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Background. Hepatic encephalopathy (HE) is a neurological and psychiatric syndrome. Recent evidence suggests that HE is not only a disease of the liver and brain but is also related to the gut. Small intestinal bacterial overgrowth (SIBO) is well known to be associated with cirrhosis, but the relationship between SIBO and HE is unclear. We conducted this comprehensive systematic review and meta-analysis to determine the association between SIBO and HE in cirrhotic patients. Methods. We conducted a comprehensive literature search of all studies on the association of SIBO and HE in cirrhotic patients using the PubMed and Embase electronic databases. Studies were screened, and relevant data were extracted and analysed. We calculated the number of cases of SIBO in patients with HE and controls. We then compared the prevalence of SIBO between the two groups to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Funnel plots were constructed to identify potential publication bias. Results. Six studies with 414 participants (219 HE patients and 195 controls) met the inclusion criteria. The prevalence of SIBO in cirrhotic patients with HE was significantly higher than that in those without HE. The combined OR was 4.43 (95% CI 1.73-11.32, P = 0.002 ). The heterogeneity was moderate ( I 2 = 66 %), and the funnel plot suggested no significant publication bias. Subgroup analysis showed that the OR was 1.95 (95% CI 0.63–6.09) in studies using the lactulose breath test (LBT) and 7.60 (95% CI 3.50–16.50) in studies using the glucose breath test (GBT). The prevalence of SIBO in cirrhotic patients was also related to the severity of liver disease. Conclusions. Our meta-analysis identified a strong association between SIBO and HE, and the risk of SIBO was 4.43 times higher among cirrhotic patients with HE than among those without HE. SIBO could be a predisposing factor for the development of HE in cirrhotic patients. Therefore, the importance of SIBO should be emphasized in patients with HE.

Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting more than 1 billion people worldwide and is increasingly being identified in younger age groups and in socioeconomically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may contribute to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. A total of 217 subjects previously enrolled in a birth cohort in Amazonian Peru were monitored annually from ages 2 to 5 years. A total of 197 blood samples collected in later childhood were analyzed for 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, which were matched to extant early-life markers of enteropathy ascertained between birth and 2 years. Multivariate and multivariable regression models were fitted to test for associations, adjusting for confounders. Fecal and urinary markers of intestinal permeability and inflammation (myeloperoxidase, lactulose, and mannitol) measured in infancy were associated with later serum concentrations of soluble CD40-ligand, a proinflammatory cytokine correlated with adverse metabolic outcomes. Fecal myeloperoxidase was also associated with later levels of omentin-1. Enteric protozoa exposure showed stronger associations with later cardiometabolic markers than viruses, bacteria, and overall diarrheal episodes. Early-life enteropathy markers were associated with altered adipokine, apolipoprotein, and cytokine profiles later in childhood consistent with an adverse cardiometabolic disease risk profile in this cohort. Markers of intestinal permeability and inflammation measured in urine (lactulose, mannitol) and stool (myeloperoxidase, protozoal infections) during infancy may predict metabolic syndrome in adulthood.

To identify predictors of severe adverse events (≥grade 3) in patients with advanced hepatocellular carcinoma treated with lenvatinib.Of 41 patients, 25 and 16 were stratified into the severe and non-severe adverse events groups, respectively. Of these, 19 formed a lactulose-mannitol test subgroup, which was divided into severe adverse events (n=11) and non-severe adverse events (n=8) groups. Severe adverse events were assessed by liver disease etiology and modified albumin-bilirubin grade. Intestinal permeability by lactulose-mannitol test and serum soluble CD163, soluble mannose receptor, and zonulin levels.Severe adverse event incidence rates were higher in patients with advanced hepatocellular carcinoma related to alcoholic liver disease and nonalcoholic fatty-liver disease than in those with advanced hepatocellular carcinoma of other etiologies (p=0.014). The rates were higher for modified albumin-bilirubin grades 2a and 2b compared to modified albumin-bilirubin grade 1 (p=0.0104). Zonulin levels were higher in the severe adverse event group (p=0.0331) and were independently associated with severe adverse events (odds ratio=140, 95% confidence interval=1.66-11800; p=0.029). Patients with high zonulin levels (≥0.518 ng/ml) experienced more severe adverse events than those with low levels (0.518 ng/ml) (p=0.0137). In the lactulose-mannitol test subgroup, the urine lactulose:mannitol ratio was higher in the severe vs. non-severe adverse event group (p=0.0164). Moreover, it was higher in patients with alcoholic liver disease and nonalcoholic fatty-liver disease-related advanced hepatocellular carcinoma compared to those with other advanced hepatocellular carcinoma etiologies (p=0.0108).Serum zonulin levels predict severe adverse events in patients with advanced hepatocellular carcinoma treated with lenvatinib.

To determine whether gut permeability is associated with post-discharge growth and systemic inflammation among hospitalized children in low- and middle-income countries.Children aged 2-23 months being discharged from Civil Hospital Karachi (Pakistan) and Migori County Referral Hospital (Kenya) underwent lactulose-rhamnose ratio (LRR) permeability testing and were compared to age-matched children from their home communities. Linear mixed effect models estimated the associations between LRR among discharged children with change in length-for-age (LAZ) and weight-for-age z score (WAZ) at 45, 90, and 180 days after discharge. Linear regression tested if relationships between LRR, systemic inflammation [C-reative protein (CRP), Cluster of Differentiation 14 (CD14), Tumour Necrosis Factor Alpha (TNFα), Interleukin-6 (IL-6)], and enterocyte damage [Intestinal Fatty-Acid Binding protein (I-FABP)] differed between the hospitalized and community groups.One hundred thirty-seven hospitalized and 84 community participants were included. The hospitalized group had higher log-LRR [0.43, 95% confidence interval (CI): 0.15-0.71, P = 0.003] than the community children. Adjustment for weight-for-length z score at discharge attenuated this association (0.31, 95% CI: 0.00-0.62, P = 0.049). LRR was not associated with changes in WAZ or LAZ in the post-discharge period. Associations between LRR and CRP (interaction P = 0.036), TNFα ( P = 0.017), CD14 ( P = 0.078), and IL-6 ( P = 0.243) differed between community and hospitalized groups. LRR was associated with TNFα ( P = 0.004) and approached significance with CD14 ( P = 0.078) and IL-6 ( P = 0.062) in community children, but there was no evidence of these associations among hospitalized children.Although increased enteric permeability is more prevalent among children being discharged from hospital compared to children in the community, it does not appear to be an important determinant of systemic inflammation or post-discharge growth among hospitalized children.

Clinical progress in the development of new diagnostic modalities and therapeutic strategies for the management of patients with hepatic encephalopathy has lagged behind the vast knowledge that has been generated from basic studies. In this article, we critically assess matters that should be revisited, such as definition, classification, diagnosis and grading of hepatic encephalopathy, which are difficult to apply reproducibly using the current criteria. Many lines of investigation have confirmed that hepatic encephalopathy is irreversible in many patients and suggest the need for further studies focussing on mechanisms of neuronal injury and death, to guide future drug development for these patients. The clinical evidence behind using lactulose for all severities of hepatic encephalopathy, which is currently considered the standard of care, is poor and placebo-controlled trials for hepatic encephalopathy should be considered ethically sound. This expert opinion identifies current challenges in hepatic encephalopathy and highlights areas which require further debate and investigation in order to help advance the field both scientifically and clinically.

This study investigated the effects of 7 days of 600 mg/day anthocyanin-rich blackcurrant extract intake on small intestinal permeability, enterocyte damage, microbial translocation, and inflammation following exertional heat stress. Twelve recreationally active men (maximal aerobic capacity = 55.6 ± 6.0 ml·kg−1·min−1) ran (70% VO2max) for 60 min in an environmental chamber (34 °C, 40% relative humidity) on two occasions (placebo/blackcurrant, randomized double-blind crossover). Permeability was assessed from a 4-hr urinary excretion of lactulose and rhamnose and expressed as a ratio of lactulose/rhamnose. Venous blood samples were taken at rest and 20, 60, and 240 min after exercise to measure enterocyte damage (intestinal fatty acid-binding protein); microbial translocation (soluble CD14, lipopolysaccharide-binding protein); and interleukins 6, interleukins 10, and interleukins 1 receptor antagonist. Exercise increased rectal temperature (by ∼2.8 °C) and heart rate (by ∼123 beats/min) in each condition. Blackcurrant supplementation led to a ∼12% reduction in lactulose/rhamnose ratio (p p

Cirrhosis is associated with changes in gut microbiota in both saliva and stool. The relative linkage patterns of stool versus saliva microbiota with systemic metabolomics are unclear and may differ across countries. We hypothesized that stool microbiota have greater linkages with plasma metabolites than saliva microbiota, which may depend on country of origin.Age-balanced controls and outpatient patients with cirrhosis, compensated and decompensated, from the USA and Mexico (MX) underwent plasma collection and dietary recall. Plasma metabolomics were analysed using nuclear magnetic resonance spectroscopy. Microbiota in stool and saliva samples were analysed using 16S rRNA analyses. Correlation network differences between both saliva and stool gut microbiota and plasma metabolites were compared between subject groupings and within/between countries.A total of 313 age-balanced subjects-135 USA (47 control, 48 compensated and 40 decompensated) and 178 MX (71 control, 56 compensated and 51 decompensated)-were enrolled. Cirrhosis severity, including lactulose and rifaximin use, were comparable. Plasma metabolites differed with advancing cirrhosis, between countries and according to 90-day hospitalizations. Correlation networks demonstrated more microbiome-metabolite linkages in stool compared to saliva in both populations, although there were no salivary correlation metrics across decompensated subjects in either country. Stool Lactobacillus showed a positive correlation to plasma lactate in decompensated cirrhosis from MX but not USA.Stool microbiota were more extensively linked with systemic metabolites than were saliva microbiota, irrespective of cirrhosis severity and country. These changes were more prominent in decompensated cirrhosis and were centred around plasma lactate, which might reflect the interaction of diet and lactulose therapy.

Linaclotide, a selective agonist of guanylate cyclase C, was highly recommended for the treatment of irritable bowel syndrome with constipation (IBS-C). However, the cost-effectiveness of linaclotide in Chinese is not known, and this study aimed to assess the cost-effectiveness of linaclotide for patients with IBS-C.An economic evaluation was conducted with a Markov model from a societal perspective. The Markov model was structured to simulate the discontinuation and continuation of medication in IBS-C patients in clinical practice, as well as the revisit and non-visit of non-responding patients. The cycle of the model was 4 weeks, and the time horizon was 1 year. The efficacy data in the model was from the risk ratios obtained by the meta-analysis and the calculation of the response rate of the three medications. The utility, discontinuation rate of the medication, and revisit rate data were from published literature, while the cost data were obtained from experts' opinions and published literature. A series of sensitivity analyses was performed on parameters potentially having impact on the model outputs.The QALYs (quality-adjusted life years) gained for 1-year treatment with linaclotide, polyethylene glycol, and lactulose were 0.821, 0.795, and 0.781, respectively. The corresponding total costs were CNY 7,721 (USD 1,120), CNY 8,797 (USD 1,276) and CNY 9,481 (USD 1,375). In both comparisons, linaclotide was dominant. Compared with polyethylene glycol and lactulose, the likelihood of linaclotide being cost-effective was 100% for both, using 1 times per capita GDP per QALY as willingness-to-pay threshold.IBS-C seriously affects the quality of life of patients with IBS-C, and linaclotide can improve symptoms and quality of life at less cost.

Hydrogen and methane breath tests (HMBT) are widely used clinical investigations but lack standardization. To address this, the North American Consensus (NAC) group published evidence-based recommendations for HMBT.To evaluate results obtained using NAC recommendations for HMBT, compared to retrospective data that utilized guidelines previously recommended.HMBT data from 725 patients referred for small intestinal bacterial overgrowth (SIBO) and/or carbohydrate malabsorption (CM) testing were analyzed. Data were compared regarding dose of substrate for SIBO testing (16 vs. 10 g lactulose, and 50 vs. 75 g glucose) and the effect of post-ingestion sampling period for malabsorption testing. The effect of different recommended cut-off values for SIBO were examined.Substrate dose did not affect methane production. 10 g lactulose significantly reduced positive SIBO results compared to 16 g lactulose (42 vs. 53%, p = 0.04). 75 g glucose significantly increased positive results compared to 50 g glucose (36 vs. 22%, p = 0.04). Provoked symptoms were significantly more prevalent in patients testing positive by both North American Consensus and Ledochowski cut-off values. 34.5% of patients tested positive for CM at 180-min compared to 28% at 120-min (not significant, p = 0.19).10 g lactulose substrate produces fewer positive SIBO results than 16 g lactulose, while 75 g glucose dose produces more positive SIBO results than 50 g. Performing CM breath tests for 180 min increases number of positive results when compared to 120 min. SIBO cut-off timings require further investigation, but our findings broadly support the NAC recommendations for SIBO and CM testing.

The effect of brown and golden flaxseeds on lipid profile, oxidative stress, intestinal permeability, endotoxemia, and fasting glycaemia of perimenopausal overweight women was investigated in this clinical trial. Thirty participants were divided into control (CG), brown flaxseed (BF), and golden flaxseed (GF) groups. BF and GF received 40 g of brown and golden flaxseed for 12 weeks. Venous blood samples were collected at the beginning and at the end. Intestinal permeability analysis was performed by urinary excretion of lactulose and mannitol. There was significant reduction in intestinal permeability in flaxseed groups, with delta of lactulose/mannitol ratio smaller (

A 49-year-old Japanese man had shown developmental delay, learning difficulties, epilepsy, and slowly progressive gait disturbance in elementary school. At 46 years old, he experienced repeated drowsiness with or without generalized convulsions, and hyperammonemia was detected. Brain magnetic resonance imaging detected multiple cerebral white matter lesions. An electroencephalogram showed diffuse slow basic activities with 2- to 3-Hz δ waves. Genetic tests confirmed a diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Leukoencephalopathy was resolved following the administration of L-arginine and lactulose with a decrease in plasma ammonia levels and glutamine-glutamate peak on magnetic resonance spectroscopy. Leukoencephalopathy in HHH syndrome may be reversible with the resolution of hyperammonemia-induced glutamine toxicity.

To assess the effectiveness of partially hydrolyzed guar gum (PHGG) in improving constipation and reducing the use of laxatives among long term care facility (LTCF) residents.A single-center, prospective, randomized, placebo-controlled, single-blinded parallel-group trial from September 2021 to November 2021.Four LTCF in Hong Kong.Fifty-two LTCF residents with chronic constipation (mean age: 83.9±7.6 years, male 38%).5g PHGG mixed with 200ml water per day for 4 weeks was given to intervention group participants. Control group received 200ml water for 4 weeks. Participants continued their usual as-needed laxative (lactulose, senna or dulcolax) on their own initiative.Baseline measurements included age, gender, Charlson comorbidity index, Roackwood's Clinical Frailty Scale, body mass index and daily dietary fiber intake. Outcome measures were fecal characteristics assessed by Bristol Stool Form Scale, bowel opening frequency and laxative use frequency at baseline, first, second, third and fourth week of trial. Adverse events were measured. The study was registered on ClinicalTrial.gov; identifier: NCT05037565.There was no significant difference in bowel frequency and stool characteristics between the treatment group and control group. However, there was a significantly lower frequency of lactulose, senna, and total laxative use in the treatment group compared with controls in the third and fourth week. There was no significant difference in adverse effects between the two groups.This study showed that daily dietary fibre supplementation by using PHGG for 4 weeks in LTCF residents results in significantly less laxative use than placebo. It may be an effective way to reduce laxative dependence among older people living in LTCFs.

We aimed to examine the gut permeability in patients with schizophrenia and its relevance to schizophrenia symptoms, medication, cognitive functions, and blood immune markers.We selected 22 patients with schizophrenia (mean age: 37.9 ± 10.5 years) comprising 9 men and 13 women. Furthermore, we included 86 healthy controls (mean age: 43.5 ± 11.0 years) comprising 41 men and 45 women. All participants were biologically unrelated and of Japanese descent. We used the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS) to measure the severity of schizophrenia symptoms and cognitive functions, respectively. The lactulose-mannitol loading test was used to measure the permeability of the small intestine. Furthermore, we used the lactulose to mannitol ratio (LMR) as an index of gut permeability. We measured the C-reactive protein and natural killer (NK) cell activity in the blood as highly sensitive immune markers.The patients had a significantly higher rate of "leaky gut" (defined as LMR ≥ 0.1) compared to the control group (22.7% vs. 5.8%, odds ratio: 4.8 [95% confidence interval, 1.2-18.3], Fisher's exact test, P = 0.03). There was no significant correlation between the LMR and PANSS scores or in the daily antipsychotic dose. In addition, the LMR was negatively correlated with the total Z-score of the BACS and NK cell activity in the patients.Our results suggest a higher rate of abnormally increased gut permeability in patients with schizophrenia than in controls. Moreover, gut permeability may be related to the cognitive and cellular immunity function of patients with schizophrenia.

The results of animal studies and clinical data support the gut microbiota contribution to the pathogenesis of Alzheimer’s disease (AD). The aim of this pilot study was to evaluate the prevalence of small intestinal bacterial overgrowth (SIBO) and fecal markers of intestinal inflammation and permeability in AD patients. The study was conducted in 45 AD patients and 27 controls. Data on comorbidities, pharmacotherapy, and gastrointestinal symptoms were acquired from medical records and a questionnaire. SIBO was evaluated using lactulose hydrogen breath test. Fecal calprotectin and zonulin levels were assessed by ELISA assays. The positive result of SIBO breath test was found in 49% of the AD patients and 22% of the controls (p = 0.025). The comparative analysis between SIBO-positive and SIBO-negative AD patients with respect to the degree of cognitive impairment, comorbidities and used medications did not reveal any statistically significant difference, except for less common heartburn in SIBO-positive AD patients than in SIBO-negative ones (9 vs 35%, p = 0.038). The median fecal calprotectin and zonulin levels in the AD group compared to the control group amounted to 43.1 vs 64.2 µg/g (p = 0.846) and 73.5 vs 49.0 ng/ml (p = 0.177), respectively. In the AD patients there was no association between the presence of SIBO and fecal calprotectin level. Patients with AD are characterized by higher prevalence of SIBO not associated with increased fecal calprotectin level that may be related to anti-inflammatory effect of cholinergic drugs used in the treatment of AD.

Bowel movement (BM) frequency is used to titrate lactulose for hepatic encephalopathy (HE). However, stool consistency using the Bristol stool scale (BSS, 0-7) is often ignored.The study included pre-BSS and post-BSS cohorts. BSS was incorporated into decision-making after training in outpatients with cirrhosis. Two to 3 BMs/d and BSS 3-4 were considered normal, whereas the rest were considered high or low; concordance between the metrics was evaluated. Medication changes and 6-month admissions were compared between this group (post-BSS) and a comparable previous group (pre-BSS). Concordance and regression analyses for all-cause admissions and HE-related admissions were performed, and comparisons were made for HE-related medication stability. In the longitudinal analysis, an outpatient group seen twice was analyzed for BSS and BMs.In the post-BSS cohort, 112 patients were included with only 46% BSS and BMs concordance and modest BSS/BMs correlation (r = 0.27, P = 0.005). Compared with a pre-BSS cohort (N = 114), there was a lower 6-month total (4% vs 0.36%, P0.001) or HE-related admission (1% vs 0.12%, P = 0.002). Regression showed model for end-stage liver disease (odds ratio [OR]: 1.10, P = 0.003) and pre-BSS/post-BSS (OR: 0.04, P0.001) for all-cause admissions and HE (OR: 3.59, P = 0.04) and preera/postera (OR: 0.16, P = 0.02) for HE-related admissions as significant. HE medication regimens were more stable post-BSS vs pre-BSS (32% vs 20%, P = 0.04), which was due to patients with BSSBMs (P = 0.02). In the longitudinal analysis, 33 patients without medication changes or underlying clinical status changes were tested 36 ± 24 days apart. No changes in BSS (P = 0.73) or BMs (P = 0.19) were found.BSS is complementary and additive to BM frequency, can modulate the risk of readmissions and stabilize HE-related therapy changes in outpatients with cirrhosis, and could help personalize HE management.

Overt hepatic encephalopathy is a generally reversible neurologic complication of cirrhosis. Overt hepatic encephalopathy has been associated with poor hospitalization- and mortality-related outcomes, which is important given increasing hepatic encephalopathy-related hospitalizations over time. The aim of this narrative review is to provide an overview of hospital- and mortality-related outcomes in patients with overt hepatic encephalopathy and the pharmacologic therapies that may improve these outcomes. Guideline-recommended prophylaxis with lactulose (first-line therapy) or secondary prophylaxis with rifaximin plus lactulose decreases hospital admissions and mortality rates. Rifaximin or lactulose treatment was beneficial for reducing the hospitalization rate in patients with hepatic encephalopathy compared with no treatment. Further, retrospective studies have shown that rifaximin with or without lactulose was effective for decreasing the number of hepatic encephalopathy episodes, hepatic encephalopathy-related hospitalizations, and duration of hospitalization. Ornithine phenylacetate, an ammonia-reducing agent currently in development, is also being investigated in hospitalized patients with hepatic encephalopathy. Overall, data support that prophylaxis for the prevention of hepatic encephalopathy recurrence improves outcomes in patients with cirrhosis and a history of hepatic encephalopathy.

Aims Rifaximin-alpha as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-alpha remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-alpha as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer's perspective. Materials and methods A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. Results Treating eligible HE patients with rifaximin-alpha in addition to lactulose saves euro4,487 and costs euro249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer's perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-alpha. Optimizing rifaximin-alpha use by treating all eligible patients with the rifaximin-alpha + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer's perspective. Conclusions Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-alpha adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer's perspective, costs increase with addition of rifaximin-alpha due to relative better survival causing relatively higher drug and liver transplantation-related costs.

The intestinal permeability (IP) of sugars and their derivatives has been widely used to assess mucosal damage in gastrointestinal diseases. Ulcerative colitis (UC) is a recurring and relapsing disease that causes inflammation of the gut. IP of sugars can be evaluated and correlated with the flare of UC.A prospective study was conducted on 91 patients with active UC at the tertiary care center in North India. Mayo grading system assessed disease activity, and IP was assessed by measuring sucrose, lactulose, mannitol, and sucralose in urine samples from UC patients. A high-performance liquid chromatography (HPLC) method to detect all of these sugars simultaneously using a refractive index detector was developed and further validated in patients with UC.The analytical recovery rate of the tested sugars ranged from 95% to 146% in the urine matrix. The limit of detection and limit of quantification were 78.838 mg/L and 262.79 mg/L for sucrose, 84.994 mg/L and 283.31 mg/L for lactulose, 74.789 mg/L and 249.30 mg/L for mannitol, and 50.908 mg/L and 169.69 mg/L for sucralose.The standardized HPLC method is sensitive and suitable for the simultaneous detection and determination of different sugar moieties in the urine sample. Patients with UC can be evaluated indirectly for the flare by estimating the recovery rate of sugars through gut permeability. The procedure is noninvasive and thus improves the quality of life of chronically ill patients.

Objective Quality of life (QoL) is impaired in patients with hepatic encephalopathy and rifaximin-α can improve QoL within 6 months. This study assessed the importance of QoL as a therapeutic objective in hepatic encephalopathy management; whether QoL is routinely assessed in hepatic encephalopathy patients in clinical practice and the role of rifaximin-α in this context. Methods A survey was conducted of healthcare professionals (HCPs) from Europe and Australia involved in hepatic encephalopathy management. HCPs rated the importance of a range of therapeutic objectives on a 1–7 Likert scale (1 = not at all important; 7 = extremely important). HCPs were also required to provide three patient record forms (PRFs) based on their last three hepatic encephalopathy patients. Results There were 218 HCP respondents, who provided 654 PRFs (patients treated with rifaximin-α, n = 347; patients not treated with rifaximin-α, n = 307). The mean Likert score was highest for the therapeutic objective ‘improving a patient’s QoL’ (6.4), which was rated significantly more highly than all other therapeutic objectives, including ‘reducing the patient’s likelihood of hospital readmission’ (6.1; P

Examining the role of environmental enteric dysfunction (EED) in child growth requires noninvasive, field-appropriate biomarkers. Alternatives to the traditionally used lactulose:mannitol (L:M) test have been explored, but few studies have compared the L:M test to host fecal mRNA transcripts. The objectives of this study were to examine whether 1) host fecal mRNA transcripts could predict presence and severity of EED, measured using the L:M test, and 2) EED modifies the effect of specialized nutritious foods (SNFs) on recovery from moderate acute malnutrition (MAM). This substudy was nested within a cluster randomized trial comparing four SNFs in the treatment of MAM among children 6 to 59 months in Sierra Leone. EED was assessed at enrollment using the L:M test and 15 host fecal mRNA transcripts on 522 children. Recovery from MAM was defined as achieving mid-upper arm circumference ≥ 12.5 cm within 12 weeks of supplementation. Random forest classification models were used to examine prediction of presence and severity of EED by host fecal mRNA transcripts. Logistic regression was used to test for effect modification by L:M test variables including % lactulose excreted (%L). Eight host fecal mRNA transcripts (AQP9, REG3A, IFI30, DECR1, BIRC3, SELL, PIK3AP1, DEFA6) identified EED (%L ≥ 0.2) and severe EED (%L ≥ 0.45) with high sensitivity and specificity. The L:M test variables did not modify the effect of SNFs on recovery from MAM. In this study, we found host fecal mRNA transcripts that could be biomarkers of EED but did not find EED to modify the effect of SNFs on MAM treatment.

Background. Portosystemic shunts in Hereditary Haemorrhagic Telangiectasia (HHT) are often overlooked by conventional imaging although they could reduce hepatic clearance of gut-derived toxins. Aims. To evaluate, the presence of subclinical neurological alterations (SNAs), that we named “minimal portosystemic encephalopathy” (mPSE) in HHT patients without advanced liver disease (ALD). Methods. In this cross sectional study, consecutive HHT outpatients were firstly screened by critical flicker frequency (CFF) test (abnormal ≤39Hz), and the simplified animal naming test (S-ANT1) (abnormal Results. None of the 37 enrolled patients showed portosystemic shunts at imaging techniques. However, 33 patients had normal CFF values (CFF-) and 4 displayed CFF alterations (37.0±0.7Hz, CFF+). The S-ANT1 confirmed an impaired neurological performance (10.2±2.8) in CFF+ patients thus confirming the presence of mPSE. Noteworthy, lactulose administration determined a CFF increase (39.1±0.4Hz) and S-ANT1 normalization in these patients. Neither mPSE- nor mPSE+ patients had ALD and showed similar demographic, clinical and laboratory parameters. Finally, no mPSE+ patient showed radiologically-detectable brain vascular malformations or other brain abnormalities at imaging. Conclusions. HHT patients represent a human model of mPSE secondary to portosystemic shunts escaping radiological detection. mPSE evaluation should be incorporated in HHT surveillance protocols since it can affect both health-related/social aspects and pharmacokinetics of orally administered drugs with a narrow therapeutic index and high hepatic first-pass uptake.

Environmental enteric dysfunction (EED) is a syndrome characterized by impairments of digestion and absorption and intestinal barrier failure in people living in insanitary or tropical environments. There is substantial evidence that it contributes to impaired linear growth of millions of children in low- and middle-income countries, to slowed neurocognitive development, and to diminished responses to oral vaccines. It represents the functional consequences of environmental enteropathy, an asymptomatic inflammatory disorder of the mucosa, and there is considerable overlap with the enteropathy observed in severe clinical malnutrition. The majority of studies of EED have employed functional tests based on lactulose permeation to define the presence of abnormal leak in the gut. However, where intestinal biopsies can safely be collected the opportunity then arises to study the underlying enteropathy in cellular and molecular detail, as well as to measure important functional elements such as enzyme expression. The purpose of this narrative review is to summarize the current understanding of environmental enteropathy obtained from small intestinal biopsies, and prospects for future work. We review histology, electron microscopy, transcription and protein expression, physiological measures, and the microbiome. We conclude that while noninvasive biomarkers of enteropathy and intestinal dysfunction permit large-scale studies of unquestionable value, intestinal biopsies are still required to investigate pathophysiology in depth.

The probiotics are extremely sensitive to various environmental factors, which imposes limitation on their health and functional effectiveness. Thus, development of delivery system for protection of viable cells while passing through different stages of the human digestion system is key factor in application of probiotic products. In our study, the effects of several polysaccharides such as alginate, κ-carrageenan, locust bean gum, gellan gum, xanthan gum and their combination with various prebiotic components (resistant starch, lactulose, lactosucrose) on encapsulation of probiotic Lactobacillus casei 01 strain were studied. Both regular and unregular beads with size distributions from 2 mm up to 5 mm were obtained. The encapsulation efficiencies varied from 64.4% up to 79%. Based on the texture's profiles, the capsules can be grouped into 5 clusters with squared Euclidean distance 3.5. Meanwhile, the starch-alginate and the lactosucrose LS55L - alginate beads were found to be the most stable and to have massive textural properties, whereas the gellan gum - xanthan gum and the chitosan coated alginate beads emerged as the softest. Encapsulation significantly improved the degree of gastric tolerance of probiotic cells even in the presence of pepsin. The INFOGEST in vitro digestion protocol was adapted to investigate the protection effects of different capsules. The highest survival (with loss rate of lower than 1 log CFU/g) was observed in the case of the cells encapsulated in starch-alginate beads. Moreover, the alginate microcapsules combined with lactosucrose LS55L also provided very promising shield for probiotics from the low pH of gastric conditions. Our findings suggest that incorporation of prebiotics into alginate-base encapsulation would be good idea in development of micro delivery systems that helps the survival of probiotics and their delivery to the target sites of action in human body.

Background Hyperammonemic encephalopathy, a rare but fatal condition, is increasingly being reported as a possible complication of bariatric surgery. Here, we present a case of hyperammonemic encephalopathy, focusing on the clinical presentation, diagnostic measures, and our treatment methods, which resulted in a rare favorable outcome, emphasizing the unique role of renal replacement treatment. We also provide a detailed discussion of the mechanism through which hyperammonemia occurs secondarily to bariatric surgery. Case presentation A 44-year-old Moroccan Jew woman with a history of obesity presented in the hospital with urea cycle disorder that manifested after bariatric surgery. A rapid diagnostic process, together with conservative treatment with lactulose, nutritional supplementation, dietary protein restriction, and ammonia scavengers did not result in adequate improvement. Therefore, hemofiltration was performed, which yielded a favorable outcome. Conclusions The case findings indicate an association between hyperammonemic encephalopathy and bariatric surgery, and support early treatment with ammonia scavengers, as currently accepted. Nevertheless, if rapid improvement is not seen, it is advisable to consider hemodialysis or hemofiltration as early invasive strategies.

The purpose of this study was to evaluate the effects of acute ibuprofen consumption (2 × 600-mg doses) on markers of enterocyte injury, intestinal barrier dysfunction, inflammation, and symptoms of gastrointestinal (GI) distress at rest and after exercise in hypobaric hypoxia.Using a randomized double-blind placebo-controlled crossover design, nine men (age, 28 ± 3 yr; weight, 75.4 ± 10.5 kg; height, 175 ± 7 cm; body fat, 12.9% ± 5%; V̇O 2 peak at 440 torr, 3.11 ± 0.65 L·min -1 ) completed a total of three visits including baseline testing and two experimental trials (placebo and ibuprofen) in a hypobaric chamber simulating an altitude of 4300 m. Preexercise and postexercise blood samples were assayed for intestinal fatty acid binding protein (I-FABP), ileal bile acid binding protein, soluble cluster of differentiation 14, lipopolysaccharide binding protein, monocyte chemoattractant protein-1, tumor necrosis factor α (TNF-α), interleukin-1β, and interleukin-10. Intestinal permeability was assessed using a dual sugar absorption test (urine lactulose-to-rhamnose ratio).Resting I-FABP (906 ± 395 vs 1168 ± 581 pg·mL -1 ; P = 0.008) and soluble cluster of differentiation 14 (1512 ± 297 vs 1642 ± 313 ng·mL -1 ; P = 0.014) were elevated in the ibuprofen trial. Likewise, the urine lactulose-to-rhamnose ratio (0.217 vs 0.295; P = 0.047) and the preexercise to postexercise change in I-FABP (277 ± 308 vs 498 ± 479 pg·mL -1 ; P = 0.021) were greater in the ibuprofen trial. Participants also reported greater upper GI symptoms in the ibuprofen trial ( P = 0.031). However, monocyte chemoattractant protein-1 ( P = 0.007) and TNF-α ( P = 0.047) were lower throughout the ibuprofen trial compared with placebo (main effect of condition).These data demonstrate that acute ibuprofen ingestion aggravates markers of enterocyte injury and intestinal barrier dysfunction at rest and after exercise in hypoxia. However, ibuprofen seems to suppress circulating markers of inflammation.

There are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis.To determine whether a stool metagenome-derived signature accurately detects hepatic decompensation and mortality risk in cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) METHODS: Shotgun metagenomic sequencing was performed on faecal samples collected at study entry from a prospective cohort of adults with NAFLD-related cirrhosis. A Random Forest machine learning algorithm was utilised to identify a metagenomic signature of decompensated cirrhosis (defined by ascites, hepatic encephalopathy or variceal haemorrhage) and subsequently validated in an external cohort. A Cox proportional hazards regression model was used to examine predictors of all-cause mortality.In all, 25 adults with NAFLD-related cirrhosis (training cohort) were included. Among the 16 participants with decompensated cirrhosis, 33% had ascites, 56% had hepatic encephalopathy and 22% had experienced a variceal haemorrhage (not mutually exclusive). We identified a stool metagenomic signature comprising 13 discriminatory species that reliably distinguished decompensated NAFLD-related cirrhosis (diagnostic accuracy, 0.97, 95% confidence interval [CI] 0.96-0.99). Diagnostic accuracy of the 13-species signature remained high after adjustment for lactulose (area under the curve [AUC] 0.99) and rifaximin use (AUC 0.93). The discriminative ability of 13-species metagenomic signature was robust in an independent test cohort (AUC 0.95, 95% CI 0.81-1.00). The 13-species metagenomic signature (hazard ratio [HR] 1.54, 95% CI 1.10-2.15, p = 0.01) was a stronger predictor of mortality than the Model for End-Stage Liver Disease score (HR 1.25, 95% CI 1.03-1.53, p = 0.03).This study provides evidence for a gut metagenome-derived signature with high diagnostic accuracy for hepatic decompensation that predicts risk of mortality in NAFLD-related cirrhosis.

We have previously shown that the probiotic

Background and study aims: Advanced liver disease frequently culminates in hepatic encephalopathy (HE), which can be classiled as covert or overt HE, with subtle or clinically obvious changes respectively. 30-40% of patients with cirrhosis develop overt HE, which negatively affects the patients' quality of life. Next to lactulose, rifaximin-alpha has been prescribed as a second line therapy to treat and reduce the risk of recurrence of overt HE. In this study, we aimed to evaluate the effect of rifaximin-alpha therapy, both on the number of occurring infections and on the evolution in hospital admissions of patients with overt HE.Patients and methods: A total of 66 cirrhotic patients, treated for at least 6 months with rifaximin-alpha at AZ Maria Middelares, between October 1st 2014 and January 1st 2020, were included in the study analysis. Medical records of all patients were evaluated over a period of 6 months prior and after initiation of rifaximin-alpha therapy.Results: Data analysis revealed that the included cirrhotic patients were severely ill, with a mean model for end-stage liver disease (MELD) score of 21, and a median Child Pugh score of 11. Among these patients, rifaximin-alpha treatment signilcantly downgraded the total number of infections, with a main effect on respiratory infections. Furthermore, rifaximin-alpha therapy led to a signilcant decrease in HE-related, as well as in other liver-related hospital admissions.Conclusions: This study conlrms the potential value of rifaximin-alpha in reducing the number of developing infections and hospital admissions in a severely ill cirrhotic patient population. (Acta gastroenterol. belg., 2022, 85, 433-437).

BACKGROUND AND AIM Previous studies have shown a reduction of gastrointestinal symptoms in irritable bowel syndrome (IBS) patients following a low FODMAP diet (LFD). It remains unknown which disorders of gut-brain interaction (DGBI) patients would benefit most from LFD. We aimed to analyze LFD response regarding a preceding nutrient challenge test (NCT). METHODS Data of 110 consecutive DGBI patients undergoing NCT and LFD between August 2015 and August 2018 were analyzed retrospectively. LFD response was assessed by changes in IBS Symptom Severity Score (IBS-SSS). In mixed-effects linear regression models, the impact of hydrogen values and abdominal symptoms during NCT, performed with 30-g lactulose and 400-mL liquid test meal, on IBS-SSS changes were analyzed. RESULTS Low FODMAP diet induced a significant IBS-SSS reduction of 78 points (95% confidence interval [CI] 50-96; P

Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of hepatic encephalopathy (HE). MHE does not present clinically detectable neurological-psychiatric abnormalities but is characterized by imperceptible neurocognitive alterations detected during routine clinical examination via neuropsychological or psychometrical tests. MHE may affect daily activities and reduce job performance and quality of life. MHE can increase the risk of accidents and may develop into overt encephalopathy, worsening the prognosis of patients with liver cirrhosis. Despite a lack of consensus on the therapeutic indication, interest in finding novel strategies for prevention or reversion has led to numerous clinical trials; their results are the main objective of this review. Many studies address the treatment of MHE, which is mainly based on the strategies and previous management of overt HE. Current alternatives for the management of MHE include measures to maintain nutritional status while avoiding sarcopenia, and manipulation of intestinal microbiota with non-absorbable disaccharides such as lactulose, antibiotics such as rifaximin, and administration of different probiotics. This review analyzes the results of clinical studies that evaluated the effects of different treatments for MHE.

Objectives: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. Design: Retrospective observational study. Setting: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. Patients: Adults with ammonia levels above 50 μmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 μmol/L, or alanine aminotransferase ≥ 100 units/L. Interventions: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. Measurements and Main Results: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 μmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were no significant differences in outcomes between the lactulose and non-lactulose groups. Among subjects with multiple data points, lactulose did not have a dose-dependent effect on ammonia level, and was not associated with faster ammonia normalization compared to non-lactulose. When analyzed separately, patients with moderate hyperammonemia (60-99 μmol/L) who received lactulose had longer hospital and ICU length of stay compared to non-lactulose (417.8 hours vs. 208.4 hours, P = 0.003, and 229.2 hours vs. 104.7 hours, P = 0.025; respectively), though confounders were present. Conclusions: Routine use of lactulose to treat mild to moderate hyperammonemia in this patient population was not associated with improved outcomes.

Effective lowering of circulating ammonia is the mainstay strategy in the prevention and treatment of hepatic encephalopathy in cirrhosis and there is increasing interest in agents with the metabolic potential for the active removal of ammonia by the liver and skeletal muscle by agents including L-ornithine L-aspartate, branched-chain amino acids, as well as the re-purposing of benzoate and phenylacetate currently employed for the control of hyperammonaemia in congenital urea-cycle enzymopathies. Based upon results of multiple systematic reviews with meta-analyses, L-ornithine L-aspartate demonstrably lowers circulating ammonia in patients with cirrhosis with concomitantly improved mental status. Distinct mechanisms responsible include optimisation of hepatic metabolic pathways for ammonia removal as well as direct hepatoprotective effects involving the release of glutathione and of nitric oxide with beneficial effects on hepatic microcirculation. L-ornithine L-aspartate also prevents cirrhosis-related sarcopenia, leading to increased capacity for ammonia removal by skeletal muscle. Branched-chain amino acids continue to be prescribed as nutritional supplements with the potential to result in improvements in liver function. Sodium benzoate, glycerol phenylbutyrate and an analogous compound L-ornithine phenylacetate were also evaluated. Glycerol phenylbutyrate was the only agent with a beneficial effect on both hyperammonaemia and hepatic encephalopathy. None were superior to lactulose for the lowering of blood ammonia.

Fecal transplant is associated with reduction in the expression of antibiotic‐resistance genes in patients with decompensated cirrhosis. Genes focused on beta‐lactamase and vancomycin resistance reduced after fecal transplant regardless of pre‐procedure antibiotics and concurrent use of lactulose, rifaximin or PPIs., Antibiotic resistance leads to poor outcomes in cirrhosis. Fecal microbiota transplant (FMT) is associated with reduction in antibiotic resistance gene (ARG) burden in patients without cirrhosis; however, the impact in cirrhosis is unclear. We aimed to study the effect of capsule and enema FMT on ARG abundance in fecal samples, which were collected during two published FMT trials in patients with cirrhosis on rifaximin, lactulose, and proton pump inhibitors. ARGs were identified using metagenomics and mapped against the Comprehensive Antibiotic Resistance Database. Changes in ARG abundance were studied within/between groups. The capsule FMT trial involved a one‐time FMT or placebo capsule administration with stool collection at baseline and week 4 postintervention. Antibiotics+enema FMT included preprocedure antibiotics followed by FMT enema versus standard‐of‐care (SOC). Stool was collected at baseline, postantibiotics, and day 7/15 postintervention. Both trials included 20 patients each. There was no safety/infection signal linked to FMT. In the capsule trial, beta‐lactamase (OXY/LEN) expression decreased post‐FMT versus baseline. Compared to placebo, patients who were post‐FMT had lower abundance of vancomycin (VanH), beta‐lactamase (ACT), and rifamycin ARGs; the latter was associated with cognitive improvement. No changes were seen within patients treated with placebo. In the antibiotics+enema trial for postantibiotics at day 7 versus baseline, there was an increase in vancomycin and beta‐lactamase ARGs, which decreased at day 15. However, quinolone resistance increased at day 15 versus baseline. Between SOC and FMT, day 7 had largely lower ARG (CfxA beta‐lactamase, VanW, and VanX) that continued at day 15 (cepA beta‐lactamase, VanW). No changes were seen within the SOC group. Conclusion: Despite differences in routes of administration and preintervention antibiotics, we found that ARG abundance is largely reduced after FMT compared to pre‐FMT baseline and non‐FMT groups in decompensated cirrhosis.

Background Bovine colostrum with egg powder (BC/egg) is rich in essential amino acids and immunoactive compounds. Objectives This trial tested the hypothesis that a daily supplement of BC/egg would reduce linear growth faltering and environmental enteric dysfunction (EED) in Malawian infants when compared with an isoenergetic ration of corn/soy flour used as a control. EED was defined by a lactulose permeability test. Methods This was a prospective, randomized, blinded, placebo-controlled clinical trial in which 9-mo-old infants received BC/egg or a control for 3 mo. The primary outcomes were change in length-for-age z-score (ΔLAZ) and urinary lactulose excretion (%L) at 12-mo-old. Secondary outcomes included episodes of diarrhea, stunting, EED, and the 16S configuration of the fecal microbiota. Results Of the 277 children enrolled, 267 completed the intervention phase of the study. LAZ decreased in all children from 9 to 17 mo, although ΔLAZ was less in children receiving BC/egg from 9 to 12 mo (difference = 0.12 z-scores; P = 0.0011). This difference persisted after feeding was completed, with less ΔLAZ (difference = 0.09 z-scores). A lower prevalence of stunting was seen in the intervention group (n = 47/137) than the control group (n = 62/127) at 17 mo (RR = 0.70; 95% CI: 0.52, 0.94).The median %L at 12 mo of age in the children receiving BC/egg was 0.14%, compared with 0.17% in the control group (P = 0.74). In children with %L >0.45% at enrollment (severe EED), the BC/egg group had more children with normal %L at 12 mo of age (10/20, 50%) than was seen in controls (2/15, 13%; P = 0.024). Episodes of diarrhea and β-diversity of the 16S configuration of fecal microbiota did not differ between the 2 groups. Conclusions Addition of BC/egg to complementary feeding in Malawian infants resulted in less linear growth faltering. This trial was registered at clinicaltrials.gov as NCT03801317.

New findings What is the central question of this study? Is there a link between gut microbial fermentation and ventilatory responsiveness to hypoxia in humans? What is the main finding and its importance? Increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to the transient hypoxia. These findings imply a capacity for gut microbiota to modulate the peripheral chemoreflex response to hypoxia in humans. Abstract Recent animal data indicate the presence of a bi-directional link between gut microbial activity and respiratory control. Nevertheless, the presence of similar association between gut microbiota and peripheral chemoreceptor responsiveness to hypoxia in humans has not been reported to date. Therefore, we performed a within-subject, placebo-controlled study in a group of 16 healthy individuals (8 men; mean age ±SD 25.9±5.2). Participants underwent two tests (in a random order), receiving lactulose, which stimulates gut fermentation, or placebo. Ventilatory and haemodynamic responses to transient hypoxia were evaluated before and two hours after the test meal. The magnitude of these responses was related to the net hydrogen content in the exhaled air, reflecting gut fermentation intensity. Lactulose meal, compared to placebo, caused an increase in the minute ventilation (Hyp-VI; [L min-1 × (SpO2 )-1 ]) and breathing rate (Hyp-BR; [breaths min-1 × (SpO2 )-1 ]) responses to hypoxia (for Hyp-VI, mean±SD -0.03±0.059 in placebo test vs. 0.05±0.116 in lactulose test, p = 0.03; for Hyp-BR, -0.015±0.046 vs. 0.034±0.054, p = 0.01). The magnitude of these responses was positively correlated with the lactulose-induced hydrogen excretion (for Hyp-VI, r = 0.62, p = 0.01; for Hyp-BR, r = 0.73, p = 0.001). Changes in the resting parameters during normoxia did not differ significantly between the tests. Our results demonstrate that the increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to the transient hypoxia, which implies a capacity for gut microbiota to modulate the peripheral chemoreflex in humans. This article is protected by copyright. All rights reserved.

A simple and reliable in vitro model of the infant intestinal barrier is needed to study nutrient absorption and drug permeability specifically for this life stage. This study investigated the treatment of 20 day old differentiated Caco-2 monolayers with sodium butyrate at various concentrations (0-250 mM). Monolayer integrity, cytotoxicity, permeability and inflammatory response were tracked. An intestinal barrier model, with infant gut characteristics, was developed based on the treatment of mature monolayers with 125 mM sodium butyrate for 24 h. Such treatment was not cytotoxic but caused a stable transepithelial electrical resistance value of 408 ± 52 Ω cm2. The ratio of lactulose to mannitol transport across the intestinal barrier increased 1.79-fold. Redistribution of the tight junction proteins, occludin and ZO-1, in response to sodium butyrate treatment was visualized with immunofluorescence. Levels of the cytokines, TNF-α and IL-6, although modestly increased did not indicate an inflammatory response by Caco-2 to sodium butyrate. This intestinal barrier demonstrated physiologically relevant transport rates for dairy protein of 0.01-0.06%, suggesting it may be used to track permeability of proteins in infant nutritional products.

Background & Aims Altered microbiota can affect the gut-liver-brain axis in cirrhosis and hepatic encephalopathy (HE), but the impact of sex on these changes is unclear. We aimed to determine differences in fecal microbiota composition/functionality between men and women with cirrhosis and HE on differing treatments. Methods Cross-sectional stool microbiome composition (16s rRNA sequencing) and microbial functional analyses were performed in men and women with cirrhosis, and controls. Patients with HE on rifaximin+lactulose (HE-Rif), patients with HE on lactulose only (HE-Lac) and those with cirrhosis without HE (No-HE) were compared to controls using random forest classifier. Men and women were also compared. Results A total of 761 individuals were included, 619 with cirrhosis (466 men, 153 women) and 142 controls (92 men, 50 women). Men were older and more frequently used proton pump inhibitors (PPIs), but model for end-stage liver disease score, No-HE (n = 319), HE-lac (n = 130) and HE-Rif (n = 170) proportions were similar. PPI/age-adjusted AUC of differentiation between controls vs. all cirrhosis, and controls vs. No-HE were higher within women than men, but the adjusted AUC for No-HE vs. HE-Rif was higher in men. Control vs. HE-Rif differentiation was similar across sexes. Men vs. women were different in all cirrhosis, No-HE and HE-Lac but not HE-Rif on PERMANOVA and AUC analyses. Autochthonous taxa decreased and pathobionts increased with disease progression regardless of sex. In men, Lactobacillaceae were higher in HE-Lac but decreased in HE-Rif, along with Veillonellaceae. Pathways related to glutamate and aromatic compound degradation were higher in men at all stages. Degradation of androstenedione, an estrogenic precursor, was lower in men vs. women in HE-Rif, likely enhancing feminization. Conclusions There are differences in gut microbial function and composition between men and women with cirrhosis, which could be implicated in differential responses to HE therapies. Further studies linking these differences to sex-specific outcomes are needed. Lay summary Patients with cirrhosis develop changes in their brain function, and men often develop feminization with disease progression. However, the interaction between sex, microbiota and disease severity is unclear. We found that as disease progressed in men, their microbial composition began to approach that observed in women, with changes in specific microbes that are associated with male hormone metabolism.

ObjectiveTo explore the effect of probiotics combined with prebiotics on clinical hypothyroidism during pregnancy combined with small intestinal bacterial overgrowth.Methods(1) In total, 441 pregnant women were included in this study. A total of 231 patients with clinical hypothyroidism during the second trimester of pregnancy and 210 normal pregnant women were enrolled in the lactulose methane-hydrogen breath test. The positive rate of intestinal bacterial overgrowth (SIBO), gastrointestinal symptoms, thyroid function and inflammatory factors were compared between the two groups by chi-square test and two independent sample t-test. (2) SIBO-positive patients in the clinical hypothyroidism group during pregnancy (n=112) were treated with probiotics combined with prebiotics based on conventional levothyroxine sodium tablets treatment. The changes in the methane-hydrogen breath test, gastrointestinal symptoms, thyroid function and inflammatory factors were compared before treatment (G0) and 21 days after treatment (G21) by chi-square test and paired sample t test.Results(1) The positive rates of SIBO in pregnant women in the clinical hypothyroidism group and control group were 48.5% and 24.8%, respectively. (2) The incidence of abdominal distention and constipation in the clinical hypothyroidism group was significantly higher than that in the control group, and the risk of abdominal distention and constipation in SIBO-positive pregnant women was higher than that in SIBO-negative pregnant women. (3) The serum levels of hypersensitive C-reactive protein (hsCRP), IL-10, IL-6, TNF-α, low-density lipoprotein (LDL), total cholesterol (TC), free fatty acids (FFAs) and apolipoprotein B (ApoB) in the hypothyroidism group during pregnancy were higher than those in the control group. (4) After 21 days of probiotics combined with prebiotics, the incidence of pure methane positivity in the methane-hydrogen breath test in the G21 group was significantly reduced, and the average abundance of hydrogen and methane at each time point in the G21 group was lower than that in the G0 group. (5) The incidence of constipation in the G21 group was significantly lower than before treatment. (6) The levels of serum TSH, hsCRP, IL-6, TNF-α, TC and LDL in pregnant women after probiotics combined with prebiotics were lower than those before treatment.ConclusionProbiotics combined with prebiotics are effective in the treatment of pregnant patients with clinical hypothyroidism complicated with SIBO, providing a new idea to treat pregnant patients with clinical hypothyroidism complicated with SIBO.

Background Hepatic encephalopathy (HE) is a complication of cirrhosis. Rifaximin, added to lactulose, effectively maintains remission and reduces hospitalizations from HE compared with lactulose alone. Although the clinical evidence supports the use of rifaximin, concerns remain regarding the financial implications and subsequent impact on medication access and outcomes. Objective The goal of this study was to determine whether medication access to rifaximin at hospital discharge reduces readmission and office visits related to HE. Methods A retrospective study was conducted in compliance with local institutional review board including cirrhotic patients discharged with a rifaximin prescription for HE. Patients were stratified into 2 groups: those able to obtain rifaximin and those unable to obtain rifaximin upon discharge. The primary outcome was to evaluate the rate of HE recurrence in each group as defined as a composite of readmission or office visit for acute HE within 12 months of discharge. Results Access to rifaximin significantly reduced the risk of hospital admission and office visit for acute HE over 12 months. A hospitalization or office visit occurred in 24.5% of patients in the medication access group compared with 50% in the group without medication access. Only 58% of patients had access to rifaximin at discharge. Conclusion and Relevance Rifaximin use was associated with significantly reduced risk of hospitalization and office visits for HE. At discharge, 42% of patients did not have access to rifaximin regardless of being prescribed the medication, identifying that copay is a significant barrier in allowing patients to have access to rifaximin.

The non-absorbable disaccharide lactulose is mostly used in the treatment of various gastrointestinal disorders such as chronic constipation and hepatic encephalopathy. The mechanism of action of lactulose remains unclear, but it elicits more than osmotic laxative effects. As a prebiotic, lactulose may act as a bifidogenic factor with positive effects in preventing and controlling diabetes. In this review, we summarized the current evidence for the effect of lactulose on gut metabolism and type 2 diabetes (T2D) prevention. Similar to acarbose, lactulose can also increase the abundance of the short-chain fatty acid (SCFA)-producing bacteria Lactobacillus and Bifidobacterium as well as suppress the potentially pathogenic bacteria Escherichia coli. These bacterial activities have anti-inflammatory effects, nourishing the gut epithelial cells and providing a protective barrier from microorganism infection. Activation of peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP1) can influence secondary bile acids and reduce lipopolysaccharide (LPS) endotoxins. A low dose of lactulose with food delayed gastric emptying and increased the whole gut transit times, attenuating the hyperglycemic response without adverse gastrointestinal events. These findings suggest that lactulose may have a role as a pharmacotherapeutic agent in the management and prevention of type 2 diabetes via actions on the gut microbiota.

This study aimed to determine the influence of acute resistance exercise (RE) and biological sex on subjective gastrointestinal (GI) symptoms, GI epithelial damage, and GI permeability in resistance-trained males and females.Thirty resistance-trained men ( n = 15) and women ( n = 15) completed an RE bout and a nonexercise control (CON) session in a randomized counterbalanced design. The RE protocol used a load of 70% one-repetition maximum for 4 sets of 10 repetitions with a 90-s rest period length between sets and a 120-s rest period between exercises (squat, seated shoulder press, deadlift, bent-over row, and leg press). Blood samples were collected before exercise (PRE), immediately postexercise (IP), and 15-, 30-, and 60-min postexercise. Participants completed GI symptom questionnaires to assess subjective GI symptoms PRE, IP, and 60-min postexercise. Blood samples were assayed to quantify small intestine damage (I-FABP) and GI permeability (lactulose-rhamnose [L/R] ratio). Data were analyzed via separate repeated-measures ANOVA, and area under the curve (AUC) analyses were completed via one-way ANOVA.Participants reported greater GI symptoms in RE at IP compared with CON ( P0.001) with 70% of participants reporting at least one GI symptom with no differences between sexes. Nausea was the most reported GI symptom (63.3%), followed by vomiting (33.3%). I-FABP and L/R ratio did not exhibit differential responses between conditions. However, L/R ratio AUC was greater in males after RE than male CON ( P = 0.002) and both conditions for females ( P0.05). Furthermore, I-FABP AUC in the male RE condition was greater than both female conditions ( P0.05).Resistance-trained individuals experience GI distress after RE, with males incurring the greatest increases in markers of GI damage and permeability.

Background and objectives Cystic fibrosis (CF)-related diabetes (CFRD) affects 50% of CF adults. Gut microbial imbalance (dysbiosis) aggravates their inflammatory response and contributes to insulin resistance (IR). We hypothesized that probiotics may improve glucose tolerance by correcting dysbiosis. Methods A single-center prospective pilot study assessing the effect of Vivomixx (R) probiotic (450 billion/sachet) on clinical status, spirometry, lung clearance index (LCI), and quality of life (QOL) questionnaires; inflammatory parameters (urine and stool metabolomics, blood cytokines); and glucose metabolism (oral glucose tolerance test [OGTT]), continuous glucose monitoring [CGM], and homeostasis model assessment of IR (HOMA-IR) in CF patients. Results Twenty-three CF patients (six CFRD), mean age 17.7 +/- 8.2 years. After 4 months of probiotic administration, urinary cysteine (p = 0.018), lactulose (p = 0.028), arabinose (p = 0.036), mannitol (p = 0.041), and indole 3-lactate (p = 0.046) significantly increased, while 3-methylhistidine (p = 0.046) and N-acetyl glutamine (p = 0.047) decreased. Stool 2-Hydroxyisobutyrate (p = 0.022) and 3-methyl-2-oxovalerate (p = 0.034) decreased. Principal component analysis, based on urine metabolites, found significant partitions between subjects at the end of treatment compared to baseline (p = 0.004). After 2 months of probiotics, the digestive symptoms domain of Cystic Fibrosis Questionnaire-Revised improved (p = 0.007). In the nondiabetic patients, a slight decrease in HOMA-IR, from 2.28 to 1.86, was observed. There was no significant change in spirometry results, LCI, blood cytokines and CGM. Conclusions Changes in urine and stool metabolic profiles, following the administration of probiotics, may suggest a positive effect on glucose metabolism in CF. Larger long-term studies are needed to confirm our findings. Understanding the interplay between dysbiosis, inflammation, and glucose metabolism may help preventing CFRD.

Hepatic encephalopathy (HE) is an important complication of decompensated liver disease. Hospital admission for episodes of HE are very common, with these patients being managed by the hospitalists. These admissions are costly and burdensome to the health-care system. Diagnosis of HE at times is not straightforward, particularly in patients who are altered and unable to provide any history. Precipitants leading to episodes of HE, should be actively sought and effectively tackled along with the overall management. This mandates timely diagnostics, appropriate initiation of pharmacological treatment, and supportive care. Infections are the most important precipitants leading to HE and should be aggressively managed. Lactulose is the front-line medication for primary treatment of HE episodes and for prevention of subsequent recurrence. However, careful titration in the hospital setting along with the appropriate route of administration should be established and supervised by the hospitalist. Rifaximin has established its role as an add-on medication, in those cases where lactulose alone is not working. Overall effective management of HE calls for attention to guideline-directed nutritional requirements, functional assessment, medication reconciliation, patient education/counseling, and proper discharge planning. This will potentially help to reduce readmissions, which are all too common for HE patients. Early specialty consultation may be warranted in certain conditions. Numerous challenges exist to optimal care of hospitalized OHE patients. However, hospitalists if equipped with knowledge about a systematic approach to taking care of these frail patients are in an ideal position to ensure good inpatient and transition of care outcomes.