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 , , and and negatively with Clostridiales_f_g_2, , Ruminococcaceae_g_2, , and . 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. 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.

Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCC, a standardized extract of cultured Lentinula edodes mycelia produced by Amino Up Co., Ltd. (Sapporo, Japan)] has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCC on hepatic stellate cells, which are responsible for liver fibrosis. Eight-week-old male C57BL6/j mice were induced with liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCC to investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell (HHSteC) line, we analyzed the influence of AHCC on the expression of molecules related to hepatic stellate cell activation. The administration of AHCC resulted in reduced expression of collagen1a, α smooth muscle actin (αSMA), and heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCC inhibited αSMA by inducing cytoglobin via upregulating the stress-activated protein kinase/Jun NH-terminal kinase (SAPK/JNK) pathway through Toll-like receptor (TLR) 2. In addition, AHCC suppressed collagen1a production by hepatic stellate cells through TLR4-NF-κβ pathway. AHCC was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCC from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis. AHCC, a standardized extract of cultured mycelia, suppresses liver fibrosis progression by induction of cytoglobin via the Toll-like receptor 2 (TLR2)-stress-activated protein kinase/Jun NH-terminal kinase (SAPK/JNK) pathway and the inhibition of collagen production via the TLR4-NFκβ pathway in hepatic stellate cells. Daily oral administration of AHCC from the stage of MASLD may have the potential to prevent disease progression to MASH with fibrosis.

The postweaning period in pigs is a critical window where nutritional interventions are implemented to prevent postweaning diarrhea (PWD) and antibiotic use. One common strategy is feeding low-protein diets immediately following weaning. This intervention may reduce protein fermentation and pathogen proliferation, therefore decreasing the incidence of postweaning diarrhea. These effects may also be mitigated by providing dietary fiber. However, studies examining the role of protein and fiber on gastrointestinal microbiota and metabolism are complicated by the presence of other substrates, including polyphenols and antinutritional factors in complex ingredients. In this study, semipurified diets formulated to meet nutrient requirements were fed to 40 weaned pigs ( = 10/diet) to examine the effects of high protein (HP), high fiber (HF), or both (HFHP) compared with a control (CON) diet with industry-standard crude protein and fiber content. Critical alterations in host metabolism and cecal transcriptome were identified in response to the CON diet. Diets with lower protein levels (CON and HF) induced alteration in transcripts from the serine synthesis pathways and integrated stress response in cecal tissue alongside systemic increases in metabolic pathways related to lysine degradation. High protein diets did not induce increases in gastrointestinal pathogen abundance. These results challenge the practice of feeding low-protein diets postweaning, by demonstrating a detrimental effect on intestinal cell function and muscle accretion. This suggests that with careful ingredient selection, increased dietary protein postweaning could improve pig health and growth compared with a standard diet. Although low-protein diets are commonly used for weaned pigs and are thought to decrease diarrhea incidence, this study showed that low-protein diets may induce muscle catabolism and intestinal epithelial stress response. Eventhough high-protein diets increased protein fermentation by gut microbes, no increase in diarrhea was detected. Protein fermentation was mitigated by fiber while still supporting growth and intestinal epithelial cell function, suggesting new strategies for feeding weaned pigs with careful ingredient selection.

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.

Alzheimer's disease (AD) is a degenerative disease that causes a progressive decline in memory and thinking skills. Over the past few years, diverse studies have shown that there is no single cause of AD; instead, it has been reported that factors such as genetics, lifestyle, and environment contribute to the pathogenesis of the disease. In this sense, it has been shown that obesity during middle age is one of the most prominent modifiable risk factors for AD. Of the multiple potential mechanisms linking obesity and AD, the gut microbiota (GM) has gained increasing attention in recent years. However, the underlying mechanisms that connect the GM with the process of neurodegeneration remain unclear. Through this narrative review, we present a comprehensive understanding of how alterations in the GM of people with obesity may result in systemic inflammation and affect pathways related to the pathogenesis of AD. We conclude with an analysis of the relationship between GM and insulin resistance, a risk factor for AD that is highly prevalent in people with obesity. Understanding the crosstalk between obesity, GM, and the pathogenesis of AD will help to design new strategies aimed at preventing neurodegeneration.

knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 wk markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female KO mice, with the greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease. Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

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. 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 (Gb) and subsequent increase in globotriaosylsphingosine (lyso-Gb) 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-Gb 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-Gb significantly increased colonic baseline short-circuit current (). This increase in was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1, suggesting that the increase in is Cl ion independent. This response was also insensitive to inhibition by the neurotoxin, tetrodotoxin. In addition, pretreatment with lyso-Gb did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb did not significantly influence colonic tone, spontaneous contractility, or cholinergic-induced contractions. These data suggest that lyso-Gb significantly influences ion transport in mouse colon, but that accumulation of Gb may be a prerequisite for the more pronounced disturbances in GI physiology characteristic of FD. Fabry disease-associated lyso-Gb significantly influences mouse colonic ion transport in a Cl ion-independent manner.

Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults have been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when over-activated. The aim of this study is to explore the role of hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication or prevention. Here we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of IBD patients and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

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.

The cafeteria diet (CAF) is a superior diet model in animal experiments compared to the conventional high-fat diet (HFD), effectively inducing obesity, metabolic disturbances and multi-organ damage. Nevertheless, its impact on gut microbiota composition during the progression of obesity, along with its repercussions on the enteric nervous system (ENS) and gastrointestinal motility has not been completely elucidated. To gain more insight into the effects of CAF diet in the gut, C57BL/6 mice were fed with CAF or standard diet for 2 or 8 weeks. CAF-fed mice experienced weight gain, disturbed glucose metabolism, dysregulated expression of colonic IL-6, IL-22, TNFα and TPH1, and altered colon morphology, starting at week 2. Fecal DNA was isolated and gut microbiota composition was monitored by sequencing the V3-V4 16S rRNA region. Sequence analysis revealed that Clostridia and Proteobacteria were specific biomarkers associated with CAF-feeding at week 2, while Bacteroides, Actinobacteria were prominent at week 8. Additionally, the impact of CAF diet on ENS was investigated (week 8), where HuC/D+ neurons were measured and counted, and their biophysical properties were evaluated by patch-clamp. Gut contractility was tested in whole-mount preparations. Myenteric neurons in CAF-fed mice exhibited reduced body size, incremented cell density and decreased excitability. The amplitude and frequency of the rhythmic spontaneous contractions in colon and ileum were affected by the CAF diet. Our findings demonstrate, for the first time, that CAF diet gradually changes the gut microbiota and promotes low-grade inflammation, impacting the functional properties of myenteric neurons and gut contractility in mice.

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.

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with mood disorders, such as anxiety, has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4-exercise. Liver fibrosis was induced by CCl4 administration for 8 weeks, exercise was applied in the form of voluntary wheel running. After intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl4 increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl4 induced anxiety-like behavior, which was ameliorated by exercise training. In the hippocampus, CCl4-induced changes in mRNA and protein levels of factors related to anxiety, including BDNF and nNOS, were reversed by exercise. These results suggested that hepatic fibrosis-related anxiety-like behaviors are induced by excess hippocampal nNOS, and the beneficial effects of exercise were mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with anti-anxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.

Interleukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn's disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, raising the issue of neural modulation of the M(IL4)s reparative function. Thus, human (MIL4)s were treated with CGRP and the cells phagocytotic, epithelial wound repair and anti-colitic functions were assessed. Initial studies confirmed up-regulation of expression of the CGRP receptor, which was localized to the cell surface and was functional as determined by CGRP-evoked increases in cAMP. M(IL4,CGRP)s had increased mannose receptor (CD206) and FcgRIIa (CD32a) mRNA expression, a subtle, but significant increase in phagocytosis, and decreased chemokine production following exposure to . When delivered systemically (10 cells, ip.) to oxazolone-treated mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same blood donor. Conditioned medium (CM) from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM in the human CaCo2 epithelial cell line wounding assay. Moreover, M(IL4,CGRP)s displayed increased cyclooxygenase (COX)-1 and prostaglandin D, and CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers. These data confirm the human M(IL4)s' anti-colitic effect that was enhanced by CGRP, and may be partially dependent on macrophage COX1/PDG activity. Thus, input from neurone-derived molecules is a local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer.

Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, (MYO5B∆IEC) and (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 MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5B∆IEC small intestine. Consistent with these observations , 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, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5B∆IEC tissues and enteroids. The present study demonstrated that the highly soluble LPAR5-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 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 treatment of MVID symptoms induced by different point mutations in MYO5B.

The choline-deficient L-amino acid defined-high fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat and resmetirom.Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 weeks and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat or resmetirom were profiled as treatment intervention for 8 weeks, starting after 6 weeks of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 weeks, starting 3 weeks after CDAA-HFD diet feeding. Additionally, benefits of dietary intervention (chow reversal) for 8 weeks were characterized following 6 weeks of CDAA-HFD feeding. CDAA-HFD mice demonstrated a non-obese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 weeks of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention, but not as treatment intervention. Elafibranor was the only interventional drug to improve fibrosis. In comparison, chow-reversal resulted in complete steatosis regression with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.