS: Factors possibly related to the risk of bleeding were analyzed by univariate analysis. Those variables which were significant in the univariate analysis were then entered into a forward conditional logistic regression model. RESULTS: Biopsy-related bleeding events defined as clinically overt complication (n = 10; 1.6%), an otherwise unexplained drop in serum hemoglobin concentration of greater than 2 g/dl (n = 45; 7.1%) or intra- or extrahepatic hematoma assessed by ultrasound (n = 17; 2.7%) were identified in 72 patients. 58% of the bleeding events occurred in patients with particular risk factors for bleeding. Biopsy-related mortality in the study cohort was 0.48%. Logistic regression analysis indicated mycobacterial infection [odds ratio (OR) 24.0], pre-biopsy prophylactic platelet substitution (OR 9.9), acute liver failure (OR 9.1), heparin administration on the day of biopsy (OR 8.7), advanced liver cirrhosis (OR 5.1), therapy with corticosteroids (OR 3.5) or metamizole (OR 2.8) and leukemia or lymphoma (OR 2.8) as significant (p < or = 0.05) independent risk factors. Delayed bleeding (>24 h after biopsy) was identified in 70% of the bleeding events. CONCLUSIONS: In our study cohort which comprised a high proportion of patients with particular risk factors for bleeding, biopsy-related bleeding occurred more frequently and later than commonly observed and was associated with only a few prognostic factors. Considering these predictors before liver biopsy will aid to reduce the rate of bleeding complications.