American journal of physiology. Gastrointestinal and liver physiology最新文献

Dysphagia is common in patients with preserved contraction phase of esophageal peristalsis, such as those diagnosed with functional dysphagia (FD) or esophagogastric junction outflow obstruction (EGJOO); it amounts to ≥50% patients undergoing high-resolution manometry impedance (HRMZ) study. We aimed to characterize the distension phase of esophageal peristalsis (bolus domain) and identify abnormalities that may contribute to dysphagia in these patients. HRMZ recordings from 35 healthy controls, 35 patients with FD, and 35 patients with EGJOO were analyzed. Distension-contraction plots were used to assess the luminal cross-sectional area, bolus pressure, and regions without bolus ("no-bolus areas") within the bolus domain of peristalsis. The proportion of no-bolus area was compared among groups, and receiver operating characteristic (ROC) analysis evaluated diagnostic performance. Esophageal wall compliance during the distension phase was also determined. Both FD and EGJOO groups exhibited a significantly greater proportion of no-bolus area within the bolus domain compared with controls, particularly in the distal esophagus (P < 0.001). Pressure peaks frequently occurred in the absence of bolus, indicating pseudo-bolus pressures. Ultrasound imaging revealed transient luminal collapse against the manometry catheter in the "pseudo-bolus" zone. Esophageal wall compliance was reduced in both patient groups. ROC analysis demonstrated that the percentage of no-bolus area discriminated patients from controls with high accuracy (area under the curve 0.83 for FD, 0.88 for EGJOO). We propose that impaired esophageal distensibility and transient luminal collapse within the bolus domain cause functional obstruction and possibly dysphagia.NEW & NOTEWORTHY This study introduces a novel impedance-based method to analyze the bolus domain of esophageal peristalsis, emphasizing bolus pressure and bolus mismatch. Patients with functional dysphagia and EGJOO demonstrated impaired esophageal distension, reduced wall compliance, and frequent pseudo-bolus pressures from transient luminal collapse during peristalsis. These findings suggest that dysphagia may result from dynamic obstruction due to esophageal collapse during peristalsis rather than fixed outflow obstruction, highlighting bolus domain mechanics as a complementary diagnostic tool.

Primary aging associates with an imbalanced gut microbiome and cardiovascular disease (CVD) risk in mice and humans. Strong evidence from clinical and preclinical studies supports that habitual physical exercise improves cardiovascular function and intestinal health in adults. Here we tested the hypothesis that exercise training, even when initiated late-in-life, reestablishes a beneficial and cooperative intestinal microbiome to an extent that associates with reduced risk for CVD. At 21 mo of age, male C57BL/6 mice started a progressive resistance treadmill training program 6 days per week (Old + ETR) for 12 wk. Twenty-one-month-old (Old) and 4-mo-old (Adult) male mice remained sedentary. First, reductions in exercise capacity and soleus muscle citrate synthase activity displayed by Old vs. Adult mice were restored in Old + ETR animals. Next, systolic function [fractional shortening (FS)], diastolic function (E/A ratio), and overall left-ventricular function [myocardial performance index (MPI)] otherwise depressed in Old vs. Adult mice were normalized in Old + ETR animals. Third, elevated trimethylamine (TMA) and TMA N-oxide (TMAO), and heightened inflammatory markers [e.g., interferon (IFN)-γ and keratinocyte-derived chemokine (KC)], observed in Old vs. Adult mice were lowered in Old + ETR animals. Importantly, the abundance of beneficial microbial features, including Bacteroides, Muribaculaceae, Parabacteroides, and the Rikenellaceae RC9 gut group, otherwise depressed by aging, was normalized in Old + ETR mice. Finally, the Rikenellaceae RC9 gut group was positively correlated with FS, and Parabacteroides was negatively correlated with IFN-γ. These findings support that late-in-life exercise training beneficially remodels the gut microbiome to an extent that associates with reduced CVD risk in male mice.NEW & NOTEWORTHY It is unknown whether exercise training, if started late-in-life, reestablishes a beneficial and cooperative intestinal microbiome. Here we demonstrate that a 12-wk treadmill running program in older mice rejuvenates the gut microbiome and attenuates markers of cardiovascular disease (CVD) risk. Notably, specific microbial taxa correlate with activity-induced improvements in overall myocardial performance and inflammation, highlighting the importance of gut health on CVD and illustrating the restorative benefits that can be attained from a low-cost lifestyle intervention.

The gut microbiota produces numerous metabolites that influence the epithelial barrier function. Bacterial catabolism of amino acids produces a wide variety of metabolites whose effects on the intestinal epithelium remain to be identified. In this study, we investigated the effects of amino acid derived metabolites (isovalerate, isobutyrate, 2-methylbutyrate, 5-aminovalerate, cadaverine, putrescine, and tryptamine) in cell monolayers derived from porcine ileum organoids. Our results show that the branched-chain fatty acid (BCFA) isovalerate improved the epithelial barrier function, as assessed by transepithelial electrical resistance measurement and paracellular permeability assay. Isovalerate upregulated the expression of genes involved in innate immunity, markers of absorptive and enteroendocrine cells while reducing the expression of stem cells and mucus related genes. Most of the effects of isovalerate on epithelial cells were also observed with the butyrate, an inhibitor of the epigenetic enzymes histone deacetylases (HDAC). We found that isovalerate also inhibited HDAC, although to a lesser extent than butyrate. Furthermore, the structurally unrelated HDAC inhibitor trichostatin A improved epithelial barrier function and upregulated SLPI and IL10RA gene expression, as observed with isovalerate and butyrate. Interestingly, the other two BCFAs isobutyrate and 2-methylbutyrate did not replicate the effects of isovalerate. Overall, our in vitro results suggest that targeting the bacterial production of isovalerate may be useful to promote gut health. In this perspective, we performed an in silico analysis that identified species belonging to dominant gut microbiota genera such as Prevotella, Blautia, Christensenella, Clostridium, and Ruminococcus, as potential producers of BCFAs through the POR enzymatic pathway.

Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how Bifidobacterium longum (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their co-stimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic Escherichia coli (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS) -induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-LI expression in EGCs, and inducing the conversion of CD4+T cells into regulatory T (Treg) cells through the PD-LI/PD-I pathway. This process promotes Treg cell expansion, inhibits pathogenic T helper type 17 (Th17) cell, increasing IL-10 production, and reduces TNF-a and IL-lβ production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggests that B.l induces the conversion of CD4+T cells into Treg cells by acting on EGCs, and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells, but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD.

Glucocorticoid (GC) and stress-induced SGK1 signaling rapidly modulate intestinal epithelial transport, yet whether epithelial SGK1 is required to couple GC signaling to functional CFTR output in vivo has remained unclear. We examined this question using Villin-Cre;Sgk1^flox/flox conditional knockout (Sgk1cKO) and littermate heterozygous controls (Sgk1cHET) mice treated with dexamethasone (DEX; 2mg/kg i.p.) for 1h or 4h. Outcomes included CFTR protein abundance, immunolocalization (immunoblotting and immunofluorescence), CFTR-ion transport measured by short-circuit current (Isc) in Ussing chambers, epithelial Sgk1/2/3 expression, intestinal loop fluid accumulation, and CD45⁺ cell signal as a readout of early immune engagement. Acute DEX treatment activated SGK1 signaling and elevated CFTR protein in Sgk1cHET but also in Sgk1cKO. However, only Sgk1cHET exhibited a rise in CFTR-dependent ΔIsc, whereas Sgk1cKO failed to increase secretion despite higher total CFTR. Sgk2 and 3 were upregulated in Sgk1cKO but did not restore function. CD45⁺ signal rose transiently at 1h and normalized by 4h, consistent with early, self-limited immune engagement. In an intestinal loop assay, short-term DEX treatment did not exacerbate cGMP-evoked fluid accumulation. Together, these data identify epithelial SGK1 signaling as a necessary node that translates acute stress-induced CFTR stabilization into functional secretion and a transient epithelial-immune response. These findings help reconcile expression-function discrepancies and suggest that targeting SGK1 or its downstream steps may be required to achieve functional CFTR gains under acute stress in the intestine.

Classically known for their roles in facilitating lipid digestion and absorption, bile acids are now also appreciated as enterocrine hormones that modulate many aspects of intestinal physiology. We have previously shown lithocholic acid (LCA), a secondary bile acid, to be protective against colonic inflammation. Here, we investigated whether LCA also regulates colonic epithelial fluid and electrolyte transport. T₈₄ cell monolayers were mounted in Ussing chambers for measurements of transepithelial Cl^- secretion. CFTR mRNA and protein expression were analyzed by qRT-PCR and Western blotting in T₈₄ cells and human-derived colonic organoids. CFTR promoter activity was assessed using a luciferase promoter/reporter assay in HEK293 cells. Pretreatment of T₈₄ cells with LCA inhibited Cl^- secretory responses to the cAMP-dependent agonist, forskolin (FSK), with maximal effects occurring at a concentration of 10 µM after 24 h of treatment. Under these conditions, LCA also inhibited responses to the Ca²⁺-dependent secretagogues, thapsigargin, and histamine. In nystatin-permeabilized T₈₄ monolayers, LCA reduced FSK-stimulated apical Cl^- conductances, an effect that correlated with reduced CFTR Cl^- channel expression. Although LCA activated both farnesoid X receptor (FXR) and vitamin D receptor (VDR), its effects on CFTR expression and Cl^- conductances were mimicked only by an FXR agonist, GW4064, and not by a VDR agonist, calcitriol. Finally, LCA inhibited CFTR promoter activity in HEK3 cells, but only when FXR was expressed. LCA, at physiologically relevant concentrations, chronically inhibits colonic epithelial Cl^- secretion, likely via FXR-induced downregulation of CFTR. These data broaden our knowledge of the regulatory roles of LCA in the colon and highlight its potential as a therapeutic target for intestinal disorders.NEW & NOTEWORTHY This study reveals a previously unrecognized role for lithocholic acid (LCA) in chronically suppressing colonic epithelial chloride secretion. We demonstrate a genomic mechanism of action for LCA that is likely mediated by FXR-induced downregulation of CFTR expression and function. These findings highlight LCA as a key modulator of intestinal fluid and electrolyte transport and underline the therapeutic potential of targeting bile acids and their receptors for the treatment of diarrheal diseases.

Parkinson's disease is a neurodegenerative disorder pathologically characterized by accumulation of misfolded α-synuclein in the central and peripheral nervous systems, influencing symptomology at both sites. Calcitonin gene-related peptide (CGRP), a neuropeptide produced in the brain and intestine, has been linked with altered α-synuclein aggregation. This study examines the role of calcitonin gene-related peptide in modulating enteric α-synuclein accumulation and enteric glial cell reactivity using an ex vivo slice culture model from A53T^+/- human α-synuclein mutant mice. In slices treated with calcitonin gene-related peptide, α-synuclein immunoreactivity was elevated in myenteric neurons within 24 h. A stark elevation in gut mucosal calcitonin gene-related peptide immunoreactivity was revealed to be predominantly S100β+ enteric glia cells rather than neuronal fibers, pointing toward a reactive enteric glial cell phenotype. In addition, CGRP treatment increased enteric glial cell count in the mucosa in wildtype colon slices without evidence of incorporation of the DNA synthesis marker 5-ethynyl-2'-deoxyuridine indicating a lack of cell proliferation. Mucosal increases in enteric glial cell counts were accompanied by a decrease in these cells in the submucosa. This supports the idea that an inflamed gut environment may shift enteric glial cells to a reactive phenotype, inducing alterations in their number and anatomic localization. These data implicate calcitonin gene-related peptide in the accumulation of enteric α-synuclein, an effect potentially driven by an inflammatory environment that we hypothesize is due in part to enteric glial cell activation.NEW & NOTEWORTHY Gastrointestinal symptoms of Parkinson's disease (PD) are an emerging area of investigation with implications for disease etiology. Utilizing intestinal ex vivo slices from a PD mouse model, Templeton et al., identify calcitonin gene-related peptide (CGRP) as a key modulator of enteric α-synuclein accumulation and enteric glial reactivity. These findings suggest that targeting peripheral CGRP signaling pathways in the enteric nervous system may represent a novel therapeutic approach for early intervention in PD.

Hookworm infects over 400 million people globally and causes gastrointestinal morbidity, yet its physiological effects remain poorly defined. Controlled human hookworm infection is also being explored as a therapy for gut diseases. We performed an exploratory study to evaluate the impact of experimental Necator americanus infection on gastrointestinal transit, motility, and luminal pH in 10 healthy adults (mean age 41 yr, 60% females) infected with 30 larvae via skin application. Assessments using the SmartPill Wireless Motility Capsule were performed at baseline, week 6 (acute infection), and week 24 or 48 (chronic infection). Parameters included gastric emptying time, small bowel and colonic transit, whole gut transit, intraluminal pressures, contraction frequency, motility index, and segmental pH, analyzed with paired t tests or ANOVA. All participants developed patent infections. No significant differences were observed in gastric emptying, small bowel, colonic, or whole gut transit times, nor in motility indices or contraction frequencies. However, during acute infection, duodenal (6.14 ± 0.19 vs. 5.80 ± 0.24, P < 0.05) and small bowel pH (6.96 ± 0.37 vs. 6.50 ± 0.37, P < 0.05) were significantly reduced compared with baseline, normalizing by the chronic phase. No other significant pH alterations were detected. Thus, these data suggest that controlled N. americanus infection in healthy adults induces a transient reduction in duodenal and small-intestinal pH without affecting gastrointestinal transit or motility. This acidification may contribute to acute-phase symptoms and nutrient malabsorption in endemic settings, whereas the absence of sustained motility disturbance supports the safety of controlled hookworm infection for therapeutic investigation.NEW & NOTEWORTHY This exploratory study using SmartPill technology found that controlled hookworm infection in healthy adults caused a transient drop in duodenal and small-intestinal pH during the acute phase, but no lasting changes in gut motility or transit. The findings, the first of their kind in humans, suggest that the physiological effects of controlled doses of hookworm are subtle and short-lived, offering reassurance for therapeutic trials while highlighting a potential mechanism for symptoms and malabsorption in endemic regions.

Epigenetic regulations link environmental factors to the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). We determined the role of hepatocyte histone deacetylase 4 (HDAC4) in the pathogenesis of MASLD. Male and female hepatocyte-specific Hdac4 knockout (Hdac4^HKO) mice and control Hdac4 floxed (Hdac4^fl/fl) mice were fed a high-fat, high-sucrose, high-cholesterol diet for 16 wk to induce obesity and MASLD. The loss of hepatic Hdac4 increased serum alanine transaminase activity and exacerbated hepatic steatosis with higher liver weights and triglyceride levels than Hdac4^fl/fl mice in males. Hepatic expression of lipogenic genes was significantly higher in male and female Hdac4^HKO mice than in controls. Moreover, primary hepatocytes and the liver of Hdac4^HKO mice exhibited perturbed insulin signaling, characterized by reduced phosphorylated AKT2. Interestingly, hepatocyte Hdac4 loss increased inflammatory and fibrogenic genes in gonadal white adipose tissue (gWAT). Serum cytokine array and proteomic analysis demonstrated alterations in several serum factors, which may contribute to crosstalk between the liver and WAT in Hdac4^HKO, leading to obesity-induced metabolic dysfunction in gWAT. In conclusion, hepatocyte Hdac4 loss exacerbates hepatic steatosis, accompanied by disturbed insulin signaling and WAT inflammation and fibrosis in obese mice, underscoring its crucial role in liver-WAT crosstalk.NEW & NOTEWORTHY We examined the role of hepatocyte histone deacetylase 4 (HDAC4) in the development of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) using Hdac4-deficient mice with hepatocyte-specific deletion. We found that deleting Hdac4 in hepatocytes worsens hepatic steatosis and disrupts insulin signaling in the liver. In addition, this deletion caused inflammation and fibrosis in the white adipose tissue of obese mice, highlighting the role of HDAC4 in the liver-adipose axis.