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

Gastroesophageal refluxes (GERs) are universal in newborns and may induce deleterious consequences, especially in preemies. We have previously shown that nasal continuous positive airway pressure (nCPAP) inhibits GERs in full-term lambs, complementing similar results in adult humans. The effect of high-flow nasal cannula (HFNC) on GERs, however, remains unknown. This study aimed to assess the effects of nCPAP and HFNC on GERs in our preterm lamb model. Eleven preterm lambs born 14 days before full-term (∼34 wk of human gestation) were studied. Esophageal pH-impedancemetry and polysomnography recordings were performed simultaneously for 6 h under three randomly ordered conditions: nCPAP 6 cmH₂O, HFNC 7 L/min, and no respiratory support (control). The indexes (/h) of GERs and air-containing swallows were analyzed during each condition. The states of alertness and cardiorespiratory events were also analyzed during the identified GERs. nCPAP significantly decreased the GER index compared with control and HFNC during both quiet wakefulness and nonrapid eye movement sleep, whereas HFNC did not alter the GER index. In addition, nCPAP significantly increased the air-containing swallow index compared with control and HFNC. No significant differences were observed between the tested conditions for GER-related cardiorespiratory events, which were nevertheless rarely observed. Similar to full-term lambs, nCPAP strongly inhibited GERs in the preterm lamb, despite an increase in air-containing swallows. In contrast, HFNC did not impact GERs. Our results are clinically relevant when discussing the use of CPAP in preemies with GERs.NEW & NOTEWORTHY Nasal CPAP inhibited gastroesophageal refluxes in preterm lambs, despite increasing air-containing swallows. High-flow nasal cannula did not impact GERs. Nasal respiratory support did not alter the rare cardiorespiratory events observed during GERs.

We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes Arntl/Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On day 4, separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of Fgf15 and Nr0b2. In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation.NEW & NOTEWORTHY This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition.

Physiologists may play critical roles in the development of clinician-scientists who aspire to an academic career. The complexity of contemporary biomedical science and economic matters regarding postgraduate education pose real conundrums. We report a more than 22-year follow-up of surgical trainees pursuing bench laboratory science experience through a collaboration between a physiology postgraduate program and a surgical researcher program within a single public medical school. The sources and resources include selection, funding, physiology classroom work, and laboratory studies with personal involvement by faculty that have seldom been recorded, especially with longer term career outcomes. These selected PhD candidates have subsequently pursued several lines of activity, many with distinguished careers and major influences upon future generations of academic surgeons.

Intestinal ischemia and reperfusion injury (IRI) is a deadly and common condition. Death is associated with sepsis due to insufficient epithelial repair, requiring stem cell-driven regeneration, typically beginning 48 h after injury. Animal models are critical to advancing this field. To effectively study epithelial healing, models must survive clinically relevant intestinal ischemic injury extending to the crypt. Although mouse models are indispensable to intestinal research, their application for studying epithelial repair following severe IRI may be limited. Ischemic injury was induced in mouse and porcine jejunum for up to 3 h, with up to 72 h of reperfusion. Histologic damage was scored by Chiu-Park grade, and animal survival was assessed. Findings were compared between species. A mouse IRI literature review was performed to evaluate the purported degree of injury, duration of recovery, and reported survival rates. In mice and pigs, 3 h of ischemia induced severe, reliable injury extending into the crypt. However, at 48 h, mouse survival was only 23.5% compared with 100% survival in pigs. In literature, ischemia was induced for >1 h in only 4 of 102 mouse studies and none to 3 h. Recovery was attempted for 48 h in only six reports. Forty-seven studies reported intestinal crypt injury. Of those that featured histologic intestinal crypt damage, survival rates at 48 h ranged from 10 to 50% (median 30%). Mouse models are not ideal for studying intestinal stem cell-mediated recovery from severe IRI. Alternative large animal models, like pigs, are recommended.NEW & NOTEWORTHY Additional research is needed to improve recovery from severe intestinal ischemia. The selection of the ideal animal model is critical to facilitating this work. Based on our experimentation and literature review, porcine models, with increased translatability and an improved ability to survive both prolonged ischemia and the recovery period, appear to be the most appropriate choice for future studies.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A leading to the accumulation of globotriaosylceramide (Gb₃) and subsequent increase in globotriaosylsphingosine (lyso-Gb₃) in different cells and organs, including the gastrointestinal (GI) tract. GI symptoms represent some of the earliest manifestations of FD and significantly impact quality of life. The origin of these symptoms is complex, and the exact mechanisms remain poorly understood. Here, we sought to determine whether lyso-Gb₃ contributes to the pathophysiology of GI symptoms associated with FD by examining its effects on mouse colonic ion transport and motility ex vivo using Ussing chambers and organ baths, respectively. Lyso-Gb₃ significantly increased colonic baseline short-circuit current (I_sc). This increase in I_sc was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1, suggesting that the increase in I_sc is Cl^- ion independent. This response was also insensitive to inhibition by the neurotoxin, tetrodotoxin. In addition, pretreatment with lyso-Gb₃ did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb₃ does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb₃ did not significantly influence colonic tone, spontaneous contractility, or cholinergic-induced contractions. These data suggest that lyso-Gb₃ significantly influences ion transport in mouse colon, but that accumulation of Gb₃ may be a prerequisite for the more pronounced disturbances in GI physiology characteristic of FD.NEW & NOTEWORTHY Fabry disease-associated lyso-Gb₃ significantly influences mouse colonic ion transport in a Cl^- ion-independent manner.

This study was designed to investigate the effects of three hypoabsorptive bariatric surgeries, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), on bile acids (BAs) and to assess whether the changes in BA plasma levels were associated with the metabolic and homeostatic effects of the surgeries. Male Wistar rats, either fed a high- (HF) or a low-fat (LF) diet, were divided into seven groups: RYGB HF, BPD-DS HF, SADI-S HF, sleeve-gastrectomy (SG) HF, sham-operated (Sham) HF, Sham LF, and Sham HF-pair-weighed to BPD-DS (Sham HF-PW). The rats were treated for 56 days. The results demonstrate the ability of RYGB, BPD-DS, and SADI-S to raise plasma levels of BAs, whose elevations were likely due to changes in gene expression of transporters, enzymes, and receptors in the liver and small intestine. This increase, most notably of the secondary BAs (deoxycholic acid, ursodeoxycholic acid, and lithocholic acid), was negatively associated with body weight gain, fat gain, and fasting insulin levels, and positively with plasma peptide tyrosine-tyrosine (PYY). Plasma BAs also correlated positively with the fecal levels of Clostridium, Sutterella, and Enterobacteriaceae and negatively with Clostridiales_f_g_2, Christensenellaceae, Ruminococcaceae_g_2, Oscillibacter, and Oscillospira. In addition, they are associated positively with the short-chain fatty acid (SCFA) levels of propionate, butyrate, isobutyrate, valerate, and isovalerate. Altogether, the present study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce circulating BA elevations that predict the beneficial consequences of those hypoabsorptive bariatric surgeries on energy and glucose homeostasis and circulating levels of PYY. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are linked to significant fat losses and metabolic health improvements.NEW & NOTEWORTHY The study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce elevated circulating bile acids levels and changes in the gene expression of transporters, enzymes and receptors in the liver and small intestine, predicting positive effects on energy and glucose homeostasis as well as PYY levels. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are also linked to significant fat losses and metabolic health improvements. These findings provide valuable insights into the mechanisms underlying the positive effects of these surgical interventions.

Functional loss of the motor protein myosin Vb (MYO5B) induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, namely, microvillus inclusion disease (MVID). Utilizing the MVID model mice Vil1-Cre^ERT2;Myo5b^flox/flox (MYO5BΔIEC) and Vil1-Cre^ERT2;Myo5b^flox/G519R [MYO5B(G519R)], we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in the MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo, RNA sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, we reported that lysophosphatidic acid (LPA) signaling ameliorated epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrated that the highly soluble LPA receptor (LPAR)5-preferred agonist Compound-1 improved sodium transporter localization and absorptive function and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on the intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for the treatment of MVID symptoms induced by different point mutations in MYO5B.NEW & NOTEWORTHY This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, previously unexplored functions of MYO5B. The alterations may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID) intestines. To examine the therapeutic potential of progenitor-targeted treatments, the effects of the LPAR5-preferred agonist Compound-1 were investigated utilizing several MVID model mice and enteroids. Our observations suggest that Compound-1 may provide a therapeutic approach for treating MVID.

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 DSS-induced colitis mouse colon.

Methods: male C57BL/6N mice (12-week-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.

Results: in the motility study, veratridine-induced colonic contractions were significantly suppressed in DSS-induced colitis mice compared to 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 to 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 to normal mice. In addition, NOS inhibitor significantly enhanced veratridine-induced colonic contractions in DSS-induced colitis mice compared with normal mice.

Conclusions: 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.

Cyclic vomiting syndrome (CVS) is a disorder of brain-gut interaction characterized by recurrent episodes of nausea and vomiting interspersed with asymptomatic periods and associated with autonomic nervous system dysfunction. We examined the dysautonomic response to noxious stimuli seen in CVS patients using our previously validated approach to integrate peripheral autonomic outflow metrics, temporal summation of pain, and brain fMRI. BOLD fMRI and ECG were acquired from CVS patients and healthy adults during a rest condition and a sustained cuff pressure pain stimulus at the leg. After the latter scan, participants rated pain for the full 6-minute pain stimulus as well as first, middle, and last two-minutes to calculate temporal summation. During sustained pain, patients (n=13) exhibited greater reduction in heart rate variability within the high-frequency range (HF-HRV) and reduced anticorrelation between HF-HRV and fMRI signal in the anterior insula, pregenual anterior cingulate cortex, and ventrolateral and dorsolateral prefrontal cortex relative to healthy adults (n=13). Compared to healthy adults (n=14), patients (n=14) exhibited increasing pain intensity over the course of sustained cuff pressure. Seed-based functional connectivity analysis revealed for healthy adults (n=13), pain sensitization correlated with pain-induced increases in connectivity between primary somatosensory cortex and regions of interest in both left anterior insula/posterior orbitofrontal cortex and right pre-supplementary motor area, while this correlation was disrupted in CVS (n=10). Our results support altered central coding of nociceptive stimuli and autonomic responsivity of CVS patients in key brain regions implicated in autonomic control and interoception.