American Journal Of Physiology. Gastrointestinal And Liver Physiology[JOURNAL]
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200 papers
The spatiotemporal development of mesenteric lymphatic changes in the mouse model of terminal ileitis.
Keane K, Stephens M, Roizes S … +3 more , Xue J, Liao S, von der Weid PY
Am J Physiol Gastrointest Liver Physiol · 2025 May · PMID 40062472 · Publisher ↗
Crohn's disease (CD) is a chronic inflammatory bowel disease, which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of or directly contribute to t...
Crohn's disease (CD) is a chronic inflammatory bowel disease, which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of or directly contribute to the inflammation is unknown. Here, we characterized the spatial and temporal development of these events in the mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8, 12, 20, and 28 wk of age, specific pathogen-free (SPF), germ-free (GF) and wild-type (WT) mice were assessed for ileitis via myeloperoxidase (MPO) activity while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF occurred in a stepwise manner between 8 and 28 wk of age beginning with the development of mesenteric lymphadenopathy at 8 wk despite no significant ileitis. By 12-wk ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLVs) and clustering of CD45 immune cells around them. At 20 wk, significant lymphangiogenesis of the initials (initial lymphatic vessel) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 wk, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-wk-old GF , while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with mesenteric lymph node lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and tertiary lymphoid organ formation being entirely dependent of its presence. The mesenteric lymphatic system displays striking morphological alterations in Crohn's disease. To assess the importance of these changes in the perpetuation of the disease, we established the timeframe of their occurrence with respect to the development of ileitis in a mouse model of Crohn's disease and in the same model derived germ-free where intestinal inflammation does not occur. Although immune-related alterations seem to depend on microbiome, changes specifically affecting lymphatic vessels persist in its absence.
Differential responses to prostaglandins in the circular and longitudinal muscle layers of the murine ileum.
Kwon JG, Hwang SJ, Beckett EAH … +2 more , Sanders KM, Ward SM
Am J Physiol Gastrointest Liver Physiol · 2025 Jul · PMID 40047296 · Full text
Prostaglandin E (PGE) actions on intestinal motility are complex due to the differential expression of the PGE receptors EP-EP. We sought to determine the actions of PGE on electrical pacemaker and contractile activity o...
Prostaglandin E (PGE) actions on intestinal motility are complex due to the differential expression of the PGE receptors EP-EP. We sought to determine the actions of PGE on electrical pacemaker and contractile activity of the circular and longitudinal muscle layers of the murine small intestine. Intracellular microelectrode and isometric force measurements were performed to examine the effects of PGE receptor activation on circular and longitudinal muscle layers. In the two muscle layers, PGE produced differential responses. In the circular muscle layer, PGE caused dose-dependent membrane hyperpolarization and a reduction in slow-wave amplitude, accompanied by a decrease in the amplitude of phasic contractions. Membrane hyperpolarization and the reduction in slow-wave amplitude and phasic contractions were insensitive to tetrodotoxin (TTX) and -nitro-l-arginine (l-NNA) but inhibited by the K channel antagonist glibenclamide. The actions of PGE on the circular muscle layer were mimicked by the selective EP and EP agonists ONO AE1-259 and ONO AE1-329, respectively. The actions of PGE were partially inhibited by the EP antagonist ONO AE3-208. The EP agonist ONO-DI-004 produced little effect, whereas the EP3 agonist ONO-AE-248 caused dose-dependent membrane depolarization. In comparison, PGE produced increased tone and phasic contractions in the longitudinal muscle layer that was mimicked by ONO-DI-004 and ONO-AE-248, whereas EP and EP agonists had little effect on contractile activity. These data suggest that differential expression of PGE receptors on intestinal muscle layers can produce antagonistic actions on intestinal motility. Prostaglandins are lipid mediators that have complex actions on gastrointestinal motility that are highly dependent on the expression of the receptor subtypes where they exert their actions. PGE has inhibitory or excitatory effects on circular or longitudinal muscle layers of the small intestine. Despite many studies of the effects of prostaglandins on tissue contractility, little is known about the specific receptors eliciting these effects. The present study examines functional receptor expression in the small intestine.
Combination of dietary fiber and exercise training improves fat loss in mice but does not ameliorate MASLD more than exercise alone.
Kovynev A, Charchuta MM, Begtašević A … +3 more , Ducarmon QR, Rensen PCN, Schönke M
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40033967 · Publisher ↗
Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber...
Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber and exercise on the modulation of gut-liver axis and MASLD amelioration. Here, we studied the impact of the combination of exercise training and a fiber-rich diet on the amelioration of MASLD. Male APOE*3-Leiden.CETP mice were fed a high-fat high-cholesterol diet with or without the addition of fiber (10% inulin) and exercise trained on a treadmill, or remained sedentary. Exercise training and fiber supplementation reduced fat mass gain and lowered plasma glucose levels. Only the combination treatment, however, induced fat loss and decreased plasma triglyceride and cholesterol levels compared with sedentary control mice. Exercise training with and without the addition of fiber had a similar ameliorating effect on the MASLD score. Only exercise without fiber decreased the hepatic expression of inflammatory markers. Fiber diet was mainly responsible for remodeling the gut microbial composition, with an increase in the relative abundance of the short-chain fatty acid (SCFA)-producing genera and , whereas, surprisingly, exercise training alone and with fiber resulted in the highest increase of SCFA production. Overall, the combination of exercise training and dietary fiber decreases fat mass and improves glucose and lipid homeostasis but does not have an additional synergistic positive effect on liver health compared with exercise training alone. The combination of dietary fiber intake and exercise training has a synergetic beneficial effect on the metabolic health, resulting in fat loss, lowered blood glucose, and lowered plasma lipid levels in mice with steatotic liver disease. However, fiber supplementation, despite a positive remodulation of the gut-liver axis, does not have an additional positive effect on liver health compared with exercise training alone.
Dynamics of circulatory monocytes trafficking and transitioning to gastric resident macrophages in diabetic gastroparesis.
Singh R
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 40033937 · Publisher ↗
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Progressive impairment in gastric and duodenal slow waves and autonomic function during progression of type 2 diabetes in rats.
Wu G, Li F, Li Y … +3 more , Li S, Alam MJ, Chen JDZ
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 39993032 · Full text
The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis, which is highly prevalent in type 2 diabetes (T2D). Although relatively well-investigated in diabetic...
The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis, which is highly prevalent in type 2 diabetes (T2D). Although relatively well-investigated in diabetic enteric neuropathy, abnormalities and progressive impairments of gastric slow waves (GSWs) and duodenal slow waves (DSWs) are underinvestigated during the progression of T2D. The aim of this study was to explore alterations in GSW and DSW during the development of diabetes induced by high-fat diet (HFD) followed by a low dose of streptozotocin (STZ). Weekly recordings of slow waves from healthy, prediabetic to diabetes stages exhibited a progressively decreased percentage of normal slow waves (%NSW) starting after HFD feeding (prediabetic stage) in the fasting state and starting after STZ injection (diabetic stage) in the postprandial state. The postprandial increase in the power of slow waves observed in normal control rats was absent starting from 2 wk after HFD and persisted after STZ. The mechanism might be attributed to both progressively increased blood glucose (BG) and impaired autonomic function in view of the following results: ) the %NSW was negatively correlated with the fasting BG; ) during the oral glucose tolerance test, %NSW of DSW and BG exhibited a positive correlation in rats with hemoglobin A1C (HbA1C) < 5.0%, but a negative correlation in rats with HbA1C ≥ 5.0%; and ) in comparison with baseline (healthy stage) of the same cohort, plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased, whereas plasma norepinephrine (reflecting sympathetic activity) was progressively increased. This study recorded the progressive impairment in the regularity of gastric and duodenal slow waves in a rat model mimicking the progression to type 2 diabetes including the stage of health, prediabetic stage, and diabetes. The progressive impairment in gastric/duodenal slow waves might be attributed to the progressive increase in blood glucose and impairment in autonomic function.
Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after UDCA treatment for intrahepatic cholestasis of pregnancy.
Basu S, Običan SG, Bertaggia E … +4 more , Staab H, Izquierdo MC, Gyamfi-Bannerman C, Haeusler RA
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 39947696 · Full text
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard the...
Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP. This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.
Mass cytometric analysis of circulating monocyte subsets in a murine model of diabetic gastroparesis.
AlAsfoor S, Jessen E, Pullapantula SR … +19 more , Voisin JR, Hsi LC, Pavelko KD, Farwana S, Patraw JA, Chai XY, Ji S, Strausbauch MA, Cipriani G, Wei L, Linden DR, Hou R, Myers R, Bhattarai Y, Wykosky J, Burns AJ, Dasari S, Farrugia G, Grover M
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 39947648 · Full text
Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the d...
Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the dynamics of Mo in the development of DGE in an animal model are unknown. Using cytometry by time-of-flight and computational approaches, we show a high heterogeneity within the Mo population. In DGE mice, via unbiased clustering, we identified two reduced Mo clusters that exhibit migratory phenotype (Ly6CCCR2CD62LLy6GCD45RMERTKLGALS3CD14CX3CR1Siglec-H) resembling classical Mo (CMo-like). All markers enriched in these clusters are known to regulate cell differentiation, proliferation, adhesion, and migration. Trajectory inference analysis predicted these Mo as precursors to subsequent Mo lineages. In gastric muscle tissue, we demonstrated an increase in the gene expression levels of chemokine receptor C-C chemokine receptor type 2 () and its C-C motif ligand 2 (), suggesting increased trafficking of classical-Mo. These findings establish a link between two CMo-like clusters and the development of the DGE phenotype and contribute to a better understanding of the heterogenicity of the Mo population. Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the - axis.
Carbon monoxide produced by HO-1 upregulation is the main factor behind the abnormal motility seen in experimental ulcerative colitis in mice.
Zhao M, Lei Y, Wang M … +7 more , Chen Y, Hou S, Dai X, Gao D, Liu Y, Mazet B, Sha L
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39925143 · Publisher ↗
The colonic motility is altered in patients with ulcerative colitis (UC), but the mechanism is not clear. Carbon monoxide (CO) is the molecule regulating the resting membrane potential (RMP) gradient across colonic smoot...
The colonic motility is altered in patients with ulcerative colitis (UC), but the mechanism is not clear. Carbon monoxide (CO) is the molecule regulating the resting membrane potential (RMP) gradient across colonic smooth muscle wall. Changes in RMP will affect the contractility of smooth muscle. In this study, we investigated the altered colonic motility in dextran sodium sulfate-induced UC mice and the role of CO. The results showed that in the UC group, the frequency of spontaneous colonic contractions was increased while the AUC was decreased compared with the control group. HO-1-, but not HO-2-, positive cells were increased in the colonic smooth muscle wall of the UC group. These HO-1-positive cells were mainly in the myenteric plexus and PGP9.5 positive, suggesting neuronal overproduction of CO. The RMP of circular smooth muscle cells (SMCs) in the colon of UC group was hyperpolarized compared with that of control group. In control group, application of CORM-3, a CO donor, altered colonic spontaneous contractions by increasing their frequency and decreasing amplitude. In the UC group, ZnPPIX, a HO-1 inhibitor, reduced the frequency and increased the amplitude. CORM-3 hyperpolarized the RMP of colonic SMCs and abolished its gradient in the control group, while ZnPPIX depolarized the RMP of colonic SMCs and restored its gradient in the UC group. CO produced by HO-1 upregulation is the main factor behind the altered colonic motility seen in UC mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility. Carbon monoxide (CO) produced by HO-1 upregulation in myenteric plexus is the main factor that abolishes the RMP gradient across colonic muscle wall causing the altered colonic motility seen in experimental ulcerative colitis (UC) mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer from abnormal colonic motility.
Voltage-gated calcium channel αδ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice.
Yang Y, Yamane S, Harada N … +8 more , Ikeguchi-Ogura E, Yamamoto K, Wada N, Fauzi M, Murakami T, Yabe D, Hayashi Y, Inagaki N
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39918794 · Publisher ↗
Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca channel has been...
Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca channel αδ-1 subunit (Caαδ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of Caαδ-1 by gabapentin (GBP), an inhibitory ligand of the αδ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific , a gene encoding Caαδ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that Caαδ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity. In this study, we establish high expression of the voltage-gated Ca channel αδ-1 subunit (Caαδ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.
The central neural control of the posterior belly of the digastric muscles during swallowing in rats.
Tsutsui Y, Chotirungsan T, Pan CR … +5 more , Kawada S, Magara J, Tsujimura T, Okamoto K, Inoue M
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39908006 · Publisher ↗
The aim of this study was to clarify whether the posterior belly of the digastric (post-Dig) muscle is activated during the swallowing reflex and whether the post-Dig muscle is directly controlled by the swallowing centr...
The aim of this study was to clarify whether the posterior belly of the digastric (post-Dig) muscle is activated during the swallowing reflex and whether the post-Dig muscle is directly controlled by the swallowing central pattern generator (CPG) in anesthetized rats, using physiological and immunohistochemical approaches. In physiological study, electromyograms (EMGs) of the post-Dig, sternohyoid and thyrohyoid muscles, and the diaphragm were recorded during respiration and swallowing with and without airway stenosis. In the immunohistochemical study, c-Fos immunoreactivity for expression of cells during swallowing was analyzed. Motoneurons were identified using immunohistochemistry with Fluoro-gold (FG). EMG bursts were observed in the hyoid muscles during the inspiratory phase and swallowing. With airway stenosis, the swallowing EMG activity was facilitated in terms of duration and area only in the post-Dig muscle. The coordination of these EMG activities during swallowing was maintained with airway stenosis. In contrast, the offset of the post-Dig EMG burst was delayed with airway stenosis. c-Fos-positive cells were observed in the accessory facial nucleus (Acs7), but only in the rostral portion. FG-labeled cells were observed in Acs7. Several c-Fos/FG double-labeled cells were observed only in the rostral Acs7. These results suggested that the post-Dig muscle is activated during swallowing, the activation of which is controlled by the swallowing CPG, and that the distribution of Acs7 neurons, which innervate the post-Dig muscle, was uneven in the nucleus. In addition, the modulation of post-Dig muscle activity during inspiration might be due to changes in peripheral conditions via respiratory CPG. The posterior belly of the digastric muscle is activated during the inspiratory phase and swallowing. Increased airway resistance facilitates both inspiratory and swallowing activities of this muscle. Immunohistochemistry revealed that the motoneurons innervating the posterior belly of the digastric muscle were activated during swallowing only in the rostral portion of the accessory facial nucleus. These results suggested that the posterior belly of the digastric muscle is controlled by the respiratory and swallowing central pattern generators.
Dysregulated hepatic alcohol metabolism: a key factor involved in the pathogenesis of alcohol-associated liver disease.
Srinivasan M, Kota S, Bhopale K … +8 more , Caracheo A, Kaphalia L, Linares J, Romsdahl T, Russell W, Popov V, Boor P, Kaphalia B
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39907561 · Full text
Alcohol use disorder is a major risk factor for alcohol-associated liver disease (ALD), characterized by reduced hepatic alcohol dehydrogenase (ADH) activity, increased body burden of alcohol, and its nonoxidative metabo...
Alcohol use disorder is a major risk factor for alcohol-associated liver disease (ALD), characterized by reduced hepatic alcohol dehydrogenase (ADH) activity, increased body burden of alcohol, and its nonoxidative metabolism to fatty acid ethyl esters (FAEEs). However, the mechanism(s) underlying ALD remain unclear. This study investigated the metabolic basis and mechanism(s) of ALD in chronic ethanol (EtOH)-fed hepatic ADH1-deficient (ADH) deer mice administered with a single dose of binge EtOH with/without FAEEs. Hepatic ADH and ADH normal (ADH) deer mice fed chronic EtOH daily for 3 mo, followed by a single dose of binge EtOH (3 g/kg·body wt) with/without FAEEs (100 mg/kg·body wt), 1 wk before euthanasia. Blood alcohol and acetaldehyde and liver injury markers in the plasma, hepatic FAEEs, lipids, and inflammatory markers were analyzed. Hepatic histology, ultrastructure, protein/mRNA expression of genes involved in alcohol metabolism and lipogenesis, cyclic adenosine monophosphate (cAMP), phosphodiesterase (PDE) activity, and AMP-activated protein kinase (AMPKα) signaling were assessed. Blood alcohol, hepatic lipids and FAEEs, inflammation, oxidative stress, and the expression of lipogenic proteins/genes were significantly increased in various chronic EtOH-fed groups of ADH versus ADH deer mice. In addition, hepatic cAMP levels were reduced, whereas PDE activity and plasma transaminases were elevated. Binge EtOH with/without FAEEs did not significantly exacerbate the liver injury in chronic EtOH-fed ADH as well as ADH deer mice. Overall, an increased body burden of EtOH and endogenously formed FAEEs due to hepatic ADH deficiency, along with dysregulated cAMP and AMPKα signaling, could be the determining factors for EtOH-induced liver injury leading to ALD. Using hepatic alcohol dehydrogenase deficient (ADH) deer mouse, which mimics the metabolic conditions observed in chronic alcoholics, we found significant hepatic injury along with degenerative changes in endoplasmic reticulum and mitochondria. Our findings suggest that an increased nonoxidative alcohol metabolism under hepatic alcohol dehydrogenase deficiency and associated hepatic lipid dysregulation and injury appear to be the key factors involved in the pathogenesis of alcohol-associated liver disease.
Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.
Mitchell AL, Tough IR, Fan HM … +9 more , Lövgren-Sandblom A, Ovadia C, Chambers J, Fonseca Pedro P, Tsakmaki A, Bewick GA, Marschall HU, Cox HM, Williamson C
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 39888313 · Publisher ↗
Sulfated progesterone metabolites (PMxSs) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterized by pruritus and elevated serum bile acids. PMxSs interac...
Sulfated progesterone metabolites (PMxSs) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterized by pruritus and elevated serum bile acids. PMxSs interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxSs were quantified in pre-/postprandial serum samples ( = 21) and feces ( = 18) by ultra performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (Δ) in wildtype, , and mice by PMxS metabolites, 5β-pregnan-3α,-20α-diol-3-sulfate (PM3S) and 5α-pregnan-3β-ol-20-one-sulfate (PM5S), and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition ( = 6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and murine crypts and human colonoids was measured by ELISA ( = 3). Serum PMxSs increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxSs are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -Δ in wildtype ( < 0.01) but not or colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids ( < 0.001). ASBT inhibition blunted -Δ by 68% after apical PM3S and PM5S addition ( < 0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy. Sulfated progesterone species (PMxSs) increase postprandially in women with intrahepatic cholestasis of pregnancy (ICP) but not in women with uncomplicated pregnancy. PMxS can be enterohepatically recycled via active transport from the gut lumen by apical sodium-dependent bile acid transporter (ASBT) and stimulate gut hormone secretion. Active reabsorption of PMxS may play a role in the pruritus suffered by women with ICP. ASBT inhibition is a plausible therapy for ICP-associated pruritus.
Modeling the kinetics of interorgan arginine metabolism during bacterial sepsis in swine.
Vonderohe C, Burrin D
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39880393 · Full text
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Diet-microbiome-ENS connection: impact of the cafeteria diet.
Balasubramaniam A, Srinivasan S
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39873427 · Full text
The interplay between diet-induced obesity and gastrointestinal dysfunction is an evolving area of research with far-reaching implications for understanding the gut-brain axis interactions. In their study, Ramírez-Maldon...
The interplay between diet-induced obesity and gastrointestinal dysfunction is an evolving area of research with far-reaching implications for understanding the gut-brain 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 and 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.
Regulation of pathologic fibroblast functions in digestive diseases: a role for hypoxia?
Ohlendieck CM, Matellan C, Manresa MC
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39873349 · Publisher ↗
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 respon...
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. Although 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 tumor necrosis factor superfamily members have been identified as possible mediators driving the acquisition of inflammatory and 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 cross talk between hypoxia and inflammation is well-documented, with an abundance of studies suggesting that oxygen-sensing enzymes may have regulatory effects on inflammatory signaling 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.
Duodenogastric reflux in health and disease: insights from a computational fluid dynamics model of the stomach.
Kuhar S, Seo JH, Pasricha PJ … +2 more , Camilleri M, Mittal R
Am J Physiol Gastrointest Liver Physiol · 2025 Apr · PMID 39873302 · Publisher ↗
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 bac...
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. An in silico model of the stomach is presented to study the phenomenon of duodenogastric reflux. We use the model to investigate the role of pyloric incompetence, food properties, and gastroparesis on reflux. This first-ever in silico study of duodenogastric reflux provides new insights into the mechanisms and factors implicated in this reflux and the sequelae of conditions that result from the exposure of the stomach lumen to bile.
Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine.
Rose EC, Simon JM, Gomez-Martinez I … +4 more , Magness ST, Odle J, Blikslager AT, Ziegler AL
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39853303 · Full text
Intestinal ischemic injury damages the epithelial barrier and predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age dependency in intestinal recovery in that neonates ar...
Intestinal ischemic injury damages the epithelial barrier and predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age dependency in intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier compared with 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 the predicted upstream regulator, colony stimulating factor-1 (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 by ischemia and documented that CSF-1 and colony-stimulating factor-1 receptor (CSF1R) co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued neonates. Furthermore, the CSF-1 blockade reduced restitution in vitro, and CSF-1 improved barrier function in injured neonatal pigs 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. These studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for the medical management of patients with ischemia-mediated intestinal injury.
Prenatal lipopolysaccharide stimulation modulates gastrointestinal immunity and oxidative status in weaned pigs.
Mitchell TM, Burdick Sanchez NC, Carroll JA … +4 more , Broadway PR, Legako JF, Bowen BM, Petry AL
Am J Physiol Gastrointest Liver Physiol · 2025 Mar · PMID 39853237 · Publisher ↗
Gastrointestinal immunity and antioxidant defenses may be bolstered in young animals through prenatal immune stimulation (PIS), but this is largely uninvestigated in swine. This study tested the hypothesis that PIS could...
Gastrointestinal immunity and antioxidant defenses may be bolstered in young animals through prenatal immune 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 lipopolysaccharide (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 (Control, CON) or LPS from O111:B4 (2.5 µg/kg of body wt). A subset of 34 weaned barrows ( = 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 wt) from 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, stem cell factor was modulated with heightened expression in PIS than CON ( ≤ 0.05). In the ileum alone, PIS exhibited heightened expression of proinflammatory cytokines and chemokines, including TNFα, IL-6, IL-1β, and CCL3L1, compared with CON ( ≤ 0.05). Exposure to PIS resulted in reduced systemic total antioxidant capacity at and postchallenge ( = 0.004). Piglets exposed to PIS had decreased jejunal tissue malondialdehyde concentrations ( = 0.049). Together, these data indicate that exposure to PIS alters the inflammatory profile of the gastrointestinal immune response and oxidative status in weaned pigs. These studies represent novel investigations into the influence of prenatal immune stimulation (PIS) in swine on the gastrointestinal immune response and oxidative status of offspring following subsequent immune challenge. Notable alterations were observed in gut protein biomarkers, particularly the upregulation of proinflammatory cytokines TNFα, IL-6, and IL-1β in PIS-exposed pigs, but has variable effects on oxidative status. Altered intestinal immune development may contribute to an increased risk for inflammatory disease associated with prenatal immune stimulation.
Bile acid sequestrant inhibits gluconeogenesis via inducing hepatic cysteine dioxygenase type 1 to reduce cysteine availability.
Matye DJ, Wang H, Wang Y … +2 more , Xiong L, Li T
Am J Physiol Gastrointest Liver Physiol · 2025 Feb · PMID 39819116 · Full text
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 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, whereas 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 is 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. Hepatic cysteine availability is a key driver of hepatic gluconeogenesis. Bile acid sequestrant inhibits gluconeogenesis by inducing CDO1-mediated cysteine catabolism to reduce cysteine availability. Dietary protein restriction causes hepatic cysteine deficiency without overall amino acid deficiency. The glucose-lowering effect of dietary protein restriction is largely mediated by lower dietary cysteine intake. The anti-obesity effect of chronic dietary protein restriction is largely mediated by lower dietary cysteine intake.
Rhamnogalacturonan promotes intestinal mucosal repair through increased cell migration.
Baggio CH, Shang J, Périco LL … +9 more , Dos Santos RC, Gordon MH, Da Luz BB, Stephens M, Nascimento AM, Werner MFP, von der Weid PY, Cipriani TR, MacNaughton WK
Am J Physiol Gastrointest Liver Physiol · 2025 Feb · PMID 39819015 · Publisher ↗
Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aime...
Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aimed to evaluate the effect of RGal in intestinal epithelial wound healing. Confluent cancer cell lines and colonoid monolayers were wounded, treated with RGal for 48 h, and assessed using a live cell imaging system. Proliferation and apoptosis of cells were evaluated using 5-ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, respectively. Inhibitors were used to determine the receptor and signaling pathways involved. Female and male mice with DSS-induced colitis were treated orally with RGal for 7 days during the recovery phase. RGal enhanced wound healing in Caco-2, T84, and primary cells by increasing cell migration. Inhibition of pretranscriptional signaling pathways FAK, Src, PI3K, Rho family, and JNK reversed the RGal-induced wound healing. RNAseq data from Caco-2 and primary cells treated with RGal showed the upregulation of the NF-κB pathway at 12 h. Actinomycin D, Bay 11-7082 or JSH-23, and NS-398 treatment significantly reversed the effect of RGal on wound healing, confirming that the response was also transcriptionally dependent and involved NF-κB signaling and downstream COX-2 protein activity. RGal treatment of male mice enhanced recovery from DSS colitis. RGal promoted wound healing in cancer and primary cells by increasing cell migration and accelerated epithelial mucosal healing in male mice. Our findings show a novel mechanism of action of RGal in wound healing that could help in mucosal healing and the resolution of intestinal inflammation. RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.
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