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

Olanzapine-induced fatty liver disease continues to pose vital therapeutic challenges in the treatment of psychiatric disorders. In addition, we observed that some patients were less prone to hepatic steatosis induced by olanzapine. Therefore, we aimed to investigate the role and the underlying mechanism of the intestinal flora in olanzapine-mediated hepatic side effects and explore the possible countermeasures. Our results showed that patients with different susceptibilities to olanzapine-induced fatty liver disease had different gut microbial diversity and composition. Furthermore, we performed fecal microbiota treatment (FMT), and confirmed that the gut microbiome of patients less prone to the fatty liver caused by olanzapine exhibited an alleviation against fatty liver disease in rats. In terms of mechanism, we revealed that the cross talk of leptin with the gut-short-chain fatty acid (SCFA)-liver axis play a critical role in olanzapine-related fatty degeneration in liver. These findings propose a promising strategy for overcoming the issues associated with olanzapine application and will hopefully inspire future in-depth research of fecal microbiota-based therapy in olanzapine-induced fatty liver disease.NEW & NOTEWORTHY Patients who were less inclined to have olanzapine-induced fatty liver had different gut microbiota profiles than did those in the susceptible cohort. Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Butyricicoccaceae, and Christensenellaceae were enriched in patients who were less prone to fatty liver disease caused by olanzapine. Fecal microbiota treatment (FMT) with these fecal samples promoted short-chain fatty acid (SCFA) production, which attenuated the circulating leptin and inhibited FASN and ACC1, thereby suppressing lipid synthesis in the liver, ultimately leading to alleviation of hepatic steatosis.

The goal of this study was to determine whether the influence of a high-fat high-sugar diet (Western diet) on intestinal function and health was reversible. We measured transepithelial short circuit current (I_sc), across freshly isolated segments of jejunum from male C57Bl/6J mice randomly assigned to one of the following groups for the study duration: high-fat high-sugar diet for 24 wk (HFHS), HFHS diet for 12 wk then switched to standard chow and water for a further 12 wk (Std), and lean controls (standard chow and water for 24 wk). At the completion of the study, segments of jejunum were frozen for Western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum and tissue assays were performed. Basal I_sc was significantly decreased (by 42%, P < 0.05) in HFHS versus leans. This decrease in I_sc was fully reversed by switching to Std diet. The HFHS-induced decrease in I_sc was attributed to a significant loss of calcium-activated chloride channel (ClC2) expression. Changes in inflammatory state (TNF-α) and intestinal health [myeloperoxidase (MPO) activity] were associated with body weight changes. Our data suggests that the reduced basal jejunal I_sc in HFHS mice is reversible. Better understanding of Western diet-mediated intestinal disturbances may permit for improved treatment options for gastrointestinal abnormalities in obese individuals.NEW & NOTEWORTHY Our data suggests that the reduced basal jejunal I_sc (decreased secretory function) in Western diet-fed mice is reversible. A better understanding of Western diet-mediated intestinal disturbances may permit improved treatment options for gastrointestinal abnormalities in obese individuals.

This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged, as defined by unique gene expression profiles, indicating potentially novel biological functions. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions. Our analysis of subtype-specific gene expression and pathway enrichment showed variances in tuft cell subtypes between healthy individuals and those with inflammatory bowel disease (IBD). The frequency of TC1 and TC2 differed between healthy controls and IBD. Relative to healthy controls, TC1 and TC2 in IBD tissue showed an upregulation of gene expression, favoring increased metabolism and immune function. These findings provide foundational knowledge about the complexity of the human colon tuft cell population and hint at their potential contributions to gut health. They provide a basis for future studies to explore the specific roles these cells may play in gut function during homeostasis and disease. We demonstrate the value of in silico approaches for hypothesis generation in relation to the putative functions of low-frequency gut cells for subsequent physiological analyses.NEW & NOTEWORTHY This study reveals the nuanced and novel landscape of human colonic tuft cells through integrative scRNA-seq analysis. Four distinct tuft cell subtypes were identified, varying markedly between healthy and individuals with IBD. We uncovered human colonic tuft cell subtypes with unexpected antimicrobial and progenitor-like gene expression signatures. These insights into tuft cell diversity offer new avenues for understanding gut health and disease pathophysiology.

The interplay between diet-induced obesity and gastrointestinal dysfunction is an evolving area of research with far-reaching implications for understanding the gutbrain axis interactions. In their study, Ramírez-Maldonado et al. employ a cafeteria (CAF) diet model to investigate the effects on gut microbiota, enteric nervous system (ENS) integrity and function, and gastrointestinal motility in mice. Their work provides notable insights while also presenting opportunities for further exploration. The findings highlight early shifts in gut microbiota composition, notably increased Clostridia and Proteobacteria populations, and their association with ENS remodeling and motility impairment. This innovative use of a CAF diet strengthens the relevance of the model to real-world dietary patterns. Future studies will determine the mechanisms linking these microbial changes to neuronal dysfunction, particularly in terms of excitability deficits. The longitudinal approach is a commendable aspect of the study, yet certain dimensions, such as sex-specific responses and long-term outcomes, are underexplored. Further emphasis on these factors could provide a more nuanced understanding of the dietary effects on gastrointestinal health. While inflammation is identified as a mediator, more in-depth analysis of the pathways involved would help substantiate its role in ENS remodeling. Overall, this study makes a valuable contribution to the field, offering a solid foundation for future research. Expanding on the mechanistic insights and addressing the outlined gaps could further the translational relevance of these findings in tackling obesity-related gastrointestinal disorders.

The stomach is responsible for physically and chemically processing the ingested meal before controlled emptying into the duodenum through the pyloric sphincter. An incompetent pylorus allows reflux from the duodenum back into the stomach, and if the amount of reflux is large enough, it could alter the low pH environment of the stomach and erode the mucosal lining of the lumen. In some cases, the regurgitated contents can also reach the esophagus leading to additional complications. In this work, "StomachSim", an in-silico model of the fluid dynamics of the stomach, is used to study the mechanism of duodenogastric reflux. The effects of variations in food properties and motility disorders on reflux are investigated. The simulations show that the primary driver of reflux is the relaxation of the antrum after a stomach contraction terminates near the pylorus. The region of the stomach walls exposed to the regurgitated contents depends significantly on the density of the stomach contents. For stomach contents of higher viscosity, the increased pressure required to maintain gastric emptying reduces the amount of duodenogastric reflux. Concomitant stomach motility disorders that weaken the relaxation of the walls also affect the amount of reflux. The study illustrates the utility of in-silico models in analyzing the factors at play in gastrointestinal diseases.

The recent uncovering of fibroblast heterogeneity has given great insight into the versatility of the stroma. Among other cellular processes, fibroblasts are now thought to contribute to the coordination of immune responses in a range of chronic inflammatory diseases and cancer. While the pathologic roles of myofibroblasts, inflammatory fibroblasts and cancer associated fibroblasts in disease are reasonably well understood, the mechanisms behind their activation remain to be uncovered. In the gastrointestinal (GI) tract, several interleukins and tumour necrosis factor superfamily members have been identified as possible mediators driving the acquisition of inflammatory as well as fibrotic properties in fibroblasts. In addition to cytokines, other microenvironmental factors such as nutrient and oxygen availability are likely contributors to this process. In this respect, the phenomenon of low cellular oxygen levels known as hypoxia is common in a plethora of GI diseases. Indeed, the crosstalk between hypoxia and inflammation is well-documented, with an abundance of studies suggesting that oxygen-sensing enzymes may have regulatory effects on inflammatory signalling pathways such as NF-κB. However, the impact that this has in GI fibroblasts in the context of chronic diseases has not been fully uncovered. Here we discuss the role of fibroblasts in GI diseases, the mediators that have emerged as regulators of their functions and the potential impact of hypoxia in this process, highlighting areas that require further investigation.

Gastrointestinal immunity and antioxidant defenses may be bolstered in young animals through prenatal immune system stimulation (PIS), but this is largely uninvestigated in swine. This study tested the hypothesis that PIS could regulate offspring's gastrointestinal immune response and oxidative stress profile. To this end, a PIS model was utilized in sows, delivering low-dose LPS during the final third of gestation to target the developing immune system. On day 78±1.8 of gestation, 14 Camborough sows (parity = 2.6±1.4) received either saline (CON) or LPS from E. coli O111:B4 (2.5 μg/kg of body weight). A subset of 34 weaned barrows (n=17 CON, PIS), weaned at 21±1.3 days, were anesthetized for subcutaneous temperature loggers and jugular catheter placement. Following recovery, all pigs received an intravenous injection of LPS (10 μg/kg body weight) from E. coli O111:B4. Our findings demonstrate that PIS enhances the gut immune response by upregulating key inflammatory cytokines, indicative of a proinflammatory profile. Consistently across the jejunum and ileum, SCF was modulated with heightened expression in PIS than CON (P≤ 0.05). In the ileum alone, PIS exhibited heightened expression of proinflammatory cytokines and chemokines, including TNFα, IL-6, IL-1β, and CCL3L1, compared to CON (P≤ 0.05). Exposure to PIS resulted in reduced systemic total antioxidant capacity (TAC) at hours 2-4 post-challenge (P= 0.004). Piglets exposed to PIS had decreased jejunal tissue malondialdehyde (MDA) concentrations (P= 0.049). Together, these data indicate that exposure to PIS alters the inflammatory profile of the GI immune response and oxidative status in weaned pigs.

Intestinal ischemic injury damages the epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age-dependency of intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier versus older patients. We have developed a pig model that demonstrates age-dependent failure of intestinal barrier restitution in neonatal pigs which can be rescued by the direct application of juvenile pig mucosal tissue, but the mechanisms of rescue remain undefined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells from recovering ischemic jejunum of juvenile pigs underwent single cell transcriptomics and predicted upstream regulator CSF-1 was interrogated in our model. A subcluster of absorptive enterocytes expressed several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation by colony stimulating factor-1 (CSF-1). We validated age-dependent induction of CSF-1 by ischemia and documented that CSF-1 and CSF1R co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued neonates. Further, the CSF-1 blockade reduced restitution in vitro, and CSF-1 improved barrier function in injured neonatal pig in preliminary ex vivo experiments. These studies validate an approach to inform potential novel therapeutic targets, such as CSF-1, to improve outcomes in neonates with intestinal injury in a unique pig model.

Bile acid sequestrants such as cholestyramine (ChTM) are gut-restricted bile acid binding resins that block intestine bile acid absorption and attenuate hepatic bile acid signaling. Bile acid sequestrants induce hepatic bile acid synthesis to promote cholesterol catabolism and are cholesterol lowering drugs. Bile acid sequestrants also reduce blood glucose in clinical trials and are approved drugs for treating hyperglycemia in type-2 diabetes. However, the mechanisms mediating the glucose lowering effect of bile acid sequestrants are still incompletely understood. Here we showed that ChTM treatment decreased hepatic glucose production in Western diet-fed mice with paradoxically induced hepatic gluconeogenic genes. Cysteine dioxygenase type 1 (CDO1) mediates cysteine conversion to taurine and its expression is repressed by bile acids. We show that ChTM induced hepatic CDO1 and selectively reduced hepatic cysteine availability. Knockdown of liver CDO1 increased liver cysteine and glucose production in mice, while hepatocytes cultured in cystine-deficient medium showed reduced glucose production. By using dietary protein restricted and cystine-modified Western diets that selectively alter hepatic cysteine availability, we found that reduced hepatic cysteine availability strongly inhibited glucose production in mice. Interestingly, chronic dietary protein restriction also prevented Western diet-induced obesity, which was fully reversed by restoring dietary cystine intake alone. Consistently, reduced cysteine availability dose dependently inhibited adipogenesis in vitro. In conclusion, we report that the glucose lowering effect of bile acid sequestrants are mediated by a CDO1-induced hepatic cysteine restriction mimetic effect. Furthermore, the anti-obesity effect of dietary protein restriction is largely mediated by reduced dietary cysteine intake.