The Leaky Gut and Human Diseases: "Can't Fill the Cup if You Don't Plug the Holes First".

BACKGROUND: The gut barrier is a sophisticated and dynamic system that forms the frontline defense between the external environment and the body's internal milieu and includes various structural and functional components engaged not only in digestion and nutrient absorption but also in immune regulation and overall health maintenance. SUMMARY: When one or more components of the intestinal barrier lose their structure and escape their function, this may result in a leaky gut. Mounting evidence emphasizes the crucial role of the gut microbiome in preserving the integrity of the gut barrier and provides insights into the pathophysiological implications of conditions related to leaky gut in humans. Assessment of intestinal permeability has evolved from invasive techniques to noninvasive biomarkers, but challenges remain in achieving consensus about the best testing methods and their accuracy. Research on the modulation of gut permeability is just starting, and although no medical guidelines for the treatment of leaky gut syndrome are available, several treatment strategies are under investigation with promising results. KEY MESSAGES: This review discusses the composition of the intestinal barrier, the pathophysiology of the leaky gut and its implications on human health, the measurement of intestinal permeability, and the therapeutic strategies to restore gut barrier integrity.

Probiotics in Gastrointestinal Diseases: All that Glitters Is Not Gold.

BACKGROUND: Multiple lines of evidence now support the notion that gut microbiota can contribute to digestive and extra-digestive diseases. The emergence of these observations enabled to postulate a bacteria-centric paradigm to rethink the treatment of many diseases. The goal of therapy should not be to eradicate the flora but to modify it in a way that leads to symptomatic improvement; thus, the interest in the use of probiotics to modulate microbiota composition has increased worldwide in both community and healthcare settings. SUMMARY: The results of published studies are conflicting for most probiotic strains and formulations, and clinicians and consumers need a better understanding of probiotic risks and benefits. Currently, clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions are still lacking. Here, we reviewed the studies on the use of probiotics in some diseases of relevant interest to gastroenterologists, such as Helicobacter pylori infection, irritable bowel syndrome, and inflammatory bowel disease. Key Message: Although the evidence is relevant and promising for probiotics in general, and for specific strains and combinations of strains, it is not yet sufficient to draw unequivocal conclusions and clear recommendations.

Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: an ex-vivo organ culture model of post-infectious irritable bowel syndrome.

BACKGROUND: The evidence on the role of gut microbiota in post-infectious irritable bowel syndrome (PI-IBS) is convincing. Lactobacillus spp. positively affect IBS symptoms, although the mechanisms through which probiotics exert their beneficial effects are largely unknown. The aim of the study is to evaluate the role of Lactobacillus casei DG (LC-DG) and its postbiotic (PB) in modulating the inflammatory/immune-response in PI-IBS in an ex-vivo organ culture model. METHODS: Ex vivo cultures of ileal and colonic mucosa from 10 PI-IBS, diarrhea predominant subtype (D) patients, and 10 healthy controls (HC) were treated with LPS, LC-DG and PB. Interleukin (IL)-1α, IL-6, IL-8 and IL-10 mRNA levels were assessed by real-time PCR and Toll like receptor 4 (TLR-4) protein expression by Western blotting. RESULTS: At baseline, IL-1α, IL-6 and IL-8 mRNA levels as well as TLR-4 protein expression were significantly higher while IL-10 mRNA levels were lower in PI-IBS D than in HC in both ileum and colon. LC-DG and PB significantly reduced the mRNA levels of pro-inflammatory cytokines and TLR-4 while increased that of IL-10 after LPS stimulation. The protective effect was more pronounced for PB than LC-DG treatment. CONCLUSION: LC-DG and its PB attenuate the inflammatory mucosal response in an ex-vivo organ culture model of PI-IBS D.

The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease.

The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association.

Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus.

BACKGROUND: In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. OBJECTIVE: To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy. METHODS: Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response-namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. RESULTS: Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. CONCLUSION: Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.

The professional background of a referring physician predicts the diagnostic yield of small bowel capsule endoscopy in suspected small bowel bleeding.

Background and study aims The diagnostic yield of small-bowel capsule endoscopy (SBCE) in suspected small bowel bleeding (SSBB) is highly variable. Different reimbursement systems and equipment costs also limit SBCE use in clinical practice. Thus, minimizing non-diagnostic procedures is advisable. This study aimed to assess the SBCE diagnostic yield and identify factors predicting diagnostic findings in a cohort of patients with SSBB. Patients and methods In this retrospective cohort study, we analyzed the medical records of patients who consecutively underwent SBCE for SSBB over 9 years. By logistic regression, we identified covariates predicting diagnostic findings at SBCE. Finally, we performed a post-hoc cost analysis based on previous gastroenterologist or endoscopist consultations versus direct SBCE ordering by other specialists. Results The final analysis included 584 patients. Most SBCEs were ordered by a gastroenterologist or endoscopist (74%). The number of SBCEs without any finding was significantly lower in the gastroenterologist/endoscopist group P <0.001). The SBCE diagnostic yield ordered by a gastroenterologist or endoscopist was significantly higher than that by other specialists (63% vs 52%, odds ratio [OR] 1.57; 95% confidence interval [CI] 1.07-2.26, P =0.019). At multivariate analysis, older age (OR 1.7, 95%CI 1.2-2.4, P =0.005), anemia (OR 4.9, 95%CI 1.9-12, P =0.001), small bowel transit time (OR 1, 95%CI 1-1.02, P =0.039), and referring physician (OR 1.8, 95%CI 1.1-2.7, P =0.003) independently predicted diagnostic findings. Implementing prior gastroenterologist or endoscopist referral vs direct SBCE ordering would reduce medical expenditures by 16%. Conclusions The professional background of referring physicians significantly improves the diagnostic yield of SBCE and contributes to controlling public health costs.

Impact of proton pump inhibitors on cytochrome P450 activity assessed by 13 C-aminopyrine breath test in patients with cirrhosis.

BACKGROUND: Chronic use of proton pump inhibitors (PPIs) in patients with impaired liver function may worsen cytochrome P450 (CYP450) activity, predisposing them to clinically relevant drug-drug interactions. The 13 C-aminopyrine breath test (13 C-ABT) is a non-invasive tool to study CYP450-dependent liver function. AIMS: To assess 13 C-ABT modifications with different PPIs in patients with cirrhosis METHODS: Sixty consecutive patients with HCV-related cirrhosis and indication to start PPI therapy were randomised to receive omeprazole 20 mg/day, esomeprazole 20 mg/day, lansoprazole 15 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day. 13 C-ABT was performed at baseline and on the 15th day of PPI therapy. RESULTS: At baseline, mean values of max 13 C% dose/h and 13 C% cum dose at 120 minutes did not differ significantly among groups. On the 15th day of therapy, max 13 C% dose/h and 13 C% cum dose at 120 minutes did not significantly differ with respect to baseline for pantoprazole (P = 0.184 and P = 0.309, respectively) or rabeprazole (P = 0.536 and P = 0.286, respectively), but were significantly decreased on omeprazole (P = 0.013 and P = 0.015, respectively), esomeprazole (P = 0.009 and P = 0.001, respectively), and lansoprazole (P = 0.033 and P = 0.035, respectively). CONCLUSIONS: In patients with cirrhosis, omeprazole, esomeprazole and lansoprazole inhibit microsomal activity while pantoprazole and rabeprazole do not have a significant impact. Should our data be confirmed in larger cohort studies, pantoprazole and rabeprazole could be safely recommended for patients with cirrhosis.

Gut Microbes and Hepatic Encephalopathy: From the Old Concepts to New Perspectives.

Hepatic encephalopathy (HE) is a severe complication of advanced liver disease and acute liver failure. The clinical spectrum ranges from minor cognitive dysfunctions to lethargy, depressed consciousness, and coma and significantly impact the quality of life, morbidity, and mortality of the patients. It is commonly accepted that the gut milieu is essential for the development of HE; however, despite intensive research efforts, the pathogenesis of HE is still not fully elucidated. As our knowledge of gut microbiota moves from the pioneering era of culture-dependent studies, the connection between microbes, inflammation, and metabolic pathways in the pathogenesis of HE is becoming increasingly clear, providing exciting therapeutic perspectives. This review will critically examine the latest research findings on the role of gut microbes in the pathophysiological pathways underlying HE. Moreover, currently available therapeutic options and novel treatment strategies are discussed.

Blinded Oral Challenges with Lactose and Placebo Accurately Diagnose Lactose Intolerance: A Real-Life Study.

Lactose intolerance (LI) is characterized by diarrhea, abdominal pain, or bloating occurring after lactose consumption in patients with lactose malabsorption. The National Institute of Health (NIH) proposed a double-blind placebo testing to identify LI individuals correctly. However, until now, no study used this approach in a real-life setting. We aimed to assess double-blind placebo challenge accuracy in diagnosing LI in patients with self-reported symptoms of LI. 148 patients with self-reported LI were consecutively enrolled and blindly underwent hydrogen breath test (HBT) after 25 g lactose or 1 g glucose (placebo) load. One week later, the subjects were challenged with the alternative substrate. Each subject completed a validated questionnaire, including five symptoms (diarrhea, abdominal pain, vomiting, bowel sounds, and bloating) scored on a 10-cm visual analog scale. Home questionnaire (HQ) referred to symptoms associated with the consumption of dairy products at home, while lactose questionnaire (LQ) and placebo questionnaire (PQ) referred to symptoms perceived throughout the 4-h after the administration of the substrates, respectively. After lactose load, HBT was positive in 81 patients (55%), of whom 60 (74%) reported relevant symptoms at LQ (lactose malabsorbers, LM). After placebo challenge, 45 out of 60 with a positive lactose challenge did not complain of symptoms and therefore were diagnosed as lactose intolerant, according to NIH definition. The blinded oral challenges with lactose and placebo accurately diagnose LI and identify patients who will likely benefit from a lactose-free diet.

Ultrasonography-Based Management of Sclerosing Mesenteritis: From Diagnosis to Follow-Up.

Sclerosing mesenteritis (SM) is an idiopathic disorder affecting mesentery, characterized by fat necrosis, chronic inflammation and fibrosis. The clinical presentation varies from asymptomatic cases to acute abdomen. The diagnosis is suggested by imaging but can be definitely established only by biopsies. In this paper, we discuss ultrasonography-based management of SM.

Surveillance as Determinant of Long-Term Survival in Non-Transplanted Hepatocellular Carcinoma Patients.

PURPOSE: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. METHODS: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW). RESULTS: LS patients were more frequently diagnosed under surveillance (p < 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195-1.671; p < 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer compared to the survival of not surveilled patients (p < 0.0001 and p = 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (p = 0.30). CONCLUSIONS: Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients' prognosis.

Reproducibility of shear wave elastography (SWE) in patients with chronic liver disease.

The presence of significant fibrosis is an indicator for liver disease staging and prognosis. The aim of the study was to determine reproducibility of real-time shear wave elastography using a hepatic biopsy as the reference standard to identify patients with chronic liver disease. Forty patients with chronic liver disease and 12 normal subjects received shear wave elastography performed by skilled operators. Interoperator reproducibility was studied in 29 patients. Fibrosis was evaluated using the Metavir score. The median and range shear wave elastography values in chronic liver disease subjects were 6.15 kPa and 3.14-16.7 kPa and were 4.49 kPa and 2.92-7.32 kPa in normal subjects, respectively. With respect to fibrosis detected by liver biopsy, shear wave elastography did not change significantly between F0 and F1 (p = 0.334), F1 and F2 (p = 0.611), or F3 and F4 (0.327); a significant difference was observed between the F0-F2 and F3-F4 groups (p = 0.002). SWE also correlated with inflammatory activity (Rs = 0.443, p = 0.0023) and ALT levels (Rs = 0.287, p = 0.0804). Age, sex and body mass index did not affect shear wave elastography measurements. Using receiver operator characteristic curves, two threshold values for shear wave elastography were identified: 5.62 kPa for patients with fibrosis (≥F2; sensitivity 80%, specificity 69.4%, and accuracy 77%) and 7.04 kPa for patients with severe fibrosis (≥F3; sensitivity 88.9%, specificity 81%, and accuracy 89%). Overall interobserver agreement was excellent and was analysed using an interclass correlation coefficient (0.94; CI 0.87-0.97).This study shows that shear wave elastography executed by skilled operators can be performed on almost all chronic liver disease patients with high reproducibility. It is not influenced by age, sex or body mass index, identifies severely fibrotic patients and is also related to inflammatory activity.

Lactobacillus paracasei F19 versus placebo for the prevention of proton pump inhibitor-induced bowel symptoms: a randomized clinical trial.

BACKGROUND: Proton pump inhibitors may foster intestinal dysbiosis and related bowel symptoms. AIM: To evaluate the effect of Lactobacillus paracasei F19 on bowel symptom onset in patients on long-term proton pump inhibitors. METHODS: In this randomized, double-blind, placebo-controlled study, patients with typical gastroesophageal reflux disease symptoms receiving pantoprazole 40 mg/d for six months were randomly assigned to receive: (A) Lactobacillus paracasei F19 bid for three days/week for six months; (B) placebo bid for three days/week for six months; (C) Lactobacillus paracasei F19 bid for three days/week for three months and placebo bid for three days/week for the following three months; (D) placebo bid for three days/week for three months and Lactobacillus paracasei F19 bid for three days/week for the following three months. Bloating, flatulence, abdominal pain and bowel habit were assessed monthly. RESULTS: 100/312 patients were enrolled. In the parallel groups, the treatment-by-time interaction affected bloating (p = 0.015), while Lactobacillus paracasei F19 treatment alone affected flatulence (p = 0.011). Moreover, the treatment-by-time interaction significantly affected the mean score of bloating (p = 0.01) and flatulence (p < 0.0001), the mean stool form (p = 0.03) and mean stool frequency/week (p = 0.016). Analysis of the cross-over groups, limited to the first three months because of carry-over effect, confirmed these results. CONCLUSION: Lactobacillus paracasei F19 supplementation prevents bowel symptom onset in patients on long-term proton pump inhibitors.

Simultaneous gas-chromatographic measurement of rhamnose, lactulose and sucrose and their application in the testing gastrointestinal permeability.

BACKGROUND: As it is important to test gastric and intestinal permeability simultaneously in gastrointestinal disorders such as Celiac disease, we developed a gas-chromatographic (GC) method to estimate rhamnose (L-rh), lactulose (Lacl) and sucrose (Suc) in urine. METHODS: The method is based on the use of alditol acetate derivatives giving a lower number of GC peaks than reducing sugars do. Acetate derivatives are more stable and less expensive than GC silylates and keep the flame-detector cleaner. We checked the chemical stability of alditol acetates by verifying the reproducibility of the standard curve of a sugar derivative sample which had been stored for 2 months at -20 degrees C. RESULTS: The calibration proved linear over the range 0.1-1 microg of sugar injected. Analytical sugar recovery was 88%+/-19.4% (mean+/-S.D.) for rhamnose, 105%+/-7.4% for sucrose and 102%+/-2.4% for lactulose. Mean within-day precision (CV) was 7.7% for rhamnose, 5.7% for sucrose and 1.9% for lactulose, and between-day (CV) was 6.7% for rhamnose, 3.9% for sucrose and 1.6% for lactulose. The rhamnose, lactulose and sucrose as the lactulose/rhamnose ratio clearly differentiated 25 healthy controls from 36 patients with active gluten-sensitive enteropathy. CONCLUSIONS: A fast, reliable and cheap gas-chromatographic method is presented here to evaluate gastric and intestinal permeability.

Effect of chronic administration of tacrolimus and cyclosporine on human gastrointestinal permeability.

The antirejection drug tacrolimus (FK506) has been reported to impair intestinal permeability in an early stage after orthotopic liver transplantation (OLT), and cyclosporine (CsA) has shown a similar effect in animals. We studied the chronic effect of FK506 and CsA on gastroduodenal and intestinal permeability and on blood endotoxin levels in patients 2 to 3 years after OLT. Thirty-two OLT patients (22 men and 10 women; mean age, 44.8 +/- 7.1) who had received CsA (n = 19) or FK506 (n = 13) and 10 healthy volunteers (6 male and 4 female, mean age 41.7 +/- 5.4) were assessed for gastroduodenal permeability by recovery in urine of sucrose after oral administration and for intestinal permeability by recovery in urine after oral loads of rhamnose and lactulose, which evaluate the intracellular and paracellular routes, respectively. In all subjects, plasma levels of endotoxins also were assessed. Gastroduodenal permeability was similar in patients and controls (0.03 +/- 0.003 versus 0.04 +/- 0.01%, P = NS). In regard to intestinal permeability, passage through the intracellular route was significantly reduced in OLT patients compared with controls (1.13 +/- 0.06 versus 2.74 +/- 0.17%, P <.01), but paracellular permeability was unchanged (0.14 +/- 0.007 versus 0.13 +/- 0.01%, P = NS). Serum endotoxin levels were similar in all subjects. We conclude that chronic administration of FK506 or CsA induces a clinically irrelevant, selective dysfunction of monosaccharide absorption, but does not affect gastroduodenal or intestinal permeability.