American Journal of Physiology. Gastrointestinal and Liver Physiology

Viruses are among the most prevalent enteric pathogens. While virologists historically relied on cell lines and animal models, human intestinal organoids (HIOs) continue to grow in popularity. HIOs are non-transformed, stem cell derived, ex vivo cell cultures that maintain the cell type diversity of the intestinal epithelium. They offer higher throughput than standard animal models while more accurately mimicking the native tissue of infection than transformed cell lines. Here, we review recent literature that highlights virological advances facilitated by HIOs...

The activity of the manganese (Mn) efflux transporter SLC30A10 in the liver and intestines is critical for Mn excretion and preventing Mn toxicity. Homozygous loss-of-function mutations in SLC30A10 are a well-established cause of hereditary Mn toxicity. But, the relationship between more common SLC30A10 polymorphisms, Mn homeostasis, and disease is only recently emerging. In 2021, the first coding SNP in SLC30A10 (T95I) was associated with liver disease raising the hypothesis that the T95I substitution may induce disease by inhibiting the Mn efflux function of SLC30A10...

BACKGROUND: Primary Sclerosing Cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes. METHODS: FVB/NJ and Mdr2-/- mice were treated with control or ASBT Vivo-Morpholino. We measured (i) ASBT expression and MC presence in liver/ileum; (ii) liver damage/DR; (iii) hepatic fibrosis/inflammation; (iv) biliary inflammation/histamine serum content; and (v) intestinal permeability/hepatic bacterial translocation...

Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR), toll interacting protein (TOLLIP) and A20 are major inhibitors of Toll Like Receptor (TLR) signaling induced postnatally in the neonatal intestine. Short chain fatty acids (SCFAs), fermentation products of indigestible carbohydrates produced by symbiotic bacteria, inhibit intestinal inflammation. Herein, we investigated the mechanisms by which SCFAs regulate SIGIRR, A20, and TOLLIP expression and mitigate experimental necrotizing enterocolitis (NEC)...

Extensive bowel resection can lead to short bowel syndrome and intestinal failure. Resection-induced dysbiosis may be related to the specific anatomic site of resection and influences the disease progression. While patients with end-jejunostomy are at high risk for intestinal failure, preservation of the ileocecal valve and colon counteracts this risk. The present study investigated the role of the cecum in maintaining microbial homeostasis after different types of small bowel resection. Male C57BL6/J mice were anesthetized by intraperitoneal injection of ketamine/xylazine and received extended ileocecal resection (extended ICR), limited ileocecal resection (limited ICR) or mid small bowel resection (SBR)...

BACKGROUND AND AIMS: Pregnancy induces reprogramming of maternal physiology to support fetal development and growth. Maternal hepatocytes undergo hypertrophy and hyperplasia to drive maternal liver growth and alter their gene expression profiles simultaneously. This study aimed to further understand maternal hepatocyte adaptation to pregnancy. METHODS: Timed pregnancies were generated in mice. RESULTS: In a non-pregnant state, most hepatocytes expressed Cd133, α-fetal protein (Afp,) and epithelial cell adhesion molecule (Epcam) mRNAs, whereas overall, at the protein level, they exhibited a CD133- /AFP- phenotype; however, pericentral hepatocytes were EpCAM+ ...

The machinery maintaining fecal continence prevents involuntary loss of stool and is based on synchronized interplay of multiple voluntary and involuntary mechanisms, dependent on cooperation between motor responses of the musculature of the colon, pelvic floor and anorectum, and on sensory and motor neural pathways. Knowledge of the physiology of fecal continence is key towards understanding the pathophysiology of fecal incontinence. The idea that involuntary contraction of the internal anal sphincter is the primary mechanism of continence and that external anal sphincter supports continence only by voluntary contraction is outdated...

Sterol regulatory element binding proteins (SREBPs) are master transcription factors for lipid synthesis, and SREBP-1 is important for fatty acid and triglyceride synthesis. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c, which are splicing variants transcribed from the Srebf1 gene. Although SREBP-1a exhibits stronger transcriptional activity as compared to SREBP-1c, hepatic SREBP-1c is considered more physiologically important. We generated SREBP-1a flox mice using the CRISPR/Cas9 system, and hepatocyte- and macrophage-specific SREBP-1a knockout (KO) mice (LKO, liver-knockout; and mΦKO, macrophage-knockout)...

Prenatal stress is associated with a high risk of developing adult intestinal pathologies, such as irritable bowel syndrome, chronic inflammation and cancer. Although epithelial stem cells and progenitors have been implicated in intestinal pathophysiology, how prenatal stress could impact their functions is still unknown. We have investigated the proliferative and differentiation capacities of primitive cells using epithelial crypts isolated from colons of adult male and female mice whose mothers have been stressed during late gestation...

Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT). Here, we sought to characterize the liver pathophysiology of a human transgenic mouse model for AATD with a manifestation of liver disease. Male and female transgenic mice for normal (Pi*M) and mutant variant (Pi*Z) human alpha-1 antitrypsin at 3 and 6 months of age were subjected to this study. The progression of hepatic ZAAT accumulation, hepatocyte injury, steatosis, liver inflammation and fibrotic features were monitored by performing an in vivo study...

Gastric ablation has demonstrated potential to induce conduction blocks and correct abnormal electrical activity (i.e., ectopic slow-wave propagation) in acute, intra-operative in-vivo studies. This study aimed to evaluate the safety and feasibility of gastric ablation to modulate slow-wave conduction after two-weeks of healing. Chronic in-vivo experiments were performed in weaner pigs (n=6). Animals were randomly divided into two groups: sham-ablation (n=3, control group; no power delivery, room-temperature, 5 s/point) and radio-frequency (RF) ablation (n=3; temperature-control mode, 65°C, 5 s/point)...

Chronic nausea is a widespread functional disease in children with numerous comorbidities. High resolution electrogastrogram (HR-EGG) has shown sufficient sensitivity as a non-invasive clinical marker to objectively detect distinct gastric slow wave properties in children with functional nausea. We hypothesized that the increased precision of magnetogastrogram (MGG) slow wave recordings could provide supplementary information not evident on HR-EGG. We evaluated simultaneous pre- and postprandial MGG and HR-EGG recordings in pediatric chronic nausea patients and healthy asymptomatic subjects, while also measuring nausea intensity and nausea severity...

BACKGROUND: Intestinal enterocytes have an elaborate apical membrane of actin rich protrusions known as microvilli. The organization of microvilli is orchestrated by the intermicrovillar adhesion complex (IMAC) which connects the distal tips of adjacent microvilli. The IMAC is comprised of CDHR2 and CDHR5 as well as the scaffolding proteins USH1C, ANKS4B and Myosin 7b. To create an IMAC, cells must transport the proteins to the apical membrane. Myosin 5b (MYO5B) is a molecular motor that traffics ion transporters to the apical membrane of enterocytes, and we hypothesized that MYO5B may also be responsible for the localization of IMAC proteins...

Colorectal cancer (CRC) is a leading cause of cancer-related death. There is an urgent need for new methods of early CRC detection and monitoring to improve patient outcomes. Extracellular vesicles (EVs) are secreted, lipid-bilayer bound, nanoparticles that carry biological cargo throughout the body and in turn exhibit cancer-related biomarker potential. RNA binding proteins (RBPs) are post-transcriptional regulators of gene expression that may provide a link between host cell gene expression and EV phenotypes...

Inflammatory bowel diseases (IBD), a heterogeneous group of inflammatory conditions that encompass both ulcerative colitis and Crohn's disease, represent a major public health concern. The etiology of IBD is not yet fully understood and no cure is available, with current treatments only showing long-term effectiveness in a minority of patients. A need to increase our knowledge on IBD pathophysiology is growing, in order to define preventive measures, to improve disease outcome, and to develop new effective and lasting treatments...

Hepatorenal syndrome is a complication of cirrhosis, with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the TLR4 signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney...

DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids...

Gastrointestinal motility is crucial to gut health and has been associated with different disorders such as inflammatory bowel diseases and post-operative ileus. Despite rat and mouse being the two animal models most widely used in gastrointestinal research, minimal studies in rats have investigated gastrointestinal motility. Therefore, our study provides a comparison of colonic motility in the mouse and rat to clarify species differences and assess the relative effectiveness of each animal model for colonic motility research...

Pretreatment with nicotine dose-dependently inhibited acute pancreatitis caused by infusion of ERCP contrast solution into the main pancreatic duct in mice. GTS-21, a specific partial agonist of the α7 nicotinic cholinergic receptor (α7nAChR), also protected the pancreas against ERCP-induced acute pancreatitis. The effects of GTS-21 were abolished by pretreatment with the nicotinic receptor antagonist, mecamylamine. Surgical splenectomy performed 7 days prior to ERCP-induced pancreatitis blocked the protective effects of GTS-21...

BACKGROUND: Severe acute pancreatitis (SAP) is associated with substantial morbidity and mortality. Several cytokines have been identified to have pathophysiologic significance in SAP, but studies characterizing their early trajectories are lacking. AIM: Characterize the early trajectories of seven key cytokines associated with SAP and compare them to non-SAP subjects. METHODS: Five pro-inflammatory cytokines [angiopoietin-2, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, resistin] and two anti-inflammatory cytokines [hepatocyte growth factor, and soluble tumor-necrosis-factor-α receptor-1A], were measured in a prospective cohort of acute pancreatitis subjects at the time of enrollment and then every 24-hours for five days or until discharge...