The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis.

BACKGROUND: Faecal microbiota transplantation is an experimental approach for the treatment of patients with ulcerative colitis. Although there is growing evidence that faecal microbiota transplantation is effective in this disease, factors affecting its response are unknown. AIMS: To establish a faecal microbiota transplantation treatment protocol in ulcerative colitis patients, and to investigate which patient or donor factors are responsible for the treatment success. METHODS: This is an open controlled trial of repeated faecal microbiota transplantation after antibiotic pre-treatment (FMT-group, n = 17) vs antibiotic pre-treatment only (AB-group, n = 10) in 27 therapy refractory ulcerative colitis patients over 90 days. Faecal samples of donors and patients were analysed by 16SrRNA gene-based microbiota analysis. RESULTS: In the FMT-group, 10/17 (59%) of patients showed a response and 4/17 (24%) a remission to faecal microbiota transplantation. Response to faecal microbiota transplantation was mainly influenced by the taxonomic composition of the donor's microbiota. Stool of donors with a high bacterial richness (observed species remission 946 ± 93 vs no response 797 ± 181 at 15367 rps) and a high relative abundance of Akkermansia muciniphila (3.3 ± 3.1% vs 0.1 ± 0.2%), unclassified Ruminococcaceae (13.8 ± 5.0% vs 7.5 ± 3.7%), and Ruminococcus spp. (4.9 ± 3.5% vs 1.0 ± 0.7%) were more likely to induce remission. In contrast antibiotic treatment alone (AB-group) was poorly tolerated, probably because of a sustained decrease of intestinal microbial richness. CONCLUSIONS: The taxonomic composition of the donor's intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in ulcerative colitis patients. The design of specific microbial preparation might lead to new treatments for ulcerative colitis.

Prospective multicentre clinical study on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori.

OBJECTIVES: We report on a large prospective, multicentre clinical investigation on inter- and intrapatient genetic variability for antimicrobial resistance of Helicobacter pylori. METHODS: Therapy-naive patients (n = 2004) who had undergone routine diagnostic gastroscopy were prospectively included from all geographic regions of Austria. Gastric biopsy samples were collected separately from antrum and corpus. Samples were analysed by histopathology and real-time PCR for genotypic resistance to clarithromycin and quinolones. Clinical and demographic information was analysed in relation to resistance patterns. RESULTS: H. pylori infection was detected in 514 (26%) of 2004 patients by histopathology and confirmed in 465 (90%) of 514 patients by real-time PCR. PCR results were discordant for antrum and corpus in 27 (5%) of 514 patients, indicating inhomogeneous infections. Clarithromycin resistance rates were 17% (77/448) and 19% (84/455), and quinolone resistance rates were 12% (37/310) and 10% (32/334) in antrum and corpus samples, respectively. Combination of test results per patient yielded resistance rates of 21% (98/465) and 13% (50/383) for clarithromycin and quinolones, respectively. Overall, infection with both sensitive and resistant H. pylori was detected in 65 (14%) of 465 patients. CONCLUSIONS: Anatomically inhomogeneous infection with different, multiple H. pylori strains is common. Prospective clinical study design, collection of samples from multiple sites and microbiologic methods that allow the detection of coinfections are mandatory for collection of reliable data on antimicrobial resistance patterns in representative patient populations. (ClinicalTrials.gov identifier: NCT02925091).

Consensus report: faecal microbiota transfer - clinical applications and procedures.

BACKGROUND: Faecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication. AIM: To provide an expert consensus on current clinical indications, applications and methodological aspects of FMT. METHODS: Well-acknowledged experts from various countries in Europe have contributed to this article. After literature review, consensus has been achieved by repetitive circulation of the statements and the full manuscript among all authors with intermittent adaptation to comments (using a modified Delphi process). Levels of evidence and agreement were rated according to the GRADE system. Consensus was defined a priori as agreement by at least 75% of the authors. RESULTS: Key recommendations include the use of FMT in recurrent C. difficile infection characterised by at least two previous standard treatments without persistent cure, as well as its consideration in severe and severe-complicated C. difficile infection as an alternative to total colectomy in case of early failure of antimicrobial therapy. FMT in inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and metabolic syndrome should only be performed in research settings. CONCLUSIONS: Faecal microbiota transplantation or transfer is a promising treatment for a variety of diseases in which the intestinal microbiota is disturbed. For indications other than C. difficile infection, more evidence is needed before more concrete recommendations can be made.

[Recommendations for the use of faecal microbiota transplantation "stool transplantation": consensus of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) in cooperation with the Austrian Society of Infectious Diseases and Tropical Medicine]. / Empfehlungen zur Anwendung der fäkalen Mikrobiotatransplantation "Stuhltransplantation": Konsensus der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) in Zusammenarbeit mit der Österreichischen Gesellschaft für Infektiologie und Tropenmedizin (OEGIT).

The intestinal microbiota has a pivotal role in the maintenance of health of the human organism, especially in the defense against pathogenic microorganisms. Alterations in the microbiota, also termed dysbiosis, seem to be involved in the pathogenesis of a variety of intestinal and extraintestinal diseases. Fecal microbiota transplantation (FMT), also known as stool transplantation, is a therapeutic procedure aiming at restoring an altered intestinal microbiota by administration of stool microorganisms from a healthy donor into the intestinal tract of a patient. FMT is most commonly used for recurrent forms of Clostridium difficile infections (CDI). There are currently many cohort studies in a large number of patients and a randomized controlled trial showing a dramatic effect of FMT for this indication. Therefore FMT is recommended by international medical societies for the treatment of recurrent CDI with high scientific evidence. Other potential indications are the treatment of fulminant CDI or the treatment of inflammatory bowel diseases. In the practical utilization of FMT there are currently several open questions regarding the screening of stool donors, the processing of stool and the mode of FMT application. Different modes of FMT application have been described, the application into the colon has to be preferred due to less reported side effects than the application into the upper gastrointestinal tract. So far only very few side effects due to FMT have been reported, nevertheless the use and risks of FMT are currently intensely debated in the medical community. This consensus report of the Austrian society of gastroenterology and hepatology (ÖGGH) in cooperation with the Austrian society of infectious diseases and tropical medicine provides instructions for physicians who want to use FMT which are based on the current medical literature.

Faecal microbiota transplantation--the Austrian approach.

The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Faecal microbiota transplantation (FMT) is aimed at correcting these alterations by delivering faecal microorganisms from a healthy person to the intestines of a patient. At present, recurrent Clostridium difficile infection is the only indication supported by solid scientific evidence, but many ongoing studies are investigating FMT in other dysbiosis-related diseases, such as inflammatory bowel disease. As there are no systematic methodological investigations, several questions about techniques, donor screening and safety issues remain. This shortage of evidence, especially on long-term safety concerns, is leading to worldwide controversy regarding the use of FMT. Regulations by healthcare authorities vary among different countries. This review reflects the Austrian situation and its FMT guidelines concerning indications, techniques and donor screening, recently developed by local scientific societies.

Incidence of inflammatory bowel disease in the province of Styria, Austria, from 1997 to 2007: a population-based study.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) varies widely between different countries. This large variation is also observed for the incidence of its main two forms, ulcerative colitis (UC) and Crohn's disease (CD). Controversy exists whether IBD incidence is increasing, especially in western countries. Currently no data are available for Austria. This study therefore aimed to evaluate for the first time the incidence of IBD over an eleven-year period in Styria, a province of Austria with a population of 1.2 million. METHODS: All patients with an initial diagnosis of IBD between 1997 and 2007, who were Styrian residents, were eligible for this retrospective study. Data were acquired from electronically stored hospital discharge reports and individual reports by patients and physicians. According to population density Styria was divided into two rural and one urban area. RESULTS: Throughout the study period 1527 patients with an initial diagnosis of IBD were identified. The average annual incidence was 6.7 (95% CI 6.2-7.1) per 100,000 persons per year for CD and 4.8 (95% CI 4.5-5.2) for UC. The average annual incidence increased significantly (p<0.01) for both diseases during the 11 year study period. Median age at initial diagnosis was 29 years (range 3-87) for CD and 39 years (range 3-94) for UC. At diagnosis, 8.5% of all IBD patients were <18 years of age. The incidence of both CD and UC was significantly higher in the urban area than in rural areas (CD: 8.8, 95% CI 7.8-9.8 versus 5.5, 95% CI 4.7-6.4 and 5.9, 95% CI 5.3-6.7; [p<0.001]; UC: 5.8, 95% CI 5.1-6.6 versus 4.0, 95% CI 3.4-4.7 and 4.7, 95% CI 4.1-5.4; [p=0.04]). CONCLUSION: We observed an overall increase in the incidence of ulcerative colitis and Crohn's disease in a part of Austria during an eleven year period. IBD was more predominant in the largest urban area than in rural areas.

[Inflammatory esophageal polyp with bizarre stromal cells: possible diagnostic pitfall]. / Bizarre Stromazellen in einem inflammatorischen Ösophaguspolypen: Ein möglicher diagnostischer Fallstrick.

In the gastrointestinal tract an accurate diagnosis of tumor-like lesions can be challenging. In patients with reflux disease regenerative hyperplasia of esophageal squamous epithelium may show marked pleomorphism and atypia thereby simulating malignancy. Bizarre stromal cells are another diagnostic pitfall. We present the case of a 46-year-old patient with symptoms of reflux disease who was diagnosed with a benign inflammatory polyp at the distal end of the esophagus. Histology revealed bizarre cells within the stroma of the polyp characterized by nuclear hyperchromatism and enlargement. Mitoses were not observed. The atypical cells were positive for vimentin. The Ki67/MIB-1 proliferation rate was low. The morphology and etiology of bizarre stromal cells, including helpful features for differential diagnosis are thoroughly discussed.

[Probiotics for the prevention of antibiotic-induced diarrhea]. / Probiotika in der Prävention der Antibiotika-induzierten Diarrhö.

Between 5 and 49% of patients treated with antibiotics suffer from diarrhoea. Principally all microbial agents can cause diarrhoea, especially oral agents like cephalosporines, clindamycin, broad-spectrum penicillins, and quinolones of the 3  rd and 4th generation. Manifestations of antibiotic-associated diarrhoea range from mild self-limiting forms to severe life-threatening courses. The potentially most severe form of antibiotic-associated diarrhoea is caused by Clostridium diffcile accounting for approx. 25  % of antibiotic-associated diarrhoea. In the past two decades a broad spectrum of different probiotic strains has been evaluated for the primary prevention of antibiotic-associated diarrhoea in children and adults. Based on their efficacy and clinical data, different levels of evidence and recommendations are emerging on the preventive use of probiotics in antibiotic-associated diarrhoea.

Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study.

OBJECTIVES: The lower esophageal sphincter (LES), surrounded by diaphragmatic muscle, prevents gastroesophageal reflux. When these structures become incompetent, gastric contents may cause gastroesophageal reflux disease (GERD). For treatment, lifestyle interventions are always recommended. We hypothesized that by actively training the crura of the diaphragm as part of the LES using breathing training exercises, GERD can be positively influenced. METHODS: A prospective randomized controlled study was performed. Patients with non-erosive GERD or healed esophagitis without large hernia and/or previous surgery were included. Patients were randomized and allocated either to active breathing training program or to a control group. Quality of life (QoL), pH-metry, and on-demand proton pump inhibitor (PPI) usage were assessed at baseline and after 4 weeks of training. For long-term follow-up, all patients were invited to continue active breathing training and were further assessed regarding QoL and PPI usage after 9 months. Paired and unpaired t-test was used for statistical analysis. RESULTS: Nineteen patients with non-erosive GERD or healed esophagitis were randomized into two groups (10 training group and 9 control group). There was no difference in baseline patient characteristics between the groups and all patients finished the study. There was a significant decrease in time with a pH<4.0 in the training group (9.1±1.3 vs. 4.7±0.9%; P<0.05), but there was no change in the control group. QoL scores improved significantly in the training group (13.4±1.98 before and 10.8±1.86 after training; P<0.01), but no changes in QoL were seen in the control group. At long-term follow-up at 9 months, patients who continued breathing exercise (11/19) showed a significant decrease in QoL scores and PPI usage (15.1±2.2 vs. 9.7±1.6; 98±34 vs. 25±12 mg/week, respectively; P<0.05), whereas patients who did not train had no long-term effect. CONCLUSIONS: We show that actively training the diaphragm by breathing exercise can improve GERD as assessed by pH-metry, QoL scores and PPI usage. This non-pharmacological lifestyle intervention could help to reduce the disease burden of GERD.

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

UNLABELLED: Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. INTRODUCTION AND HYPOTHESIS: Adult-type hypolactasia (HL) defined by the LCT(-13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). METHODS: Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H(2) breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. RESULTS: LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 +/- 629 microg/L vs. 2020 +/- 1130 microg/L in lactose tolerant subjects, p=0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. CONCLUSION: Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.

Effects of lactulose and polyethylene glycol on colonic transit.

BACKGROUND: The effects of lactulose and polyethylene glycol on colonic transit are poorly established. AIM: To assess the effects of these laxatives on colonic transit in normal subjects. METHODS: Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3-day ingestion of 67-134 g/day lactulose, or 59 g/day polyethylene glycol. RESULTS: At similar stool weight (lactulose: 653 +/- 120 g/day; polyethylene glycol: 522 +/- 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose - 403 +/- 55 min; polyethylene glycol - 160 +/- 41.9 min). Short chain fatty acid concentration in 24-h stool correlated significantly with counts remaining in the distal colon at 12 h (r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = -0.56) and distal colon (r = -0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P < 0.001). CONCLUSION: Lactulose accelerates colonic transit. However, compared with polyethylene glycol, transit during lactulose is prolonged.

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis.

BACKGROUND: Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication. METHODS: Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression. RESULTS: All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common. CONCLUSION: Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.

Effect of octreotide on fluid absorption and secretion by the normal human jejunum and ileum in vivo.

BACKGROUND: We hypothesized that part of the non-specific antidiarrhoeal effect of octreotide is mediated by a proabsorptive or antisecretory effect on small intestinal active electrolyte transport. METHODS: To measure the effect of octreotide on net absorption, the jejunum and ileum of normal human subjects were perfused with a balanced electrolyte solution; to measure the effect of octreotide on normal active chloride secretion, the jejunum was perfused with a bicarbonate-free solution. RESULTS: During perfusion of a balanced electrolyte solution, octreotide increased basal net fluid absorption in the jejunum and ileum by about 40 mL/h per 30 cm. In the jejunum, octreotide markedly inhibited basal and sham feeding-stimulated active chloride secretion and inhibited water secretion by 28 and 51 mL/h per 30 cm, respectively. CONCLUSIONS: Octreotide causes an increase in the net epithelial cell absorption rate of a balanced electrolyte solution in the normal jejunum and ileum. In the jejunum, this proabsorptive effect is mediated mainly by the reduction of normal active electrolyte secretion, rather than by stimulation of normal active electrolyte absorption. These results support the hypothesis that part of the antidiarrhoeal action of octreotide is due to its effects on active electrolyte transport mechanisms by normal epithelial cells of the small intestine.

Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion.

To explain the very high frequency of cystic fibrosis (CF) mutations in most populations of European descent, it has been proposed that CF heterozygotes have a survival advantage when infected with Vibrio cholerae or Escherichia coli, the toxins of which induce diarrhea by stimulation of active intestinal chloride secretion. Two assumptions underlie this hypothesis: (1) chloride conductance by the CF transmembrane conductance regulator (CFTR) is the rate-limiting step for active intestinal chloride secretion at all levels of expression, from approximately zero in patients with CF to normal levels in people who are not carriers of a mutation; and (2) heterozygotes have smaller amounts of functional intestinal CFTR than do people who are not carriers, and heterozygotes therefore secrete less chloride when exposed to secretagogues. The authors used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analogue. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less-than-normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results do not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal illnesses mediated by intestinal hypersecretion of chloride.

Discrepancies between effects of recombinant human growth hormone on absorption and secretion of water and electrolytes on the human jejunum compared to results reported on rat jejunum.

Previous studies in rats showed that the administration of recombinant human growth hormone markedly increased intestinal absorption of electrolytes and water and suggested that growth hormone would be a useful antidiarrheal agent. We therefore examined the effect of recombinant human growth hormone on the human jejunum in vivo, using a triple lumen nonabsorbable marker technique. Healthy subjects were studied on two different test days, one as a control and a second where recombinant human growth hormone was injected subcutaneously in a dose of 100 microg/kg. With this dose we achieved equal or higher growth hormone serum levels than in previous rat studies. However the administration of recombinant human growth hormone did not stimulate absorption or inhibit secretion of water and electrolytes in the human jejunum in vivo. We believe that the discrepancy between humans and rats is most likely due to the species difference rather than to differences in methods that were used. Therefore recombinant human growth hormone cannot be considered a useful proabsorptive antidiarrheal agent in humans.

Mechanisms and management of antibiotic-associated diarrhea.

Only 10%-20% of all cases of antibiotic-associated diarrhea (AAD) are caused by infection with Clostridium difficile. Other infectious organisms causing AAD include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species, and Salmonella species. Most of the clinically mild AAD cases are due to functional disturbances of intestinal carbohydrate or bile acid metabolism, to allergic and toxic effects of antibiotics on intestinal mucosa, or to pharmacological effects on motility. Saccharomyces boulardii and Enterococcus SF68 can reduce the risk of developing AAD. Patients receiving antibiotic treatment should avoid food containing high amounts of poorly absorbable carbohydrates. Mild cases of AAD that may or may not be caused by C. difficile can be resolved by discontinuation of antibiotic therapy and by dietary carbohydrate reduction. Only severe AAD caused by C. difficile requires specific antibiotic treatment.