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

Neonatal bile acid metabolism is distinct from that of adults due to developmental regulation of key transporters and enzymes. The apical sodium-dependent bile acid transporter (ASBT) is transiently repressed in the intestine after birth, yet its role in neonatal bile acid homeostasis remains unclear. Here, we demonstrate that ASBT plays a crucial role in limiting fecal bile acid loss and suppressing hepatic bile acid synthesis in neonates. ASBT-deficient pups exhibited a marked decrease in serum bile acids and concomitant increase in fecal bile acids, accompanied by upregulated hepatic bile acid synthesis genes, including CYP7A1, CYP7B1, and CYP27A1. We also illuminated a tissue-specific distinction in neonatal negative feedback regulation of bile acid synthesis, with intact hepatic regulation but impaired intestinal regulation. Our study identifies ASBT as a key regulator of neonatal bile acid homeostasis despite its strong repression early in life, highlighting its role in bile acid retention and synthesis regulation.NEW & NOTEWORTHY Despite being repressed after birth, ASBT is essential for neonatal bile acid homeostasis. This study reveals that ASBT limits fecal bile acid loss and suppresses hepatic bile acid synthesis in neonates. ASBT-deficient pups showed reduced serum bile acids, increased fecal loss, and upregulation of bile acid synthesis genes. Notably, feedback regulation of bile acid synthesis was intact in the liver but impaired in the intestine, uncovering tissue-specific control mechanisms in early life.

Intestinal barrier dysfunction and dysbiosis are critical intestinal alterations in biliary obstructive diseases, for which farnesoid X receptor (FXR) is a potential intestinal therapeutic target, but its role and mechanism in the intestinal tract remain poorly defined. Using gut-specific knockout mice, we demonstrate that intestinal Fxr deficiency caused intestinal barrier function impairment and dysbiosis, and in a biliary obstruction model, obeticholic acid (OCA)-dependent intestinal Fxr activation protected against intestinal barrier injury and dysbiosis after bile duct ligation (BDL) surgery. Furthermore, from single-cell sequencing data, Fxr may directly regulate regenerating islet-derived protein 3γ (Reg3g) to influence intestinal functions. In conclusion, we elucidated FXR actions in the intestine under physiological and biliary obstruction conditions and suggest possible molecular targets that provide new insights for the intestinal treatment of biliary obstructive diseases.NEW & NOTEWORTHY Intestinal barrier dysfunction and dysbiosis are critical in biliary obstructive diseases, making farnesoid X receptor (FXR) a potential therapeutic target. Our study shows that Fxr deficiency impairs barrier function and causes dysbiosis. In a biliary obstruction model, obeticholic acid (OCA) activation of Fxr protects against these effects. In addition, single-cell sequencing suggests that Fxr may regulate Reg3g, influencing intestinal functions. This research reveals the role of FXR and offers new molecular targets for the treatment of biliary obstructive diseases.

Host-gut microbiota interactions may impact intestinal function during sustained periods of high energy demands. Whether energy status, reflecting the balance between energy intake and expenditure, impacts those interactions is unknown. This study determined the effects of energy status during sustained high-energy demands on intestinal function and the gut microbiota. Ten healthy men completed a randomized, crossover study that included baseline (BL) testing and two 72-hour periods of high physical activity-induced energy demands (HPA; ∼2,300 kcal/day physical activity energy expenditure) followed by a 7-day recovery period (REC). During HPA, diets designed to elicit a ∼45% energy deficit (DEF; -2,047 ± 920 kcal/day) or maintain energy balance within ±10% total daily energy expenditure (BAL; 689 ± 852 kcal/day) were provided. Intestinal permeability and transit time, fecal microbiota composition and gene content, fecal short-chain fatty acids (SCFAs), and gastrointestinal symptoms were measured. Intestinal permeability was 17% higher during HPA-DEF vs. HPA-BAL (P = 0.02), and colonic transit time was slower during HPA-DEF vs. HPA-BAL [mean difference (95% CI) = -764 min (-1,345, -183)] and BL [-643 min (-1,178, -108)] (P ≤ 0.02). Fecal microbiota species richness [-40 species (-66, -13), P = 0.01] and relative abundances of multiple species (log₂ fold difference < -5, P < 0.02) were lower during HPA-BAL vs. HPA-DEF but did not differ between conditions during REC. Small bowel transit time, gastrointestinal symptoms, fecal microbiota gene pathways, and fecal SCFAs did not differ between conditions. Findings suggest that increasing dietary intake to prevent energy deficit may benefit intestinal health and function during short-term periods of high energy demands without sustained impacts on the gut microbiota.NEW & NOTEWORTHY The effect of energy status on host-gut microbiota interactions impacting intestinal function during periods of high energy demands is unknown. Herein, increasing energy intake to prevent energy deficit during three days of high physical activity-induced energy demands prevented increases in intestinal permeability and transit time, and transiently reduced gut microbiota community richness without compromising community functional potential. Results suggest minimizing energy deficits may benefit gastrointestinal function during periods of high energy demands.

Alcohol liver damage (ALD) is increasing worldwide among adolescents, along with binge drinking (BD). BD is an acute alcohol consumption pattern, strongly pro-oxidant in the liver, and may be associated with steatosis, the first step in ALD. Folic acid (FA), an antioxidant crucial for liver function, shows compromised hepatic stores after BD. Therefore, this study aims to analyze the hepatic lipid changes associated with BD-induced steatosis during adolescence in rats and to evaluate the efficacy of FA supplementation in preventing these alterations. Four groups of adolescent rats were used: control, BD (intraperitoneal alcohol exposure), control FA-supplemented, and BD-FA-supplemented. FA content was 2 ppm in control diets and 8 ppm in supplemented groups. BD impaired liver function by increasing transaminases and UGT-1 expression. BD also induced dyslipidemia and an anabolic liver lipid state by increasing hepatic cholesteryl esters depots through dysregulation of cholesterol modulators (HMGCR, SREBP1, LDLR, SR-B1, ACAT-2, and Ces1d) and enhancing FXR expression, which affected liver bile acid balance. Furthermore, BD promoted all sources of hepatic free fatty acids (de novo synthesis, dietary source, and adipose tissue uptake) and impaired their hepatic clearance, contributing to steatosis as confirmed by microvesicular lipid droplet accumulation. FA supplementation, mainly by improving hepatic cholesterol balance and stimulating free fatty acid mobilization, partially prevented these alterations, with beneficial effects on cardiovascular health. In conclusion, this study demonstrates for the first time that BD in adolescents disturbs hepatic lipid homeostasis, leading to steatosis, and that FA therapy could be used to mitigate these deleterious effects.NEW & NOTEWORTHY Binge drinking (BD) in adolescent rats disrupts hepatic lipid homeostasis, inducing dyslipidemia and cholesteryl ester accumulation. BD alters hepatic cholesterol metabolism and bile acid homeostasis. In addition, it promotes free fatty acid (FFA) accumulation and steatosis. Folic acid supplementation improves cholesterol balance and enhances FFA mobilization, offering a protective role against BD-induced liver damage.

Defecatory dysfunction (DD) is a common cause of chronic constipation resulting from functional abnormalities or structural pelvic pathologies. Accurate diagnosis requires combining anorectal manometry (ARM), balloon expulsion test (BET), and defecography. This study evaluates the diagnostic utility of these modalities and explores uncertainties in their performance and interpretation. This retrospective study included 325 adult patients assessed for DD between 2020 and 2023. All patients went through ARM, BET in the left lateral position, and defecography. Statistical associations between test outcomes were analyzed to assess diagnostic concordance and significance. A strong correlation was observed between ARM and defecography, with 65% of patients with normal anal relaxation on ARM achieving normal rectal evacuation on defecography (P < 0.0001). Conversely, patients with paradoxical contraction during ARM demonstrated a higher likelihood of evacuation failure. BET demonstrated high specificity but limited sensitivity in association with relaxation on ARM and evacuation on defecography. BET failure did not demonstrate a significant association with the presence of pelvic floor pathologies. Combining ARM, BET, and defecography provides a comprehensive framework for diagnosing DD, addressing its functional and structural components. This integrated approach facilitates targeted interventions, ultimately improving clinical outcomes.NEW & NOTEWORTHY This study demonstrates that anal relaxation on anorectal manometry significantly correlates with rectal evacuation on defecography, supporting its physiological relevance. Balloon expulsion in the left lateral position shows high specificity but low sensitivity for defecatory dysfunction. Notably, balloon expulsion test (BET) failure was not associated with anatomical abnormalities. An integrated diagnostic approach using anorectal manometry (ARM), BET, and defecography enhances accuracy in distinguishing functional from structural causes of pelvic floor dysfunction.

The Western diet (WD) has been associated with various pathologies, largely due to chronic inflammatory responses triggered by insulin spikes and excess cholesterol. However, the effects of maternal WD on offspring are currently understudied. We hypothesize that maternal WD consumption in baboons induces a hyperinflammatory state in offspring, leading to compromised intestinal barrier function. Intestinal tissue was harvested from olive baboon (Papio anubis) 0.9 gestation fetuses and juveniles (age 2-3 yr), whose mothers were fed either a high-fat/high-sugar WD or a control diet (CD) of standard monkey chow. RNA and protein were isolated and analyzed for markers of inflammation and apoptosis. Intestinal organoids (enteroids) were generated from these bowel samples and subsequently subjected to hypoxia and LPS to simulate necrotizing enterocolitis (NEC). RNA was extracted and similarly examined for inflammatory markers and markers of apoptosis. Enteroids were plated onto TransWellTM plates to evaluate barrier function. Immunohistochemistry and immunofluorescence were used to evaluate barrier proteins. The intestinal tissue of baboon fetuses and juveniles of mothers fed a Western diet exhibited evidence of a hyperinflammatory state. Although not all cytokines reached our significance set a priori at P < 0.05, interleukin-8 (IL-8) and Interferon γ (IFNγ) were significantly elevated. This trend was stable across generations. Offspring from the Western diet group exhibited decreased barrier function based on transepithelial resistance measurements. Maternal consumption of a Western diet during gestation in olive baboons leads to a generalized inflammatory state and weakened intestinal barrier function in offspring, with potential long-term health implications.NEW & NOTEWORTHY Our research examines a currently understudied area of the maternal/fetal relationship. This is especially pertinent, given the rampant access to high-fat/high-sugar foods in the Western diet. It is also noteworthy due to the findings of decreased barrier function among those in the Western diet group. This decreased function and hyperinflammatory state can prime neonates for various pathologies, such as necrotizing enterocolitis.

The enteric nervous system (ENS) continues to be exposed to various disturbances throughout life, which causes apoptosis in the ENS. Therefore, it is assumed that neurogenesis is induced to maintain the neuronal network in the adult ENS. However, these underlying mechanisms are largely unknown. We aimed to investigate adult neurogenesis in the dextran sodium sulfate (DSS)-induced colitis mouse colon. Male C57BL/6N mice (12-wk-old) were administered 2% DSS in their drinking water for 8 days. After DSS treatment, cross-sections and longitudinal muscle and myenteric plexus preparations from the colon were used for immunohistochemistry. The segments of colons were mounted in organ baths and then exposed to a voltage-gated sodium channel activator veratridine. In the motility study, veratridine-induced colonic contractions were significantly suppressed in DSS-induced colitis mice compared with normal mice. Immunohistochemical analyses revealed that the proportion of nitrergic neurons per ganglion was significantly increased in the colons of DSS-induced colitis mice compared with normal mice. Furthermore, the proportion of Sox2 (new-born neuron marker)-positive neurons per ganglion was not significantly different between normal mice and DSS-induced colitis mice, whereas the proportion of Sox2-positive nitrergic neurons to Sox2-positive neurons per ganglion was significantly increased in the colons of DSS-induced colitis mice compared with normal mice. In addition, NOS inhibitor significantly enhanced veratridine-induced colonic contractions in DSS-induced colitis mice compared with normal mice. These findings suggested that colitis caused an imbalance in the enteric neural circuit composed of excitatory neurons and inhibitory neurons in the myenteric plexus of the colon, which resulted in colonic dysmotility.NEW & NOTEWORTHY ENS continues to be exposed to various disturbances throughout life, which causes adult apoptosis in the ENS. In this study, the frequency of adult neurogenesis was not altered by colitis, whereas colitis selectively induced adult neurogenesis of nNOS-positive inhibitory motor neurons in the myenteric plexus of the colon by preferential adult neurogenesis, indicating that colitis caused an imbalance in the enteric neural circuit composed of excitatory neurons and inhibitory neurons, which resulted in colonic dysmotility.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are debilitating and complex chronic gastrointestinal disorders that affect not only the gut but also extraintestinal organs, including the heart. The gut-heart cross talk has garnered increasing attention in recent years; however, the molecular mechanisms underlying this complex interplay remain poorly understood. This review explores the gut-heart axis, focusing on how IBD disrupts gut microbiota homeostasis and promotes cardiac remodeling through systemic inflammation and various mediators, ultimately contributing to the onset or progression of heart failure. IBD compromises the integrity of the intestinal barrier, allowing microbial metabolites such as trimethylamine N-oxide and phenylacetylglutamine, along with inflammatory cytokines and microRNAs (miRNAs) (e.g., miR-155, miR-21, and let-7a), to enter the circulation and contribute to cardiac remodeling and heart failure. We identify dysfunction of nucleotide-binding oligomerization domain-containing protein 2 as a critical link between gut immunity and cardiovascular pathology. In addition, we discuss emerging microbiome-based therapeutic strategies, including fecal microbiota transplantation and IL-23 inhibitors, aimed at restoring gut homeostasis and mitigating cardiovascular risk. By integrating molecular mechanisms, clinical evidence, and therapeutic approaches, this review underscores the pivotal role of gut dysbiosis in cardiac dysfunction and offers new perspectives for managing cardiac dysfunction in patients with IBD.