The amount of liver tissue is essential for accurate histological staging in patients with autoimmune hepatitis.

The gold standard for the evaluation of liver fibrosis is histology. However, the heterogenous distribution of fibrosis limits the sensitivity of histology. The collection of two samples with a 16G needle is therefore recommended to reduce the risk of sampling error. The aim of this study was to investigate whether this standard is also applicable to patients with autoimmune hepatitis (AIH). This retrospective study included patients with AIH, who underwent mini-laparoscopic biopsy at our center between 2011 and 2020 (n = 32). Diagnosis was verified by usage of the simplified AIH score (≥ 6). Patients were categorized into three groups, based on the number of portal fields (PF) in the collected liver tissue (< 10 PF, 10 - 19 PF, ≥ 20 PF). We correlated the histological staging for these groups with the mini-laparoscopic fibrosis score (MLFS). Furthermore, non-invasive methods for the assessment of fibrosis were correlated with the histological staging (acoustic radiation force impulse (ARFI) and FIB-4 score). MLFS correlated well with histological staging (r = 0.649, p = 0.0001). The correlation between MLFS and histology improved with higher numbers of histologically analyzed portal fields (< 10 PF: r = 0.400, p = 0.378; 10 - 19 PF: r = 0.5467, p = 0.023; ≥ 20 PF: r = 0.956, p = 0.0002). The probability of collecting at least 10 or 20 portal fields was dependent on the number and diameter of the samples. For all patients with at least two 16G biopsies, 10 or more PF were available. With three 16G biopsies, at least 20 PF were obtained for all patients. ARFI correlated with MLFS and histological staging only in patients with low/moderate-grade inflammation as defined by ALT < 10xULN (upper limit of normal) (MLFS: r = 0.723; p = 0.004; histology: r = 0.619, p = 0.018). FIB-4 did not correlate with histological staging. The amount of liver tissue obtained by liver biopsy is crucial to minimalize the risk of sampling error and thus underestimation of fibrosis. This study was the first to investigate the amount of liver tissue required for histological staging in AIH. Our data suggest that diagnostic accuracy is likely to be higher with 20 PF compared to the generally recommended 10 PF. We therefore recommend to perform three biopsies with a 16G needle in (suspected) AIH patients. ARFI correlated well with histological staging unless inflammatory activity is high.

Very low-volume interval training improves nonalcoholic fatty liver disease fibrosis score and cardiometabolic health in adults with obesity and metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD) and cardiometabolic disorders are highly prevalent in obese individuals. Physical exercise is an important element in obesity and metabolic syndrome (MetS) treatment. However, the vast majority of individuals with obesity do not meet the general physical activity recommendations (i.e. 150 min of moderate activity per week). The present study aimed to investigate the impact of a highly time-saving high-intensity interval training (HIIT) protocol (28 min time requirement per week) on NAFLD fibrosis (NFS) and cardiometabolic risk scores in obese patients with MetS and elevated NFS values. Twenty-nine patients performed HIIT on cycle ergometers (5 x 1 min at an intensity of 80 - 95% maximal heart rate) twice weekly for 12 weeks and were compared to a control group without exercise (CON, n = 17). Nutritional counseling for weight loss was provided to both groups. NFS, cardiometabolic risk indices, MetS z-score, cardiorespiratory fitness (VO2max) and body composition were assessed before and after intervention. The HIIT (-4.3 kg, P < 0.001) and CON (-2.3 kg, P = 0.003) group significantly reduced body weight. There were no significant group differences in relative weight reduction (HIIT: -3.5%, CON: -2.4%). However, only the HIIT group improved NFS (-0.52 units, P = 0.003), MetS z-score (-2.0 units, P < 0.001), glycemic control (HbA1c: -0.20%, P = 0.014) and VO2max (+3.1 mL/kg/min, P < 0.001). Decreases in NFS (-0.50 units, P = 0.025) and MetS z-score (-1.4 units, P = 0.007) and the increment in VO2max (3.3 mL/kg/min, P < 0.001) were significantly larger in the HIIT than in the CON group. In conclusion, only 28 min of HIIT per week can elicit significant improvements in NFS and a several cardiometabolic health indices in obese MetS patients with increased NFS grades. Our results underscore the importance of exercise in NAFLD and MetS treatment and suggest that our low-volume HIIT protocol can be regarded as viable alternative to more time-consuming exercise programs.

Phase angle and vector analysis from multifrequency segmental bioelectrical impedance analysis: new reference data for older adults.

Phase angle (PA) and bioelectrical impedance vector analysis (BIVA) have been recommended as useful prognostic markers in various clinical settings. However, reference data for older adults measured by the novel segmental multifrequency bioelectrical impedance analysis (SMF-BIA) technique are currently lacking. This study examined 567 (286 men, 281 women) healthy older adults (65 - 97 years) and new SMF-BIA-based PA and BIVA reference values were generated stratified according to gender and 3 age groups (65 - 75 years, 76 - 85 years, > 85 years). Mean PA-values (women: 4.30 ± 0.6°, men: 4.77 ± 0.7°) were significantly lower than those previously reported for a younger reference population. Age and gender were significant determinants of PA and BIVA. PA showed a significant decrease with increasing age in both genders. The greatest changes occurred in the age group > 85 years. Men had higher Pas compared to women (except for the oldest age group), but showed a substantially steeper decline in PA, possibly due to a more pronounced reduction of muscle mass. Compared to published reference data for younger adults, there was a clear downward migration of the BIVA vector points in older adults, indicating an age-related reduction of body cell mass. Accordingly, the equation for the BIVA chart generation was modified by adding the factor age. In conclusion, this is the first study to present SMF-BIA-determined PA and BIVA reference data for healthy subjects aged ≥ 65 years. These data can be used for clinical purposes to identify individuals at increased risk for adverse health events or to monitor treatment responses.

Participation of the intestinal microbiota in the mechanism of beneficial effect of treatment with synbiotic Syngut on experimental colitis under stress conditions.

Gut-brain axis plays a central role in the regulation of stress related diseases such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). It is increasingly recognized that stress modulates gut microbiota community structure and activity and represents an important causal factor in dysbiosis. This study was designed to determine the effect of daily treatment with synbiotic (Syngut) containing inulin, Lactobacillus acidophilus, Bifidobacterium lactis W51, Lactobacillus plantarum W21 and Lactococcus lactis applied i.g. at a dose of 50 mg/kg i.g. on the colonic damage and colonic mucosal blood flow in rats with experimentally induced TNBS-colitis that were additionally exposed or not to acute stress (episodes of cold restraint stress every other day before colitis induction). Control rats received daily treatment with vehicle (saline, i.g.) or mesalazine (50 mg/kg-d i.g.), the standard drug recommended in therapy of IBD. At the termination of TNBS colitis, the histologic evaluation of colonic mucosa, mucosal malonyldialdehyde (MDA) level and plasma concentrations of proinflammatory cytokines (TNF-α, IL-1ß) and adipokine adiponectin were assessed. the samples of colonic mucosa not involving colonic lesions and surrounding the flared mucosa were excised for the determination of mRNA expression for proinflammatory biomarkers TNF-α, IL-1ß, IL-10 and COX-2 as well as antioxidazing factors SOD-1 and SOD-2. Finally, the gut microbial profiles were analyzed by 16S rRNA sequencing at phylum, family and genus level. Episodes of cold stress significantly aggravated the course of TNBS colitis, and significantly increased the release of proinflammatory cytokines as well as the significant increase in the MDA concentration has been observed as compared with non-stressed TNBS rats. These changes were followed by the significant fall in the CBF and plasma adiponectin levels and by the overexpression of mRNA of proinflammatory biomarkers. Synbiotic treatment with Syngut significantly reduced the area of colonic lesions observed macroscopically and microscopically in rats with TNBS colitis with or without exposure to cold stress, significantly increased the CBF, normalized plasma adiponectin levels and significantly attenuated the release and colonic expression of proinflammatory cytokines and biomarkers. the analysis of the gut microbiota showed a significant reduction of microbial diversity (Shannon index) in rats with TNBS colitis with or without exposure to stress. The therapy with Syngut failed to significantly affect the alpha diversity. At the phylum level, the significant rise in Proteobacteria has been observed in stressed rats with TNBS colitis and this effects was attenuated by treatment with Syngut. At family level, TNBS colitis alone or in combination with stress led to a significant decrease of SCFA producing bacterial taxa such as Ruminococaceae and Lachnospiraceae and Syngut counteracted this effect. We conclude that: 1) cold stress exacerbates the gastrointestinal inflammation in experimental colitis; 2) the synbiotic therapy with Syngut ameliorates the gut inflammation in rats with TNBS colitis combined with cold stress; 3) the beneficial effect of Syngut is accompanied by increase of anti-inflammatory taxa such as Ruminococaceae and Lachnospiraceae, and 4) the modulation of gut microbiota with Syngut alleviates stress-related intestinal inflammation suggesting a potential usefulness of synbiotic therapy in intestinal disorders accompanied by stress in patients with IBD.

COVID-19 - more than respiratory disease: a gastroenterologist's perspective.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) outbreak is the most dramatic event since World War II. Originating as a cluster of unexplained cases of pneumonia, it turned out that this viral disease termed COVID-19 is not only a respiratory infection, but a systemic disease associated with a number of extrapulmonary complications. One of the medical disciplines that is strongly affected by this viral infection is gastroenterology. COVID-19 causes in some patients typical symptoms of enteritis such as diarrhea or abdominal pain. There is also evidence that this infection may lead to liver and pancreatic injury. Since the SARS-CoV2 virus was detected in stool, a fecal-oral route of transmission is possible. Moreover, viral receptor angiotensin converting enzyme 2 (ACE2) is highly expressed in the gastrointestinal tract and enables the invasion of the gastrointestinal epithelium as demonstrated in vitro and in vivo. COVID-19 pandemic has an impact on the daily practice and the workflows in endoscopy leading to a dramatic decrease of screening and surveillance procedures. COVID-19 impacts the therapy of patients with inflammatory bowel disease (IBD), particularly those using high doses of corticosteroids, immunosuppressive agents and biologics. Patients with preexisting liver disease, especially metabolic associated liver fatty disease (MALFD) with fibrosis or liver cirrhosis, are at high risk for severe COVID-19. As long as no active vaccine against SARS-CoV2 is available, gastroenterologists have to be aware of these problems that affect their daily routine practice.

Effects of whole-body electromyostimulation exercise and caloric restriction on cardiometabolic risk profile and muscle strength in obese women with the metabolic syndrome: a pilot study.

Obesity, particularly in conjunction with further cardiometabolic risk factors, is associated with an increased risk of cardiovascular disease and mortality. Increased physical activity and dietary modifications are cornerstones of therapeutic interventions to treat obesity and related risk factors. Whole-body electromyostimulation (WB-EMS) has emerged as an innovative, time-efficient type of exercise that can provide positive effects on body composition and muscle strength. However, the impact of WB-EMS on cardiometabolic health in obese individuals with metabolic syndrome (MetS) has yet to be determined. The aim of this pilot study was, therefore, to investigate the feasibility and effects of WB-EMS on cardiometabolic risk markers and muscle strength in obese women diagnosed with MetS. Twenty-nine obese women (56.0 ± 10.9 years, BMI: 36.7 ± 4.6 kg/m2) with the clinical diagnosis of MetS were randomized to either 12 weeks of WB-EMS (n = 15) or an inactive control group (CON, n = 14). Both groups received nutritional counseling (aim: -500 kcal energy deficit/day). WB-EMS was performed 2x/week (20 min/session). Body composition, maximum strength (Fmax) of major muscle groups, selected cardiometabolic risk indices and the metabolic syndrome Z-score (MetS-Z) were determined baseline and after the intervention. WB-EMS was well tolerated and no adverse events occurred. Body weight was significantly reduced in both groups by an average of ~3 kg (P < 0.01). The body fat percentage was only decreased in the WB-EMS group (P = 0.018). Total cholesterol concentrations decreased in the WB-EMS group (P = 0.018) and in CON (P = 0.027). Only the WB-EMS group increased Fmax significantly in all major muscle groups (P < 0.05) and improved the overall cardiometabolic risk score (MetS-Z, P = 0.029). This pilot study indicates that WB-EMS can be considered as a feasible and time-efficient exercise option for improving body composition, muscle strength and cardiometabolic health in obese women with MetS. Moreover, these findings underpin the crucial role of exercise during weight loss interventions in improving health outcomes.

Multicenter analysis of endoclot as hemostatic powder in different endoscopic settings of the upper gastrointestinal tract.

Gastrointestinal bleeding (GIB) still presents a demanding situation with high morbidity and mortality rates; thus hemostatic powders such as EndoClot (EC) have been developed to improve endoscopic armament. The aim of the present study was to determine which indications triggered the application of EC and to assess resulting hemostasis rates. Forty three patients undergoing endoscopical procedures in three hospitals; two tertiary care and one university hospital, were included. EC was applied in 48 endoscopies in 43 patients (27 male, age 65.5 years, range 28 - 92 years) following four different indications. EC was used in active GIB as rescue or first-line therapy giving a short-term and long-term hemostasis in 13/17 patients (76.5%). In the setting of non-active GIB, following conventionally achieved hemostasis or endoscopic interventions, EC was found to prevent bleeding in 19/21 patients (90.4%). EC induced hemostasis in 8/10 patients (80%) with impaired coagulation. EC failures resulted from tumor bleeding, Forrest I lesions or perforated duodenal ulcers. No major adverse events were recorded and one technical failure (2.1%) occurred. EC was applied as first line or salvage treatment in ongoing bleedings with promising results. Furthermore, EC was used after successful hemostasis or following endoscopic interventions to further reduce re-bleeding rates. We saw promising results in all indications, albeit lacking a control group.

Different nutrient intake and prevalence of gastrointestinal comorbidities in women with endometriosis.

Even though endometriosis presents one of the most common gynaecological diseases, the pathogenesis is insufficiently studied. Besides immunologic, inflammatory or oxidative processes, recent studies also suggest an influence of nutrition on disease onset and progression. Because data about the actual nutrient intake of endometriosis patients are scarce, we aimed to examine the actual nutrient intake and potential influencing factors in these women. A total of 156 women with endometriosis (EM) and 52 age-matched controls were included in this retrospective case-control study. All women filled in a validated food frequency questionnaire to acquire the nutrient intake of the past 12 months and a disease-related questionnaire for the determination of disease status, clinical symptoms and comorbidities. Patients with endometriosis suffered significantly more from diet-related comorbidities like food intolerances (25.6% versus 7.7%; P = 0.009) and allergies (57% versus 31%; P < 0.001) compared to controls. Also gastrointestinal symptoms, including constipation, flatulence, pyrosis, diarrhea or frequent defecation, were higher in the EM group (77% versus 29%; P < 0.001). The nutrient intake of patients with endometriosis differed significantly compared to controls with a significantly lower ingestion of organic acids (P = 0.006), maltose (P = 0.0.16), glycogen (P = 0.035), tetradecenoic acid (P = 0.041), methionine (P = 0.046), lysine (P = 0.048), threonine (P = 0.046) and histidine (P = 0.049). The total intake of animal proteins was significantly lower in the EM group compared to the controls (P = 0.047). EM patients showed a decreased intake of vitamin C (P = 0.031), vitamin B12 (P = 0.008) and magnesium (P = 0.043) compared to controls. This study confirms a high association of endometriosis and gastrointestinal disorders accompanied by an altered nutrient intake. A dietary intervention by a professional nutritionist may help to reduce disease burden in the affected women.

Anticoagulant-related gastrointestinal bleeding: a real-life data analysis on bleeding profiles, frequency and etiology of patients receiving direct oral anticoagulants versus vitamin K antagonists.

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

Microbial patterns in patients with histamine intolerance.

Histamine intolerance represents a controversially discussed disorder. Besides an impaired degradation of orally supplied histamine due to diamine oxidase (DAO) deficiency, a deranged gut flora may also contribute to elevated histamine levels. Our aim was to determine the intestinal bacterial composition in patients with proven histamine intolerance in comparison to other food intolerances and healthy controls. A total of 64 participants were included in the study, encompassing 8 patients with histamine intolerance (HIT), 25 with food hypersensitivity (FH), 21 with food allergy and 10 healthy controls (HC). All participants underwent blood testing for total and food-specific immunoglobulin E, plasma histamine and DAO serum activity. Stool samples were used to analyze stool histamine and zonulin levels and bacterial composition by 16s rRNA sequencing. No significant differences in stool histamine levels were observed, but HIT patients showed elevated levels of stool zonulin. Microbiota analysis revealed increased levels of Proteobacteria (5.4%) and a significantly reduced alpha-diversity in the HIT group (P = 0.019). On family level, HC showed a significantly higher abundance of Bifidobacteriaceae compared to other study groups (P = 0.005), with lowest levels in the HIT group (P = 0.036). Also significantly reduced abundances of the genera Butyricimonas (P = 0.026) and Hespellia (P = 0.025) were observed in the HIT patients, whereas Roseburia were significantly elevated (P = 0.021). We concluded that the altered occurrence of Proteobacteria and Bifidobacteriaceae, reduced alpha-diversity as well as elevated stool zonulin levels suggest a dysbiosis and intestinal barrier dysfunction in histamine intolerant patients, which in turn may play an important role in driving disease pathogenesis.

Hypoglycemic side effects of sulfonylureas and repaglinide in ageing patients - knowledge and self-management.

Insulinotropic oral antidiabetics (OAD) such as sulfonylureas and (SU) glinides are among the frequently prescribed OAD. Side effects are the potential to induce hypoglycemias and weight gain. The aim was to assess the self-managing skills in case of a hypoglycemic event in an elderly type 2 diabetic patient population. In a 2-year period, 160 hospitalized patients (mean age 77.4 years) under insulinotrophic OAD were interviewed using a standardized questionnaire. Additionally, possible dementia was evaluated by using the Mini-Mental State Examination (MMSE) and the Clock-Drawing Test (CDT). The mean HbA1c was 7.6%. MMSE and CDT did intraindividually correlate well and 23.8% of the patients had moderate dementia (10 - 20 points MMSE), 13.1% had severe dementia (0 - 10 points MMSE) at the time of the survey. When under treatment with a sulfonylurea, only 16.0% of patients were aware of the potential hypoglycemia-inducing side effect. Moreover, only 11.8% of patients treated with a combination of a sulfonylurea and insulin knew this side effect of the OAD. The awareness of the side effects of repaglinide was 21.6% (without insulin therapy) versus 21.4% in the insulin-comedicated group. Only 42.6% of patients treated with sulfonylureas or repaglinide knew how to act in the case of hypoglycemia. Even under comedication with insulin, only in 41.2% of the respondents in the comedicated group knew how to take action if they were to experience hypoglycemia. Our findings raise concerns and demonstrate, that the self-managing skills in an elderly patient group are not good, which may become an increasing problem in an ageing population. The prescription or the re-prescription of insulinotropic OAD needs to be adapted to the current cognitive situation and re-evaluated regularly.

[Therapeutic modulation of intestinal microbiota in irritable bowel syndrome. From probiotics to fecal microbiota therapy]. / Therapeutische Modulation der Darmmikrobiota beim Reizdarmsyndrom : Von Probiotika bis zur fäkalen Mikrobiota-Therapie.

BACKGROUND: An abnormal intestinal microbiota (dysbiosis) plays a central role in the pathogenesis of the irritable bowel syndrome. METHOD: An overview of four current options for the treatment of irritable bowel syndrome, which are characterized by modulation of intestinal microbiota, is given. RESULTS AND CONCLUSIONS: Probiotics have very different effects on the individual symptoms of the irritable bowel. The choice of the appropriate preparation should therefore be based on the clinical symptomatology. The antibiotic rifaximin is effective in selected patients. Some patients also benefit from the repetition of this therapy. A FODMAP-reduced diet has shown significant alleviation of irritable bowel symptoms in studies. The fecal microbiota therapy (FMT) is a promising treatment option. At present, however, there are no such placebo-controlled studies to assess the effectiveness of this method.

Successful therapy of Clostridium difficile infection with fecal microbiota transplantation.

Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea and represents an important burden for healthcare worldwide. Symptoms of severe CDI include watery, foul-smelling diarrhea, peripheral leucocytosis, increased C-reactive protein (CRP), acute renal failure, hypotension and pseudomembranous colitis. Recent studies indicate that the main cause of CDI is dysbiosis, an imbalance in the normal gut microbiota. The restoration of a healthy gut microbiota composition via fecal microbiota transplantation (FMT) recently became more popular. The aim of the present study was to assess the effect of FMT on the healing of CDI and to analyze the changes in the level of pro-inflammatory markers (C-reactive protein, fecal calprotectin) and pro-inflammatory cytokines. Eighteen patients with CDI were included in our study (6 males and 12 females) with recurrent and/or severe CDI. The FMT was performed in 17 patients using colonoscopy, including 16 patients receiving a one-time FMT and 1 patient who needed 2 additional FMTs. One patient was treated with a single round of FMT using push-and-pull enteroscopy. In all CDI patients, before and 3 weeks after FMT, the following parameters were analyzed: C-reactive protein, fecal calprotectin, and plasma interleukin (IL)-6, IL-8 and IL-12, and tumor necrosis factor-alpha (TNF-α). In addition, the plasma level of LL-37, a cathelicidine peptide was assessed by fluorescence-activated cell sorting (FACS) before and 3 months after FMT. Finally, in 7 patients a microbiome analysis was performed by sequencing of 16SrRNA in stool probes obtained before and 3 weeks after FMT. The healing rate of CDI was 94%. In all successfully treated patients no recurrent CDI was observed during follow-up (16 months). The serum level of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-8 and IL-12) significantly decreased after FMT. Similarly, CRP and fecal calprotectin normalized after FMT. 3 months after FMT a significant increase of LL-37 in the plasma of successfully treated patients was monitored. The sequencing analysis demonstrated an elevated abundance of beneficial bacterial species such as Lactobacillaceae, Ruminococcaceae, Desulfovibrionaceae, Sutterellaceae and Porphyromonodacea after FMT. No serious side effects were observed. We concluded that FMT represented a very effective and safe treatment of recurrent and/or severe CDI and led to favorable shifts in the composition of gut microbiome.

Emerging role of fecal microbiota therapy in the treatment of gastrointestinal and extra-gastrointestinal diseases.

In the recent decade our understanding of the role of the human gut microbiome has been revolutionized by advances in development of molecular methods. Approximately, up to 100 trillion (10(14)) microorganisms per human body colonize the intestinal tract making an additional acquired organ that provides many vital functions to the host. A healthy gut microbiome can be defined by the presence of the various classes of microbes that enhance metabolism, resistance to infection and inflammation, prevention against cancer and autoimmunity and that positively influence so called braingut axis. Diet represents one of the most important driving forces that besides environmental and genetic factors, can define and influence the microbial composition of the gut. Aging process due to different changes in gut physiology (i.e. gastric hypochlorhydria, motility disorders, use of drugs, degenerative changes in enteric nervous system) has a profound effect on the composition, diversity and functional features of gut microbiota. A perturbed aged gut microbiome has been associated with the increasing number of gastrointestinal (e.g. Clostridium difficile infection - CDI) and non-gastrointestinal diseases (metabolic syndrome, diabetes mellitus, fatty liver disease, atherosclerosis etc.). Fecal microbiota transplantation (FMT) is a highly effective method in the treatment of refractory CDI. FMT is the term used when stool is taken from a healthy individual and instilled during endoscopy (colonoscopy or enteroscopy) into a gut of the sick person to cure certain disease. FMT represents an effective therapy in patient with recurrent CDI and the effectiveness of FMT in the prevention of CDI recurrence had reached approx. 90%. There is also an increasing evidence that the manipulation of gut microbiota by FMT represents a promising therapeutic method in patients with inflammatory bowel disease and irritable bowel syndrome. There is also an increased interest in the role of FMT for the treatment of metabolic syndrome and obesity which collectively present the greatest health challenge in the developed world nowadays. Targeting of gut microbiota by FMT represents an exciting new frontier in the prevention and management of gastrointestinal and non-gastrointestinal diseases that awaits further studies in preclinical and clinical settings.

Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease.

Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-α) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-α levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P ≤ 0.04). Plasma TNF-α levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-α values, but not the type of treatment. We concluded that in contrast to TNF-α, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-α secreted from mast cells in the plasma in patients with IBD is less important.

Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease--14 months follow up.

Non-alcoholic fatty liver disease (NAFLD), most common chronic hepatic pathology, that occurs in the developed countries is estimated at 1/3 of the population. Amongst the numerous pathogenetic factors, oxidative stress and apoptosis of hepatocytes initiate many inflammatory processes and are involved in the progression of disease, particularly in transformation of non-alcoholic steatohepatitis (NASH) to cirrhosis. The aim of our study was to determine the effects of tryptophan and melatonin on the selected biochemical parameters in patients with NAFLD, and additionally, to evaluate the effects of tryptophan and melatonin in improvement of liver tissue in selected NAFLD patients. Seventy four patients with NAFLD confirmed by histopathological examination of liver biopsy samples, were admitted to the study. They were randomly assigned to three groups. Group I received the preparation Essentiale forte in the dose of 3 x 1 tablet per day and tryptophan 2 x 500 mg/day over the period of 14 months, group II received Essentiale forte and melatonin 2 x 5 mg/day over 14 months and group III received only Essentiale over the period of 14 months. In nine patients of groups I, II, and III, the liver biopsy was performed after 14-months of treatment period. Out of nine patients whom biopsy was performed, three of them were from group I, four from group II and two of them were from group III, respectively. After the 14-month treatment period, gamma-glutamyl transferase (GGPT) activity and levels of triglycerides and LDL-cholesterol were found to be significantly reduced in group I and II. The level of melatonin after the therapy was significantly elevated in group I and II and did not change in group III. Statistically significantly lower levels of IL-1, IL-6 and TNF-α were observed in patients receiving melatonin and tryptophan, comparing with group III treated with Essentiale forte only. These study findings demonstrate that melatonin and tryptophan substantially reduce the levels of pro-inflammatory cytokines and improve some parameters of fat metabolism in patients with NAFLD. In few patients with NASH melatonin and tryptophan reduced the inflammation in liver. We conclude that melatonin is worth considering for the therapy of NAFLD, particularly in patients with impaired fat metabolism accompanied by hypertriglyceridemia and hyper-LDL cholesterolemia.

Melatonin and omentin: influence factors in the obstructive sleep apnoea syndrome?

The incidence of the obstructive sleep apnoea syndrome (OSAS) is rising as it is often associated with obesity. Actually, the adipose tissue is working as an endocrine organ with complex interactions. Recently, many adipokines such as omentin-1 were discovered. The role of omentin-1 in the pathogenesis of OSAS has not been clearly determined. Melatonin has a known influence on the sleep and wake rhythm. The data on the involvement of melatonin in OSAS are rare. Therefore we evaluated the changes in plasma levels of omentin-1 and melatonin before and after continuous positive airway pressure (CPAP) therapy in OSA patients. 10 patients with newly diagnosed OSAS were included in the study. They underwent diagnostic polysomnography with blood drawings in a 2 hour interval for 24 hours. In the second night sufficient CPAP therapy was established. After three months of CPAP therapy the measurements were repeated. As controls 10 healthy volunteers were recruited. The same blood analysis and a polygraphic measurement were made and compared with the patients. OSA patients showed significantly higher omentin-1 plasma levels (17.22±13.94 versus 9.24±4.85 ng/ml, p<0.05). After three months of therapy the plasma levels of omentin-1 decreased toward the values observed in the controls at 8.00 a.m. Melatonin showed the usual peak at 2.00 a.m. in the volunteer group. OSA patients showed a later peak of melatonin at 6.00 a.m. which returned to 2.00 a.m. after CPAP therapy. We conclude that omentin as well as melatonin seem to be involved in pathogenesis of OSAS. To what exent, further studies will have to face that question.

Gastrin mediated down regulation of ghrelin and its pathophysiological role in atrophic gastritis.

The gastric hormone ghrelin is known as an important factor for energy homeostasis, appetite regulation and control of body weight. So far, ghrelin has mainly been examined as a serological marker for gastrointestinal diseases, and only a few publications have highlighted its role in local effects like mucus secretion. Ghrelin can be regarded as a gastroprotective factor, but little is known about the distribution and activity of ghrelin cells in pathologically modified tissues. We aimed to examine the morphological changes in ghrelin expression under several inflammatory, metaplastic and carcinogenic conditions of the upper gastrointestinal tract. In particular, autoimmune gastritis showed interesting remodeling effects in terms of ghrelin expression within neuroendocrine cell hyperplasia by immunohistochemistry. Using confocal laser microscopy, the gastrin/cholecystokinin receptor (CCKB) could be detected on normal ghrelin cells as well as in autoimmune gastritis. Functionally, we found evidence for a physiological interaction between gastrin and ghrelin in a primary rodent cell culture model. Additionally, we gathered serological data from patients with different basic gastrin levels due to long-term autoimmune gastritis or short-term proton pump inhibitor treatment with slightly reactive plasma gastrin elevations. Total ghrelin plasma levels showed a significantly inverse correlation with gastrin under long-term conditions. Autoimmune gastritis as a relevant condition within gastric carcinogenesis therefore has two effects on ghrelin-positive cells due to hypergastrinemia. On the one hand, gastrin stimulates the proliferation of ghrelinpositive cells as integral part of neuroendocrine cell hyperplasia, while on the other hand, plasma ghrelin is reduced by gastrin and lost in pseudopyloric and intestinal metaplastic areas. Ghrelin is necessary for the maintenance of the mucosal barrier and might play a role in gastric carcinogenesis, if altered under these pre neoplastic conditions.

Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, interacts with gastric oxidative metabolism and enhances stress-induced gastric lesions.

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase known to exert vasoconstriction of vascular bed. The elevation of ADMA has been considered as the cardiovascular risk factor associated with hyperlipidemia, hypercholesterolemia and metabolic syndrome. ADMA is produced by the action of dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine. Previous studies have shown that endogenous NO plays an important role in the mechanism of gastric mucosal defense, but the role of ADMA in the pathogenesis of serious clinical entity, such as the acute gastric mucosal injury induced by stress has been little studied. In present study, we determined the effect of intragastric (i.g.) pretreatment with ADMA applied in graded doses ranging from 0.1 up to 20 mg/kg on gastric mucosal lesions induced by 3.5 h of water immersion and restraint stress (WRS). The number of gastric lesions was determined by planimetry and the gastric blood flow (GBF) was assessed by laser Doppler technique. The malondialdehyde and 4-hydroxynonenal (MDA+4-HNE) concentration, as an index of oxygen radical-lipid peroxidation was assessed in the gastric mucosa in rats exposed to WRS with or without ADMA administration. Proinflammatory cytokines IL-1ß, TNF-α, superoxide dismutase (SOD) and glutathione peroxidase (GPx) mRNAs in the gastric mucosa and plasma levels of ADMA, IL-1ß and TNF-α were analyzed by RT-PCR and ELISA, respectively. The exposure of rats to WRS for 3.5 h produced acute gastric lesions accompanied by a significant rise in the plasma ADMA levels and a significant fall in the GBF, an increase in MDA+4-HNE concentrations and the significant increase in the expression and release of IL-1ß and TNF-α. The pretreatment with ADMA, applied i.g. 30 min before WRS dose-dependently, aggravated WRS damage and this effect was accompanied by a further significant fall in the GBF. The ADMA induced exacerbation of WRS lesions and the accompanying rise in the plasma ADMA levels and the fall in GBF were significantly attenuated by concurrent treatment with glyceryl trinitrate (GTN) (10 mg/kg i.g.) in the presence of ADMA. Administration of ADMA resulted in a significant decrease in the expression of SOD and GPx mRNAs and the up-regulation of mRNA for IL-1ß and TNF-α followed by an increase in these plasma cytokine levels as compared to respective values observed in vehicle-pretreated animals. We conclude that 1) ADMA could be implicated in the mechanism of WRS-induced ulcerogenesis, 2) ADMA exacerbates WRS-induced gastric lesions due to enhancement in neutrophil dependent lipid peroxidation and overexpression and release of proinflammatory cytokines IL-1ß and TNF-α and a potent depletion of antioxidative enzymes SOD and GPx expression and activity.

Analysis of immediate ex vivo release of nitric oxide from human colonic mucosa in gastrointestinally mediated allergy, inflammatory bowel disease and controls.

Nitric oxide (NO) is a local mediator in inflammation and allergy. The aim of this study was to investigate whether live incubated colorectal mucosal tissue shows a direct NO response ex vivo to nonspecific and specific immunological stimuli and whether there are disease-specific differences between allergic and chronic inflammatory bowel disease (IBD). We took biopsies (n=188) from 17 patients with confirmed gastrointestinally mediated food allergy, six patients with inflammatory bowel disease, and six control patients. To detect NO we employed an NO probe (WPI GmbH, Berlin, Germany) that upon stimulation with nonspecific toxins (ethanol, acetic acid, lipopolysaccharides), histamine (10(-8)-10(-4)M), and immune-specific stimuli (anti-IgE, anti-IgG, known food allergens) directly determined NO production during mucosal oxygenation. Non-immune stimulation of the colorectal mucosa with calcium ionophore (A23187), acetic acid, and ethanol induced a significant NO release in all groups and all biopsies. Whereas, immune-specific stimulation with allergens or anti-human IgE or -IgG antibodies did not produce significant release of NO in controls or IBD. Incubation with anti-human IgE antibodies or allergens produced a ninefold increase in histamine release in gastrointestinally mediated allergy (p<0.001), but anti-human IgE antibodies induced NO release in only 18% of the allergy patients. Histamine release in response to allergens or anti-human IgE antibodies did not correlate with NO release (r(2)=0.11, p=0.28). These data show that nonspecific calcium-dependent and toxic mechanisms induce NO release in response to a nonspecific inflammatory signal. In contrast, mechanisms underlying immune-specific stimuli do not induce NO production immediately.