American Journal of Physiology. Gastrointestinal and Liver Physiology

OATP1B3-1B7 (LST-3TM12) is a member of the OATP1B ( SLCO1B )-family. This transporter is not only functional, but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3-1B7 is a splice variant of SLCO1B3 where the initial part is encoded by SLCO1B3 , whereas the rest of the mRNA originates from the gene locus of SLCO1B7 . In this study we not only showed that SLCO1B3 and the mRNA encoding for OATP1B3-1B7 share the 5' untranslated region, but also that silencing of an initial SLCO1B3 exon lowered the amount of SLCO1B3 and of SLCO1B7 mRNA in Huh-7 cells...

Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) gene mutations are a risk factor for Crohn´s disease and also associated with worse outcome in short bowel syndrome (SBS) patients, independent of the underlying disease. The aim of the study was to analyze the effect of Nod2 deficiency on barrier function and stool microbiome after extensive ileocecal resection in mice. Male C57BL6/J wild-type and Nod2 knock-out mice underwent 40% ileocecal resection. Sham control mice received simple transection of the ileum...

The secondary bile acid, ursodeoxycholic acid (UDCA), has long been known to have medicinal properties. As the therapeutically active component of bear bile, it has been used for centuries in traditional Chinese Medicine to treat a range of conditions, while manufactured UDCA has been used for decades in Western medicine to treat cholestatic liver diseases. The beneficial qualities of UDCA are thought to be due to its well-established cytoprotective and anti-inflammatory actions. In addition to its established role in treating liver disease(s), UDCA is now under investigation for numerous conditions associated with inflammation and apoptosis, including neurological, ocular, metabolic, and cardiovascular disorders...

Melatonin was discovered in 1958 by Aaron Lerner; its name comes from the ability of melatonin to change the shape of amphibian melanophores from stellate to roundish. Starting from the 80s, the role of melatonin in the regulation of mammalian circadian and seasonal clocks has been elucidated. Presently, several other effects have been identified in different organs. For example, he beneficial effects of melatonin in models of liver damage have been described. This review gives first a general background on experimental and clinical data on the use of melatonin in liver damage...

Advances in data collection technologies reveal that an imbalance (dysbiosis) in the composition of host-associated microbial communities (microbiota) is linked to many human illnesses. This association makes dysbiosis a central concept for understanding how the human microbiota contributes to health and disease. However, it remains problematic to define the term dysbiosis by cataloguing microbial species names. Here we discuss how incorporating the germ-organ concept, ecological assumptions and immunological principles into a theoretical framework for microbiota research provides a functional definition for dysbiosis...

Exosomes and exosome-like vesicles participate in cell-to-cell communication in animals, plant and bacteria. Dietary exosomes in bovine milk are bioavailable in non-bovine species, but a fraction of milk exosomes reaches the large intestine. We hypothesized that milk exosomes alter the composition of the gut microbiome in mice. C57BL/6 mice were fed AIN-93G diets, defined by their content of bovine milk exosomes and RNA cargos: exosome/RNA-depleted (ERD) versus exosome/RNA-sufficient (ERS) diets. Feeding was initiated at age three weeks and cecum content was collected at ages 7, 15 and 47 weeks...

The pancreas consists of both the exocrine (acini and ducts) and endocrine (islets) compartments to participate in and regulate the body's digestive and metabolic activities. These activities are subjected to neural modulation, but characterization of the human pancreatic afferent and efferent nerves remains difficult due to the lack of 3-D image data. Here we prepare transparent human donor pancreases for 3-D histology to reveal the pancreatic microstructure, vasculature, and innervation in a global and integrated fashion...

Exacerbation of alcoholic hepatitis (AH) with comorbid metabolic syndrome is an emerging clinical problem, where microbiota plays a profound role in the pathogenesis. Here, we investigated the effect of rifaximin (RFX) on liver injury following chronic-binge ethanol (EtOH) administration in KK-Ay mice, a rodent model of metabolic syndrome. Female, 8-week-old KK-Ay mice were fed Lieber-DeCarli diet (5% EtOH) for 10 days, following a single EtOH gavage (4 g/kg BW). Some mice were given RFX (0.1 g/L, in liquid diet) orally...

BACKGROUND: Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full thickness gastric biopsies from gastroparesis patients. AIM: We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients...

Early administration of Lactobacillus reuteri DSM 17938 (LR) prevents necrotizing enterocolitis and inhibits Treg-deficiency-associated autoimmunity in mice. In humans, LR reduces crying time in breastfed infants with colic, modifies severity in infants with acute diarrheal illnesses, and improves pain in children with functional bowel disorders. In healthy breastfed newborns with evolving microbial colonization, it is unclear if early administration of LR can modulate gut microbiota and their metabolites in such a way as to promote homeostasis...

The overall objectives of this review are to summarize actionable biomarkers for organic etiology of lower functional gastrointestinal diseases (FGIDs) that lead to individualized treatment for their FGIDs, and to assess the pipeline for novel approaches to the management of constipation, diarrhea, and chronic abdominal pain in lower FGIDs. The new approaches to therapy include ion exchangers/transporters for functional constipation (SGLT1, NHE3, and SLC26A3 inhibitors), bile acid modulators for constipation such as IBAT inhibitors and FGF19 analog for functional constipation, and bile acid sequestrants or FXR agonists for functional diarrhea...

Bariatric surgery may induce protein malabsorption, although data are scarce. This study aims at evaluating dietary protein bioavailability after different bariatric surgeries in rats. Diet-induced, obese Wistar rats were operated for vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB). The control group was composed of pair-fed, sham-operated rats (Sham). Two weeks after surgery, rats were fed a 15 N protein meal. Protein bioavailability was assessed by determination of 15 N recovery in the gastrointestinal tract and organs 6 h after the meal...

We previously demonstrated that administration of norepinephrine, dopamine and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are mainly released from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles ofthe noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex...

Post-traumatic stress disorder(PTSD) is associated with cirrhosis in Veterans and therapeutic results are suboptimal. An altered gut-liver-brain axis exists in cirrhosis due to hepatic encephalopathy(HE), but the added impact of PTSD is unclear. Aim: Define linkages between gut microbiota and cognition in cirrhosis with/without PTSD. Cirrhotic Veterans (with/without prior HE) underwent cognitive testing (PHES, inhibitory control test,ICT and block design BDT), serum lipopolysaccharide-binding protein(LBP) and stool collection for 16SrRNA microbiota composition and predicted function analysis(PiCRUST)...

AIM: Non-alcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-week dietary mouse model of NASH and to validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH...

In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of eATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental AP. Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice by one-day or 2-day caerulein, caerulein + LPS and L-arginine models...

Gastric cancer (GC) is one of the most common cancers in the world and remains a heavy burden of health worldwide. Adenylate cyclase 3 ( ADCY3 ) is a widely expressed membrane-associated protein in human tissues and has been identified to be a new molecular target of GC. Long non-coding RNAs (lncRNAs) have substantial influence on tumorigenesis and progression of tumors by binding to microRNAs (miRNAs). Therefore, this study is to clarify the mechanism by which LINC00319 sponges miR-335-5p to influence development of GC...

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a 'cold' tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS, formerly called G17DT and Gastrimmune) used alone or in combination with a PD-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME)...

Congenital Tufting Enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule ( EPCAM ) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAMenteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels...

T The cardiac glycoside digoxin was identified as a potent suppressor of PKM2-HIF-1a pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin by the clinically relevant oral route to reduce non-alcoholic steatohepatitis (NASH) in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high fat diet (HFD) for 10 weeks and started concurrently with the gavage of digoxin (2...