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

The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and non-epithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, 3D mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the non-epithelial and microbial components of the intestinal microenvironment. As such, several co-culture systems have been developed to co-culture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These co-culture models allow researchers to recreate the complex intestinal environment and study the intricate crosstalk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid co-cultures, and each approach has its own strengths and limitations. This review discusses the existing methods for co-culturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with anxiety has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl₄)-sedentary, and CCl₄-exercise. Liver fibrosis was induced by CCl₄ administration for 8 wk, exercise was applied in the form of voluntary wheel running. After an intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl₄ increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl₄ induced anxiety-like behavior, and the anxiolytic effects of exercise occurred in both healthy and liver-fibrotic mice. In the hippocampus, CCl₄-induced changes in neuronal nitric oxide synthase (nNOS) were reversed by exercise, and exercise enhanced brain-derived neurotrophic factor (BDNF) induction, even in a state of severe liver fibrosis. These results suggested that hepatic fibrosis-related anxiety-like behaviors may be induced by excess hippocampal nNOS, and the beneficial effects of exercise could be mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with antianxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.NEW & NOTEWORTHY This study explores how exercise affects liver fibrosis-related anxiety in mice. Researchers found that regular exercise reversed carbon tetrachloride (CCl₄)-induced liver fibrosis and reduced anxiety, even in mice with liver fibrosis. Exercise increased brain-derived neurotrophic factor (BDNF) and decreased neuronal nitric oxide synthase (nNOS) in the hippocampus. These findings suggest that exercise has therapeutic potential for treating anxiety associated with chronic liver disease by modulating specific brain factors.

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. Although alternative slow-wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (V_m) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256 × 256 pixel cameras. Motion artifact was corrected using a marker-based motion-tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and V_m morphology against alternative nonoptical technologies. Nonantegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and nonantegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored.NEW & NOTEWORTHY This article introduces a novel method for imaging gastric electrophysiology and mechanical function simultaneously in anesthetized, open-abdomen pigs. We demonstrate it by observing propagating slow-wave depolarization and repolarization along with the strength, spatial distribution, and direction of contractions. In addition, we observe that in this animal preparation, slow waves often do not propagate from the proximal to distal stomach and are frequently asymmetric between the anterior and posterior sides of the stomach.

Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCC, a standardized extract of cultured Lentinula edodes mycelia produced by Amino Up Co., Ltd. (Sapporo, Japan)] has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCC on hepatic stellate cells, which are responsible for liver fibrosis. Eight-week-old male C57BL6/j mice were induced with liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCC to investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell (HHSteC) line, we analyzed the influence of AHCC on the expression of molecules related to hepatic stellate cell activation. The administration of AHCC resulted in reduced expression of collagen1a, α smooth muscle actin (αSMA), and heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCC inhibited αSMA by inducing cytoglobin via upregulating the stress-activated protein kinase/Jun NH₂-terminal kinase (SAPK/JNK) pathway through Toll-like receptor (TLR) 2. In addition, AHCC suppressed collagen1a production by hepatic stellate cells through TLR4-NF-κβ pathway. AHCC was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCC from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis.NEW & NOTEWORTHY AHCC, a standardized extract of cultured Lentinula edodes mycelia, suppresses liver fibrosis progression by induction of cytoglobin via the Toll-like receptor 2 (TLR2)-stress-activated protein kinase/Jun NH₂-terminal kinase (SAPK/JNK) pathway and the inhibition of collagen production via the TLR4-NFκβ pathway in hepatic stellate cells. Daily oral administration of AHCC from the stage of MASLD may have the potential to prevent disease progression to MASH with fibrosis.

The postweaning period in pigs is a critical window where nutritional interventions are implemented to prevent postweaning diarrhea (PWD) and antibiotic use. One common strategy is feeding low-protein diets immediately following weaning. This intervention may reduce protein fermentation and pathogen proliferation, therefore decreasing the incidence of postweaning diarrhea. These effects may also be mitigated by providing dietary fiber. However, studies examining the role of protein and fiber on gastrointestinal microbiota and metabolism are complicated by the presence of other substrates, including polyphenols and antinutritional factors in complex ingredients. In this study, semipurified diets formulated to meet nutrient requirements were fed to 40 weaned pigs (n = 10/diet) to examine the effects of high protein (HP), high fiber (HF), or both (HFHP) compared with a control (CON) diet with industry-standard crude protein and fiber content. Critical alterations in host metabolism and cecal transcriptome were identified in response to the CON diet. Diets with lower protein levels (CON and HF) induced alteration in transcripts from the serine synthesis pathways and integrated stress response in cecal tissue alongside systemic increases in metabolic pathways related to lysine degradation. High protein diets did not induce increases in gastrointestinal pathogen abundance. These results challenge the practice of feeding low-protein diets postweaning, by demonstrating a detrimental effect on intestinal cell function and muscle accretion. This suggests that with careful ingredient selection, increased dietary protein postweaning could improve pig health and growth compared with a standard diet.NEW & NOTEWORTHY Although low-protein diets are commonly used for weaned pigs and are thought to decrease diarrhea incidence, this study showed that low-protein diets may induce muscle catabolism and intestinal epithelial stress response. Eventhough high-protein diets increased protein fermentation by gut microbes, no increase in diarrhea was detected. Protein fermentation was mitigated by fiber while still supporting growth and intestinal epithelial cell function, suggesting new strategies for feeding weaned pigs with careful ingredient selection.

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 wk markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with the greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease.NEW & NOTEWORTHY Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

Alzheimer's disease (AD) is a degenerative disease that causes a progressive decline in memory and thinking skills. Over the past few years, diverse studies have shown that there is no single cause of AD; instead, it has been reported that factors such as genetics, lifestyle, and environment contribute to the pathogenesis of the disease. In this sense, it has been shown that obesity during middle age is one of the most prominent modifiable risk factors for AD. Of the multiple potential mechanisms linking obesity and AD, the gut microbiota (GM) has gained increasing attention in recent years. However, the underlying mechanisms that connect the GM with the process of neurodegeneration remain unclear. Through this narrative review, we present a comprehensive understanding of how alterations in the GM of people with obesity may result in systemic inflammation and affect pathways related to the pathogenesis of AD. We conclude with an analysis of the relationship between GM and insulin resistance, a risk factor for AD that is highly prevalent in people with obesity. Understanding the crosstalk between obesity, GM, and the pathogenesis of AD will help to design new strategies aimed at preventing neurodegeneration.