Probiotics for people with hepatic encephalopathy

Background Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro‐organisms, which when administered in adequate amounts, may confer a health benefit on the host. Objectives To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. Search methods We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. Selection criteria We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random‐effects model meta‐analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). Main results We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias. We found no effect on all‐cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low‐quality evidence). No‐recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate‐quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low‐quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low‐quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low‐quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta‐analysed; low‐quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD ‐8.29 μmol/L, 95% CI ‐13.17 to ‐3.41; low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. When probiotics were compared with lactulose, the effects on all‐cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low‐quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low‐quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low‐quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low‐quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low‐quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low‐quality evidence); quality of life (results not meta‐analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD ‐2.93 μmol/L, 95% CI ‐9.36 to 3.50; very low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. Authors' conclusions The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High‐quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics

Probiotics for patients with hepatic encephalopathy

Background Hepatic encephalopathy is a disorder of brain function as a result of liver failure and/or portosystemic shunt. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning and represent a significant burden on health care resources. Probiotics are live microorganisms, which when administered in adequate amounts may confer a health benefit on the host. Objectives To quantify the beneficial and harmful effects of any probiotic in any dosage, compared with placebo or no intervention, or with any other treatment for patients with any grade of acute or chronic hepatic encephalopathy as assessed from randomised trials. Search methods We searched the The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, conference proceedings, reference lists of included trials and the WHO international clinical trials registry until April 2011 registry platform to identify new and ongoing trials. Selection criteria We included randomised trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in patients with hepatic encephalopathy. Data collection and analysis Three authors independently assessed the risk of bias of the included trials and extracted data on relevant outcomes, with differences resolved by consensus. We conducted random‐effects model meta‐analysis due to obvious heterogeneity of patients and interventions. A P value of 0.05 or less was defined as significant. Dichotomous outcomes are expressed as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). Main results We included seven trials of which 550 participants were randomised. Four of the seven trials compared a probiotic with placebo or no treatment in 245 participants, another trial compared a probiotic with lactulose in 40 participants , and the remaining two trials compared a probiotic with both placebo and lactulose in 265 participants. Each trial used different types of probiotics. Duration of administration of the experimental intervention varied from 10 days to 180 days. Two trials were industry funded, and five were unclear about origin of funding. All trials had high risk of bias. When probiotics were compared with no treatment, there was no significant difference in all‐cause mortality (2 trials, 105 participants; 1/57 (2%) versus 1/48 (2%): RR 0.72; 95% CI 0.08 to 6.60), lack of recovery (4 trials, 206 participants; 54/107 (50%) versus 68/99 (69%): RR 0.72; 95% CI 0.49 to 1.05), adverse events (3 trials, 145 participants; 2/77 (3%) versus 6/68 (9%): RR 0.34; 95% CI 0.08 to 1.42), quality of life (1 trial, 20 participants contributed to the physical quality of life measurement, 20 participants contributed to the mental quality of life: MD Physical 0.00; 95% CI ‐5.47 to 5.47; MD Mental 4.00; 95% CI ‐1.82 to 9.82), or change of/or withdrawal from treatment (3 trials, 175 participants; 11/92 (12%) versus 7/83 (8%): RR 1.28; 95% CI 0.52 to 3.19). No trial reported sepsis or duration of hospital stay as an outcome. Plasma ammonia concentration was significantly lower for participants treated with probiotic at one month (3 trials, 226 participants: MD ‐2.99 μmol/L; 95% CI ‐5.70 to ‐0.29) but not at two months (3 trials, 181 participants: MD ‐1.82 μmol/L; 95% CI ‐14.04 to 10.41). Plasma ammonia decreased the most in the participants treated with probiotic at three months (1 trial, 73 participants: MD ‐6.79 μmol/L; 95% CI ‐10.39 to ‐3.19). When probiotics were compared with lactulose no trial reported all‐cause mortality, quality of life, duration of hospital stay, or septicaemia. There were no significant differences in lack of recovery (3 trials, 173 participants; 47/87 (54%) versus 44/86 (51%): RR 1.05; 95% CI 0.75 to 1.47), adverse events (2 trials, 111 participants; 3/56 (5%) versus 6/55 (11%): RR 0.57; 95% CI 0.06 to 5.74), change of/or withdrawal from treatment at one month (3 trials, 190 participants; 8/95 (8%) versus 7/95 (7%): RR 1.10; 95% CI 0.40 to 3.03), plasma ammonia concentration (2 trials, 93 participants: MD ‐6.61 μmol/L; 95% CI ‐30.05 to 16.84), or change in plasma ammonia concentration (1 trial, 77 participants: MD 1.16 μmol/L; 95% CI ‐1.96 to 4.28). Authors' conclusions The trials we located suffered from a high risk of systematic errors ('bias') and high risk of random errors ('play of chance'). While probiotics appear to reduce plasma ammonia concentration when compared with placebo or no intervention, we are unable to conclude that probiotics are efficacious in altering clinically relevant outcomes. Demonstration of unequivocal efficacy is needed before probiotics can be endorsed as effective therapy for hepatic encephalopathy. Further randomised clinical trials are needed

Examination of the Anaerobic Growth of Campylobacter concisus

Campylobacter concisus is an oral bacterium that is associated with intestinal diseases. C. concisus was previously described as a bacterium that requires H2-enriched microaerobic conditions for growth. The level of H2 in the oral cavity is extremely low, suggesting that C. concisus is unlikely to have a microaerobic growth there. In this study, the anaerobic growth of C. concisus was investigated. The growth of fifty-seven oral C. concisus strains and six enteric C. concisus strains under various atmospheric conditions including anaerobic conditions with and without H2 was examined. The atmospheric conditions were generated using commercially available gas-generation systems. C. concisus putative virulence proteins were identified using mass spectrometry analysis. Under anaerobic conditions, 92% of the oral C. concisus strains (52/57) and all six enteric strains grew without the presence of H2 and the presence of H2 greatly increased C. concisus growth. An oral C. concisus strain was found to express a number of putative virulence proteins and the expression levels of these proteins were not affected by H2. The levels of H2 appeared to affect the optimal growth of C. concisus. This study provides useful information in understanding the natural colonization site and pathogenicity of C. concisus

Investigation of campylobacter concisus gastric epithelial pathogenicity using AGS cells

Campylobacter concisus is an oral bacterium. Recent studies suggest that C. concisus may be involved in human gastric diseases. The mechanisms, however, by which C. concisus causes human gastric diseases have not been investigated. Here we examined the gastric epithelial pathogenicity of C. concisus using a cell culture model. Six C. concisus strains and the human gastric epithelial cell line AGS cells were used. IL-8 produced by AGS cells after incubation with C. concisus was measured using enzyme-linked immunosorbent assay (ELISA), and AGS cell apoptosis was determined by caspase 3/7 activities. The effects of C. concisus on actin arrangement in AGS cells was determined using fluorescence staining. The effects of C. concisus on global gene expression in AGS cells was determined by transcriptomic analysis and quantitative real-time PCR (qRT-PCR). The role of the upregulated CYP1A1 gene in gastric cancer survival was assessed using the Kaplan-Meier method. C. concisus induced production of IL-8 by AGS cells with strain variation. Significantly increased caspase 3/7 activities were observed in AGS cells incubated with C. concisus strains when compared to AGS cells without bacteria. C. concisus induced actin re-arrangement in AGS cells. C. concisus upregulated 30 genes in AGS cells and the upregulation of CYP1A1 gene was confirmed by qRT-PCR. The Kaplan-Meier analysis showed that upregulation of CYP1A1 gene is associated with worse survival in gastric cancer patients. Our findings suggest that C. concisus may play a role in gastric inflammation and the progression of gastric cancer. Further investigation in clinical studies is warranted

Prevalence of Campylobacter Species in Adult Crohn's Disease and the Preferential Colonization Sites of Campylobacter Species in the Human Intestine

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). A high prevalence of Campylobacter concisus was previously detected in paediatric CD and adult UC. Currently, the prevalence of C. concisus in adult CD and the preferential colonization sites of Campylobacter species in the human intestine are unknown. In this study, we examined the prevalence of Campylobacter species in biopsies collected from multiple anatomic sites of adult patients with IBD and controls. METHODS: Three hundred and one biopsies collected from ileum, caecum, descending colon and rectum of 28 patients IBD (15 CD and 13 UC) and 33 controls were studied. Biopsies were used for DNA extraction and detection of Campylobacter species by PCR-sequencing and Campylobacter cultivation. RESULTS: A significantly higher prevalence of C. concisus in colonic biopsies of patients with CD (53%) was detected as compared with the controls (18%). Campylobacter genus-PCR positivity and C. concisus positivity in patients with UC were 85% and 77% respectively, being significantly higher than that in the controls (48% and 36%). C. concisus was more often detected in descending colonic and rectal biopsies from patients with IBD in comparison to the controls. C. concisus was isolated from patients with IBD. CONCLUSION: The high intestinal prevalence of C. concisus in patients with IBD, particularly in the proximal large intestine, suggests that future studies are needed to investigate the possible involvement of C. concisus in a subgroup of human IBD. To our knowledge, this is the first report of the association between adult CD and C. concisus as well as the first study of the preferential colonization sites of C. concisus in the human intestine

IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis

The International Liver Disease Genetics Consortium (ILDGC).Genetic variation in the IFNL3–IFNL4 (interferon-λ3–interferon-λ4) region is associated with hepatic inflammation and fibrosis1,2,3,4. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3–IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4–Ser70) and those encoding fully active IFN-λ4–Pro70. The two proposed functional variants (rs368234815 and rs4803217)5,6 were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis.M.E., M.D., and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, and by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and NHMRC Project Grants (APP1107178 and APP1108422). G.D. is supported by an NHMRC Fellowship (1028432)

IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis

Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom

Background: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care./ Objective: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients./ Methods: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data./ Results: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home./ Conclusions: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients