The swallowing reflex can be induced by peripheral stimulation of the larynx. Although previous studies have suggested that potassium ions exert facilitatory effects on the initiation of swallowing, little information is available on the mechanism underlying the potassium ion-evoked swallowing reflex. In this study, we evaluated the effects of potassium ions on peripheral afferent responses and the initiation of swallowing in conscious and anesthetized rats. Furthermore, the possible receptors involved were explored. The topical application of potassium chloride (KCl) significantly facilitated the swallowing reflex; these facilitatory effects were more prominent than those of distilled water (DW) or sodium chloride (NaCl). This phenomenon depended not on the concentrations of anions but on those of potassium ions. The potassium ion-induced response in the superior laryngeal nerve was most prominent after treatment with KCl, especially at the early stage. In chronic rats, without differences in licking behavior between DW, NaCl, and KCl, the intervals between swallows were the smallest during KCl-associated licking. Inward rectifier potassium channel (Kir)3.1- and Kir6.2-positive cells were detected in the nodose ganglion and vocal folds. The rate of expression of these molecules in immunoreactive cells was relatively high at 74.1% for Kir3.1 and 75.3% for Kir6.2. Kir3.1- and Kir6.2- blockers significantly decreased the number of KCl-induced swallows. Possible mechanisms underlying potassium ion-induced swallowing are discussed. Our findings suggest that Kir3.1 and Kir6.2 are involved in K ion-induced swallowing in rats.

Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern. Approximately one-quarter of patients have non-alcoholic steatohepatitis (NASH), which leads to the development of hepatocellular carcinoma. Several studies have shown the involvement of iron in NASH, but it remains unclear which cell of iron is at issue.

In functional dyspepsia, increased gut permeability, low-grade inflammation and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone(CRH) have been shown to increase small bowel permeability in a mast-cell dependent fashion. Moreover, eosinophil-derived CRH has been implicated in mast-cell activation. The aim of this study was to evaluate whether CRH administration alters duodenal permeability and immune activation in healthy volunteers(HVs). An intravenous bolus of 100μg CRH or placebo was administered in HVs in a crossover, double-blind, randomized fashion. Two hours later, a gastroscopy was performed to measure permeability in Ussing chambers and to count mast-cells and eosinophils on duodenal biopsies. Supernatant was assessed for eosinophil-derived neurotoxin(EDN), tryptase and chymase. In addition, CRH was administrated ex-vivo to baseline biopsies pretreated with or without lodoxamide. Results are described as mean±SD. p-values<0.05 were considered significant. Twenty HVs completed the study. Mast-cell or eosinophil counts were not significantly altered after CRH versus placebo(respectively p=0.31 and p=0.069). Tryptase but not chymase, significantly decreased after CRH (resp. p=0.037 and p=0.44) with a trend for a decrease in EDN(p=0.053). Permeability was unaltered comparing both conditions. Ex-vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared to baseline(p=0.010), which was not prevented by pre-treatment with lodoxamide. In-vivo CRH administration reduced tryptase levels in supernatant of duodenal biopsies without affecting permeability, whereas ex-vivo duodenal permeability increased regardless of mast51 cell stabilization. These results suggest the involvement of mast-cells in regulating gut permeability in HVs in response to CRH, possibly influenced by in-vivo compensatory mechanisms.

Normothermic machine perfusion (NMP) is used to preserve and assess the viability of (extended criteria) high-risk donor livers. Long-term NMP (LT-NMP; ≥24h) is emerging as a method to improve or repair livers initially deemed unsuitable for transplantation. This study investigated metabolism during LT-NMP, focusing on hepatic energy consumption and nitrogen and electrolyte balances to better understand long-term perfusion requirements. In this study, we measured oxygen consumption (V̇ CO2) and carbon dioxide production (V̇ O) to determine the energy expenditure of 14 human livers during LT NMP for 7 days. Additionally, hepatic balances of glucose and lactate, as well as of nitrogen and electrolytes were determined. Initial high metabolic rates during the first day of LT-NMP decreased and stabilized at nearly 50% on day 3, suggesting a quiescent state until day 7. Most energy was derived from glucose (75-88%). Continuous amino acid supplementation was essential to maintain an anabolic state, whereas livers without supplementation became catabolic. While net electrolyte balances were close to zero, significant uptake and release of electrolytes occurred throughout LT-NMP. During LT-NMP, livers reached a metabolically quiescent state after 3 days with decreased energy consumption. Tailoring perfusate composition and supplementation protocols to the specific needs of the liver could enhance organ preservation and potentially expand the pool of viable donor livers after LT-NMP.

Considerable evidence suggests the gut-brain axis can influence behaviour. However, there has been a conspicuous lack of technology to provide targeted wireless activation of the gut-brain axis in conscious freely moving animals. We utilised a miniature fully implantable battery-free device to apply highly controlled optogenetic stimuli to the terminal region of GI-tract, in conscious freely moving mice. The optical stimulator was implanted and secured on the serosal surface of the distal colon and rectum to characterize the behavioural responses evoked by optogenetic stimulation of axons expressing channelrhodopsin (ChR2) driven by the Trpv1 promoter (Trpv1 ChR2 mice). In freely moving Trpv1 ChR2 mice, trains of blue light pulses to the distal colon and rectum induced increased abdominal grooming and reduced movement. In contrast to stimulation of the gut, trains of stimuli applied to the peritoneal cavity evoked writhing and abdominal contraction. Anterograde labelling from nodose ganglia revealed sparse vagal afferent axons and endings in the proximal and mid colon, with no labelled axons caudal of the mid colon (within 30 mm of the anus). The distal colon and rectum were densely innervated by spinal afferents. The findings demonstrate that wireless optogenetic stimulation of the gut-brain axis can induce specific behavioural patterns in conscious freely moving rodents, using fully implantable battery-free technology.

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.

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.

The global prevalence of ulcerative colitis (UC) and Crohn's disease (CD) is increasing, placing greater burdens on national health systems. The pathophysiology of diarrhea, the commonest debilitating symptom in UC and CD patients, has been studied more extensively in UC, where it reflects defective colonic Na absorption combined with changes in colonic Cl and K transport which greatly reduce colonic water absorption. Dysfunctional ion transport in patients with UC is accompanied by abnormalities in tight junctional protein distribution and function, which cause the inflamed colonic epithelium to become 'leakier'. Progress in understanding how abnormal colonic ion transport in UC might be influenced pharmacologically has been hampered by the low availability of clinical material. To counter this, various animal models of acute colitis have been developed, but differ in the way mucosal inflammation is induced. Identifying models that closely mimic human UC in terms of pathology and ion transport abnormalities remains challenging. However, the introduction of human colonic epithelial organoids (colonoids) has added a new and exciting dimension to research in this area. Here, we review current knowledge about abnormal colonic ion transport and barrier function in experimental and human colitis as well as the use and potential of human colonoids to better understand the pathophysiology of UC, which may ultimately lead to novel approaches to the treatment of diarrhea in this disease.

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.

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.

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 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.

Prostaglandin E (PGE) actions on intestinal motility are complex due the differential expression of the PGE receptors EP1-EP4. 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 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 TTX and 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 EP4 antagonist ONO AE3-208. The EP agonist ONO DI-004 produced little effect while 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, while 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.

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 TNF mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8-, 12-, 20-, and 28 weeks of age, specific pathogen-free (SPF), germ-free (GF) TNF and WT mice were assessed for ileitis via myeloperoxidase activity (MPO) while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF TNF occurred in a stepwise manner between 8 and 28 weeks of age beginning with the development of mesenteric lymphadenopathy at 8 weeks despite no significant ileitis. By 12 weeks ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLV) and clustering of CD45 immune cells around them. At 20 weeks, significant lymphangiogenesis of the initials (ILV) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 weeks, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-week-old GF TNF, while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The TNF mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with MLN lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and TLO formation being entirely dependent of its presence.

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by accumulation of fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance of hepatic Aryl hydrocarbon Receptor (AhR) signaling in cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers of high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific Aryl hydrocarbon Receptor knockout mice (AhR-hKO) exhibited aggravated steatosis, inflammation, and fibrosis compared to control AhR-floxed livers. Moreover, treatment with a tryptophan catabolite, CA reduced body weight gain and significantly attenuated hepatic steatosis, inflammation, ballooning, fibrosis, and liver injury only in AhR-floxed but not in AhR-hKO mice, strongly indicating that the CA-mediated protection against steatohepatitis is AhR-dependent. Furthermore, protection against lipotoxicity by CA-activated AhR signaling was confirmed by utilizing an human hepatocyte model of MASLD. Mechanistically, CA-induced AhR-dependent signaling augmented AMP-activated protein kinase (AMPK) leading to the upregulation of peroxisome proliferator-activated receptor-c coactivator-1a (PGC1α) and attenuation of sterol regulatory element-binding protein-1 (SREBP1) to regulate hepatic lipid metabolism. Collectively, our findings indicate that CA-mediated protection against MASH is dependent on hepatic AhR signaling and selective endogenous AhR agonists that regulate lipogenesis can serve as promising future therapeutics against MASLD.

The gastrointestinal (GI) tract is made up of specialized organs that work in tandem to facilitate digestion. The colon regulates the final steps in this process where complex motor patterns in proximal regions facilitate formation of fecal pellets that are propelled along the distal colon via self-sustaining neural peristalsis and temporarily stored prior to defecation. Historically, our understanding of colonic motility has focused primarily on distal regions, and the intrinsic reflex circuits of the enteric nervous system (ENS) involved in neural peristalsis have been defined, but we do not yet have a clear grasp on the mechanisms orchestrating motor function in proximal regions. New approaches have brought to the forefront the unique structural, neurochemical, and functional characteristics that exist in distinct regions of the mouse and human colon. In this mini-review, we highlight key differences along the proximal-distal colonic axis and discuss how these differences relate to region-specific motor function.

Paratuberculosis is an infectious disease caused by the bacterium, subspecies (MAP). MAP infection of ruminants triggers progressive wasting disease characterized by granulomatous lymphadenitis, enteritis, and severe intestinal pathology that often requires early culling of the animal. The resulting economic burden is significant and MAP exposure in the workplace constitutes a significant zoonotic risk. While it has been established the MAP propagates within resident immune cells, less is known about how it traverses the epithelium. It's currently thought that MAP infects the small intestinal epithelium by targeting both enterocytes and M cells, with a potential tropism for the latter. In the current study, we developed and validated an enteroid-based in vitro assay containing functional M cells to identify the target cells for MAP's entry. Upon exposure to MAP, the bacteria were detected within both enterocytes and M cells, however quantitative image analysis revealed significant tropism for the latter. Complementary studies using the Caco-2/Raji-B co-culture system provided similar results. Since other mycobacteria have been shown to initiate cell attachment and entry by using a fibronectin-bridging process, we tested whether these interactions were involved in MAP's targeting of M cells. We found that MAP's M cell tropism was enhanced by fibronectin and that this effect was abolished when monolayers were pretreated with an integrin blocking peptide. Our data demonstrate that MAP preferentially targets M cells and that this involves a fibronectin-bridging process. Furthermore, our study supports the utility of M cell containing enteroids to study host-pathogen interaction at the intestinal epithelium.

Exposure to hypobaric hypoxia during rapid ascent to high altitudes significantly impacts intestinal barrier function. Goblet cells, as one of the primary cell types in the intestinal mucosa, play a crucial role in maintaining this barrier. However, the effects of hypobaric hypoxia on goblet cell function and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of hypobaric hypoxia exposure (simulating an altitude of 6,000 meters) and studied its effects on colonic goblet cells by transcriptomic analysis. Additionally, the hypoxia-treated (1% O) goblet cell line Ls174t was used to investigate potential mechanisms underlying hypoxia-induced changes in goblet cells. In the present study, we discovered that hypobaric hypoxia exposure not only reduced the number of colonic goblet cells in mice by 27.6% but also impaired their mucus secretion. Transcriptome sequencing analysis of sorted goblet cells from the mice colon revealed significant changes in gene expression profiles, particularly in the expression of canonical goblet cell markers such as calcium-activated chloride channel regulator 1 (Clca1) and Fcγ-binding protein (Fcgbp). We confirmed the effects of hypobaric hypoxia/hypoxia exposure on CLCA1 and FCGBP expression at both mRNA and protein levels in mouse colonic tissues and in Ls174t cells. The expression of these canonical goblet cell marker genes was dependent on HIF-1α activity; their expression decreased upon hypoxia-induced activation of HIF-1α and increased when HIF-1α was knocked down using siRNA. Thus, hypobaric hypoxia exposure regulates the distribution and function of colonic goblet cell subsets through the HIF-1α signaling pathway.