American Journal of Physiology. Gastrointestinal and Liver Physiology

Mouse atonal homolog 1 (Math1/Atoh1) is a basic helix-loop-helix transcription factor important for the differentiation of secretory cells within the intestinal epithelium. The analysis of Paneth depletion efficiency upon Math1lox/lox VilCreERT2 ( Math1∆IEC ) mice treatment with Tamoxifen in the presence or absence of intestinal microbiota, showed a failure on Paneth cell depletion in germ-free mice as compared to SPF mice. However, goblet cells were efficiently depleted in Math1∆IEC germ-free mice...

Newborns with FATP4 mutations exhibit ichthyosis prematurity syndrome (IPS), and adult patients show skin hyperkeratosis, allergies, and eosinophilia. We have previously shown that the polarization of macrophages is altered by FATP4 deficiency, however, the role of myeloid FATP4 in the pathogenesis of non-alcoholic steatohepatitis (NASH) is not known. We herein phenotyped myeloid-specific Fatp4-deficient (Fatp4M-/ - ) mice under chow and high-fat/high-cholesterol (HFHC) diet. Bone-marrow-derived macrophages (BMDMs) from Fatp4M-/- mice showed significant reduction in cellular sphingolipids in males and females, and additionally cellular phospholipids in females...

The COVID-19 pandemic has resulted in the infection of hundreds of millions of individuals over the past three years, coupled with millions of deaths. Along with these more acute impacts of infection, a large subset of patients developed symptoms that collectively comprise "post-acute sequelae of COVID-19" (PASC, also known as long COVID), which can persist for months and maybe even years. In this review, we outline current knowledge on the role of impaired microbiota-gut-brain (MGB) axis signaling in the development of PASC and the potential mechanisms involved, which may lead to better understanding of disease progression and treatment options in the future...

Systemic and portal hypertension, liver fibrosis, and hepatomegaly are manifestations associated with autosomal recessive polycystic kidney disease (ARPKD), which is caused by malfunctions of fibrocystin/polyductin. The goal is to understand how liver pathology occurs and to devise therapeutic strategies to treat it. We injected 5-day old Pkhd1del 3-4/del3-4 mice for one month with the CFTR modulator, VX-809, designed to rescue processing and trafficking of CFTR folding mutants (1). We used immunostaining and immunofluorescence techniques to evaluate liver pathology...

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogues has emerged as a promising drug candidates for the treatment of non-alcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the aetiology and hallmarks of the human disease. To this end, we evaluated the long-acting FGF21 analogue PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH...

Calorie restriction can enhance the regenerative capacity of the injured intestinal epithelium. Among other metabolic changes, calorie restriction can activate the autophagy pathway. While independent studies have attributed the regenerative benefit of calorie restriction to downregulation of mTORC1, it is not known whether autophagy itself is required for the regenerative benefit of calorie restriction. We used mouse and organoid models with autophagy gene deletion to evaluate the contribution of autophagy to intestinal epithelial regeneration following calorie restriction...

Hepatic lipotoxicity, the deleterious effects of ectopic lipid accumulation in hepatocytes, plays a central role in the pathogenesis of non-alcoholic fatty liver disease; however, the underlying mechanisms remain elusive. Here, using palmitate exposure of hepatocytes as the in vitro hepatic lipotoxicity model, we found that palmitate exposure upregulates expression of CD36, a class B scavenger receptor mediating long-chain fatty acids uptake, in hepatocytes. Despite being a well-established target gene of PPARγ transactivation in various cell types, our data demonstrated that the palmitate-induced CD36 upregulation in hepatocytes is in fact PPARγ-independent...

BACKGROUND AND PURPOSE: Gastric pacing has shown preclinical success in modulating bioelectrical slow wave activity and has potential as a novel therapy for functional motility disorders. However, the translation of pacing techniques to the small intestine remains preliminary. This paper presents the first high-resolution framework for simultaneous pacing and response mapping of the small intestine. METHODS: A novel surface-contact electrode array, capable of simultaneous pacing and high-resolution mapping of the pacing response was developed and applied in vivo on the proximal jejunum of pigs...

BACKGROUND: Consuming adequate dietary fiber is a promising strategy for reducing systemic inflammation. OBJECTIVE: To evaluate relationships between dietary fiber intake, markers of metabolic endotoxemia, and systemic inflammation in adults. METHODS: This was a cross-sectional study of 129 healthy participants (age 33.6 ± 6.1 years, BMI 30.5 ± 6.9 kg/m2). Dietary fiber intake was assessed by food frequency questionnaire. Adiposity was measured using dual energy X-ray absorptiometry (DXA)...

Macrophages are essential for homeostatic maintenance of the anti-inflammatory and tolerogenic intestinal environment, yet monocyte-derived macrophages can promote local inflammation. Pro-inflammatory macrophage accumulation within the intestines may contribute to the development of systemic chronic inflammation and immunometabolic dysfunction in obesity. Using a model of high fat diet-induced obesity in C57BL/6J female mice, we assessed intestinal paracellular permeability by in vivo and ex vivo assays, and quantitated intestinal macrophages in ileum and colon tissues by multicolour flow cytometry after short (6 weeks), intermediate (12 weeks), and prolonged (18 weeks) diet allocation...

Clostridioides difficile (C. difficile) toxins A (TcdA) and B (TcdB) cause antibiotic-associated colitis in part by disrupting epithelial barrier function. Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell lines and organoids inherently limit these efforts. We developed adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigated the impact of toxins on apical/basal aspects of monolayers, and evaluated whether a leaky epithelial barrier enhances toxicity...

AIMS: Animals involved in common laboratory procedures experience minor levels of stress. The direct effect of limited amounts of stress on gastrointestinal function has not been reported yet. Therefore, this study aimed to assess the effect of single-day and multi-day orogastric gavages on gut physiology in mice. MAIN METHODS: Twelve-week old female C57Bl6/J mice were randomized to receive a treatment with sterile water (200 µL) delivered by orogastric gavages twice daily for a total of 1 or 10 day(s)...

Tumor heterogeneity is a hallmark of cancer but a challenging problem to dissect mechanistically. Less recognized is that cells within normal tissues are also remarkably diverse. Hepatocytes are a great example because their spatial positioning and the local microenvironment govern their genetic heterogeneity. Recent studies show that primary liver tumors display heterogeneity similar to that observed in the normal tissue providing clues to the cellular precursor of the tumor and how variations in the lobule microenvironment support tumor formation and aggressiveness...

The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. What's more, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se...

Taurine is an end-product of cysteine metabolism, while cysteine dioxygenase (CDO) and cysteine sulfinate decarboxylase (CSAD) are key enzymes regulating taurine synthesis. Sex steroids, including estrogens and androgens, are associated with liver physio-pathological processes, however, we still do not know whether taurine and sex steroids interact in regulating liver physiology and hepatic diseases, and whether there are sex differences although our recent study shows the estrogen is involved in regulating taurine synthesis in mouse liver...

Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating its crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet immense metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions. Mitochondria are also involved in terminating the regenerative process by mediating apoptosis...

The enteric nervous system (ENS) is the intrinsic nervous system of the intestine and regulates important gut functions, including motility, nutrient uptake, and immune response. The development of the ENS begins during early organogenesis and continues to develop once feeding begins, with ongoing plasticity in adulthood. There has been increasing recognition that the intestinal microbiota and ENS interact during critical periods, with implications for normal development and potentially disease pathogenesis...

Nonalcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is characterized by substantial variations in case-level severity. In this study, we used a genetically diverse Collaborative Cross (CC) mouse population model to analyze the global transcriptome and clarify the molecular mechanisms involved in hepatic fat accumulation that determine the level and severity of NAFLD. Twenty-four strains of male CC mice were maintained on a high fat/high sucrose (HF/HS) diet for 12 weeks and their hepatic gene expression profiles were determined by next-generation RNA-sequencing...

In cirrhosis, several molecular alterations such as resistance to apoptosis could accelerate carcinogenesis. Recently, mechanotransduction has been attracting attention as one of the causes of these disturbances. In patients with cirrhosis, the serum sodium levels progressively decrease in the later stage of cirrhosis, and hyponatremia leads to serum hypo-osmolality. Since serum sodium levels in patients with cirrhosis with liver cancer are inversely related to cancer's number, size, stage, and cumulative survival, we hypothesized that hypo-osmolality-induced mechanotransduction under cirrhotic conditions might contribute to oncogenesis and/or progression of hepatocellular carcinoma (HCC)...

Limited work has focused on fibroblast growth factor-19 (FGF19) secretion and function in the perinatal period. FGF19 is a potent growth factor that coordinates development of the brain, eye, inner ear, and skeletal system in the embryo, but after birth, FGF19 transitions to be an endocrine regulator of the classic pathway of hepatic bile acid synthesis. FGF19 has emerged as a mediator of metabolism and bile acid synthesis in aged animals and adults in the context of liver disease and metabolic dysfunction...