BACKGROUND & AIMS: The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. METHODS: We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll-/-mice, FAAH-/- mice, and in Cnr1(-/-)and Cnr2(-/-)mice, which have disruptions in the cannabinoid receptors 1 and 2 (CB(½)). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. RESULTS: Wild-type mice given JZL184 and Mgll-/- mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB(2) and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl(4). CONCLUSIONS: MAGL promotes hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat for conditions that expose the liver to oxidative stress and inflammatory damage.
BACKGROUND: & Aims: Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are placed on gluten-free diets. We investigated the specific effects of gluten following dietary reduction of low-fermentable, poorly-absorbed, short-chain carbohydrates (FODMAPs) in subjects believed to have NCGS. METHODS: We performed a double-blind crossover trial of 37 subjects (24-61 y, 6 men) with NCGS and irritable bowel syndrome (based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2-week diet of reduced FODMAPs, and were then placed on high-gluten (16 g gluten/day), low-gluten (2 g gluten/day and 14 g whey protein/day), or control (16 g whey protein/day) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then crossed-over to groups given gluten (16 g/day), whey (16 g/day), or control (no additional protein) diets for 3 days. Symptoms were evaluated by visual analogue scales. RESULTS: In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were observed in only 8% of participants. There were no diet-specific changes in any biomarker. During the 3-day re-challenge, participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not reproduced. An order effect was observed. CONCLUSION: In a placebo-controlled, crossover re-challenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs.
It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity.
Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks.
Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection (CDI). However, transferring undefined living bacteria entails uncontrollable risks for infectious and metabolic or malignant diseases, particularly in immunocompromised patients. We investigated whether sterile fecal filtrates (containing bacterial debris, proteins, antimicrobial compounds, metabolic products and oligonucleotides/DNA), rather than intact microorganisms, are effective in patients with CDI.
Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity.
We have limited knowledge about the association between the composition of the intestinal microbiota and clinical features of irritable bowel syndrome (IBS). We collected information on the fecal and mucosa-associated microbiota of patients with IBS and evaluated whether these were associated with symptoms.
Elafibranor is an agonist of the peroxisome proliferator activated receptor-α (PPARA) and peroxisome proliferator activated receptor-δ (PPARD). Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with non-alcoholic steatohepatitis (NASH).
Tumor cells circulate in low numbers in peripheral blood; their detection is used predominantly in metastatic disease. We evaluated the feasibility and safety of sampling portal venous blood via endoscopic ultrasound (EUS) to count portal venous circulating tumor cells (CTCs), compared to paired peripheral CTCs, in patients with pancreaticobiliary cancers (PBCs).
BACKGROUND & AIMS:: Studies of primary biliary cirrhosis (PBC) phenotypes have largely been performed using small and used selected populations. Study size has precluded investigation of important disease sub-groups, such as men and young patients. We used a national patient cohort to obtain a better picture of PBC phenotypes. METHODS:: We performed a cross-sectional study using the United Kingdom-PBC patient cohort. Comprehensive data were collected for 2353 patients on diagnosis reports, response to therapy with ursodeoxycholic acid (UDCA), laboratory results, and symptom impact (assessed using the PBC-40 and other related measures). RESULTS:: Seventy-nine percent of the patients reported current UDCA therapy, with 80% meeting Paris response criteria. Men were significantly less likely to have responded to UDCA than women (72% vs 80% response, P <.05); male sex was an independent predictor of non-response on multivariate analysis. Age at diagnosis was strongly and independently associated with response to UDCA; response rates ranged from 90% among patients who presented with PBC when they were older than 70 y, to less than 50% for those younger than 30 y ( P <.0001). Patients who presented at younger ages were also significantly more likely not respond to UDCA therapy, based on alanine aminotransferase and aspartate aminotransferase response criteria, and more likely to report fatigue and pruritus. Women had mean fatigue scores 32% higher than men's ( P <.0001). The increase in fatigue severity in women was strongly related (r=0.58, P <.0001) to higher levels of autonomic symptoms ( P <.0001). CONCLUSIONS:: Among patients with PBC, response to UDCA treatment and symptoms are related to sex and age at presentation, with the lowest response rates and highest levels of symptoms in women presenting at <50 years of age. Increased severity of fatigue in women is related to increased autonomic symptoms, making dysautonomia a plausible therapeutic target.