Rowe MC, Pettersson VL, Carbone SE
… +2 more, Gustafsson JK, Poole DP
Am J Physiol Gastrointest Liver Physiol
· 2025 Oct · PMID 40824870
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The mucus layer is an essential physical barrier that protects and lubricates mucosal surfaces in the body. The semipermeable nature of the mucus layer limits bacterial interactions with the epithelium while allowing nut...The mucus layer is an essential physical barrier that protects and lubricates mucosal surfaces in the body. The semipermeable nature of the mucus layer limits bacterial interactions with the epithelium while allowing nutrient absorption. Goblet cells (GCs) are specialized epithelial cells with a classical role to synthesize and secrete mucus to maintain the mucus layer. Emerging research has revealed the diverse nature of GC functions, including their interaction with the immune system through goblet cell-associated antigen passages to promote tolerance to dietary and bacterial antigens. Dysfunction of GCs or the mucus layer leaves the epithelium vulnerable to infection and is commonly associated with digestive disease. As such, there is a growing appreciation for the importance of GCs and the mucus layer to regulate mucosal homeostasis and protect against disease. Long-standing anatomical and pharmacological evidence indicates that the nervous system is a key regulator of GC function. However, the relative contribution from each division of the nervous system to the control of GC function is poorly defined. This is partly due to conflicting evidence from the literature and differences in experimental methods used. Furthermore, whether neurotransmitters influence GC functions and the associated mucus barrier directly or via indirect mechanisms, such as enhanced fluid secretion, remains unclear. The emergence of highly specific genetic approaches provides new opportunities to examine how specific nerve types can influence GC function. In this review, we consolidate the literature to date, with a focus on the stomach and lower gastrointestinal tract, and outline how current technologies may be useful to progress our fundamental understanding of neural-GC control.
Klatt EE, Hamdan FH, Pérez I
… +14 more, Smith HM, Kossick K, Fedyshyn Y, Sagstetter MR, Chiang D, Chini LCS, Davidson HM, Westphal MS, Gades NM, Mopuri R, Sun Z, Bamidele WO, Druliner BR, Faubion WA
Am J Physiol Gastrointest Liver Physiol
· 2025 Dec · PMID 40820933
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Mucosal homeostasis requires coordinated immune regulation and epithelial repair. Inflammatory bowel disease (IBD) arises from disrupted coordination between the immune system and intestinal epithelium, where resolution...Mucosal homeostasis requires coordinated immune regulation and epithelial repair. Inflammatory bowel disease (IBD) arises from disrupted coordination between the immune system and intestinal epithelium, where resolution and repair must occur in parallel. Interleukin-6 (IL-6) plays a dual role: it promotes epithelial regeneration but destabilizes regulatory T cells (Tregs). We aimed to determine the contribution of Treg IL-6 receptor (IL-6R) signaling to intestinal inflammation and epithelial integrity. We developed a conditional knockout mouse model in which IL-6R was deleted from Tregs (Treg IL-6R knockout). These mice were subjected to dextran sodium sulfate (DSS)-induced colitis and a T cell transfer model of colitis. Soluble IL-6R production by Tregs was assessed in vitro, and transcriptional changes in epithelial cells were analyzed by RNA-seq. Human colonic organoids from patients with IBD were treated with IL-6 or hyper-IL-6 (IL-6/sIL-6R fusion protein) to test downstream signaling effects. Tregs lacking IL-6R improved colitis to a similar extent as control Tregs in the adoptive transfer model, indicating intact suppressive function. However, Treg IL-6R knockout mice were more susceptible to DSS colitis than controls, suggesting a physiologic role for Treg IL-6R signaling in epithelial protection. In vitro, Tregs shed soluble IL-6R, enabling IL-6 trans-signaling to epithelial cells. Intestinal epithelial cells from Treg IL-6R knockout mice compared with WTcre controls revealed widespread transcriptional downregulation of genes related to survival and repair pathways at baseline, and impaired transcriptional responses following DSS treatment. In human organoids, IL-6 trans-signaling elicited stronger STAT3 activation than IL-6 alone. These findings reveal a previously unrecognized role for Treg-derived IL-6R in promoting epithelial resilience and maintaining mucosal homeostasis. This study reveals a novel role for Treg-derived IL-6R in supporting epithelial repair. Despite preserved immune-suppressive capacity, deletion of IL-6R from Tregs impairs epithelial transcription and worsens injury in colitis. We demonstrate that human intestinal organoids preferentially respond to trans- over classic IL-6 signaling. These findings introduce a Treg-specific role in immune-epithelial cross talk relevant to mucosal healing and inflammatory bowel disease.
The hypothesis of the development and origin of health and disease (DOHaD) highlights the relationship between exposure to harmful stimuli during pregnancy and the increased cardiometabolic risk in the offspring's adulth...The hypothesis of the development and origin of health and disease (DOHaD) highlights the relationship between exposure to harmful stimuli during pregnancy and the increased cardiometabolic risk in the offspring's adulthood. It is believed that the renin-angiotensin system (RAS) plays a central role in stress-induced hepatic programming. To determine the effects of prenatal stress, sex, and age on hepatic RAS of the offspring, pregnant Wistar rats were divided into control and stress groups. The unpredictable stress protocol was performed in the last week of pregnancy. The offspring were divided according to sex, age, and intervention. At 90 and 120 days, the offspring's blood and liver were collected to measure hepatic enzyme activity, isoprostane levels, and protein expression of the RAS and redox balance. At 90 days old, stress similarly reduced NOX4 in both sexes, whereas NOX2, NOX2/NOX4 ratio, and isoprostane were increased only in female offspring. Stress responses of NOX2 were still higher in females when compared with males. At 120 days, prenatal stress increased the activity of aspartate transaminase (AST) and alanine transaminase (ALT) in females, whereas it decreased AST in males. Furthermore, stress enhances the expression of angiotensin II type 1 receptor, ACE, and Mas receptor in males, whereas reducing NOX2/NOX4 ratio. Still, stress reduced ACE2 expression and continued to increase NOX2/NOX4 ratio in females at 120 days. Prenatal stress induces hepatic programming in offspring in a sex- and age-specific way, altering the RAS and NOX4 pathways at 120-day-old males while inducing early redox changes in females at 90 days and remaining at 120 days. Prenatal stress may contribute to sex- and age-specific programming of the liver in adult offspring. Our results showed that stress during pregnancy alters the hepatic renin-angiotensin system only at 120-days old and specially in male offspring. Furthermore, the prenatal stress leads to redox imbalances in females at 90 days and remaining at 120 days old independently of the renin-angiotensin system.
Nagahawatte ND, Du P, Zhang H
… +4 more, Patton HN, Rogers JM, Paskaranandavadivel N, Cheng LK
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40803705
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Gut motility is partly driven by underlying rhythmic electrical activity called slow waves. The origin and propagation of these electrical events are studied extensively in anesthetized animal models. However, the effect...Gut motility is partly driven by underlying rhythmic electrical activity called slow waves. The origin and propagation of these electrical events are studied extensively in anesthetized animal models. However, the effects of anesthesia on slow waves remain unclear. This study examined how propofol and isoflurane influence spatiotemporal features of gastric slow waves, anterior-posterior coupling, and the efficacy of gastric pacing. Pigs were anesthetized with propofol ( = 7) and isoflurane ( = 8), and baseline electrical activity was measured using high-resolution surface-contact electrode arrays placed on the anterior and posterior gastric serosa. Following baseline recordings, pacing was applied to assess its effects. Slow wave propagation patterns were quantified, and the efficacy of spatial entrainment during pacing was compared under propofol and isoflurane. Under propofol, antegrade propagation was observed with 86% symmetry between anterior and posterior gastric surfaces, whereas isoflurane reduced symmetry to 25% ( = 0.0187) with propagation patterns frequently changing. Slow wave period (18.8 ± 5.1 vs. 28.1 ± 14.3 s, = 0.016), amplitude (1.5 ± 0.7 vs. 0.7 ± 0.4 mV, = 0.002), and speed (4.4 ± 1.1 vs. 3.5 ± 0.7 mm/s, = 0.018) differed significantly between anesthetic groups at baseline, whereas only amplitude and speed differed during pacing. Spatial entrainment success was higher with propofol (83%) than with isoflurane (57%), but pacing effects remained localized to the paced surface without propagation across the greater curvature. Isoflurane induced more gastric dysrhythmias than propofol, making propofol preferable for studying normal activity and isoflurane preferred for investigating therapies. The uncoupling of anterior and posterior surfaces suggests a potential electrical barrier at the greater curvature, warranting further investigation. The influence of propofol and isoflurane on the spatial propagation of gastric slow wave activity under baseline and pacing conditions was defined for the first time. Slow waves were significantly ordered and coupled across the anterior and posterior surfaces of the stomach under propofol compared with isoflurane. Slow waves entrained during pacing were confined to the surface where pacing was applied, suggesting an electrical barrier along the greater curvature of the stomach.
Peixoto E, Pant K, Richard S
… +4 more, Popoca JP, Abrahante JE, Czaja W, Gradilone SA
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40796227
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Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary ci...Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and phosphorylated H2AX (γH2AX) quantification. An in vivo liver-specific IFT88 knockout model, generated using Albumin-Cre/Lox recombination, was used to study the loss of primary cilia in the liver. Results showed that RAD51 localized predominantly at the base of the cilium, whereas Ataxia Telangiectasia and Rad3-related protein (ATR), PARP1, CHK1, and CHK2 were also detected within the ciliary shaft. Deciliated cells displayed dysregulation in critical DNA repair pathways. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared with ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. In addition, key DDR proteins such as Ataxia Telangiectasia Mutated protein (ATM), p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA. Our study reveals a novel link between primary cilia and DNA repair in cholangiocytes. We show that DNA damage response (DDR) and repair proteins localize to cilia, and deciliation impairs survival and induces S-phase arrest under genotoxic stress. Deciliated cells exhibit increased DNA damage after cisplatin, irradiation, or methyl methanesulfonate (MMS) challenge. Following irradiation, Ataxia Telangiectasia Mutated protein (ATM), p53, and p21 are downregulated in deciliated cells. Similarly, IFT88 knockout mice show heightened DNA damage, highlighting the role of primary cilia in genome stability.
Skawratananond S, McCrea GE, Lie P
… +9 more, Buxton MB, Daly SP, Vojtkofsky NA, Smith SC, Zhang C, Hernandez M, Hindle A, Logsdon AF, Lawrence JJ
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40796226
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The human gastrointestinal tract harbors a vast and diverse microbial community, with the gut microbiome playing a fundamental role in numerous biological processes that influence overall health and disease progression....The human gastrointestinal tract harbors a vast and diverse microbial community, with the gut microbiome playing a fundamental role in numerous biological processes that influence overall health and disease progression. Emerging evidence has identified bacterial lipopolysaccharides in the hippocampus of patients with Alzheimer's disease (AD), highlighting the intricate relationship between the gastrointestinal tract, gut microbiome, and the central and enteric nervous systems-commonly referred to as the "microbiota-gut-brain axis." In this review, we explore the mechanisms by which the microbiota-gut-brain axis contributes to AD pathogenesis. We propose that sufficient levels of all-trans retinoic acid (ATRA), the bioactive form of vitamin A, enhance intestinal barrier integrity by upregulating tight junction proteins and modulating immune function through the induction of regulatory T-cell differentiation, thereby mitigating inflammation. Furthermore, dietary fiber complements this process by promoting the production of short-chain fatty acids, such as butyrate, via bacterial fermentation. Butyrate, in turn, acts as a histone deacetylase inhibitor, upregulating ATRA bioavailability by elevating aldehyde dehydrogenase gene expression. Our mechanistic framework is supported by the endotoxin hypothesis of AD, which maintains that the movement of infectious pathogens across the blood-brain barrier causes a vicious cycle of inflammation, a key factor of AD pathogenesis, leading to amyloid-β deposition, microglial activation, and CYP26A1-mediated ATRA degradation. Finally, we discuss microbiome-based therapeutic strategies and dietary interventions, including prebiotic compounds, probiotic bacteria, fecal microbiota transplantation, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and a combined approach featuring vitamins A/D and dietary fiber, as potential approaches to prevent progression to AD via the microbiota-gut-brain axis.
Jain AS, Breaux W, Robertson JK
… +6 more, Kim SE, McAdoo B, Keilin S, Fernandez F, Srinivasan S, Mittal RK
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40796219
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Hysteresis is a change in strain for a given repeated stress; it is a material property of the viscoelastic tissues. We aimed to determine hysteresis of the esophagogastric junction (EGJ) in patients with esophageal acha...Hysteresis is a change in strain for a given repeated stress; it is a material property of the viscoelastic tissues. We aimed to determine hysteresis of the esophagogastric junction (EGJ) in patients with esophageal achalasia and differences in EGJ hysteresis in different achalasia phenotypes. In a cross-sectional study design, we measured the change in EGJ distensibility index (DI) with repeated distensions (a marker of hysteresis) and the effects of atropine on the DI using functional lumen imaging probe in 40 patients with esophageal achalasia (types 1, 2, and 3). The DI increased significantly with second distension (hysteresis) as compared with first distension, but not with subsequent ones. Atropine, which ablates active smooth muscle contraction, had no effect on the DI value. Patients with type 1 esophageal achalasia and those with severe dilatation (stage III and IV disease) had a higher DI and lower hysteresis, as compared with esophageal achalasia subtypes 2 and 3. A low DI following atropine suggests that the passive elements (viscoelastic properties) of EGJ are an important cause of low DI in esophageal achalasia. Hysteresis of the EGJ, a material property of the viscoelastic tissue, is different in different achalasia subtypes. Hysteresis, a key biomechanical property of the esophagogastric junction (EGJ), may play a crucial role in achalasia pathogenesis. Using functional lumen imaging probe (FLIP) topography, we demonstrate that EGJ distensibility increases with repeated distensions, with subtype-dependent variability. Our findings suggest that hysteresis is associated with achalasia progression and treatment outcomes, offering novel insights into esophageal biomechanics. These results may guide refinements in FLIP-based diagnostics and inform future therapeutic approaches targeting determinants of hysteresis.
Willis NB, Mims TS, Antunes K
… +4 more, Peng H, Yen MI, Yen CE, Pierre JF
Am J Physiol Gastrointest Liver Physiol
· 2025 Oct · PMID 40789651
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Parenteral nutrition (PN) is a lifesaving intervention for patients unable to feed enterally but is often associated with parenteral nutrition-associated liver disease (PNALD), also called intestinal failure-associated l...Parenteral nutrition (PN) is a lifesaving intervention for patients unable to feed enterally but is often associated with parenteral nutrition-associated liver disease (PNALD), also called intestinal failure-associated liver disease (IFALD). This disease is characterized by steatosis, cholestasis, and elevated liver stress markers. Continuous PN induces hepatic injury through mechanisms including insulin resistance, lipotoxicity, systemic inflammation, and oxidative stress. Infusion cycling is known to ameliorate clinical markers of liver injury, but metabolic underpinnings have not been thoroughly investigated. Therefore, we modeled PN-induced liver injury in mice to investigate how differential infusion patterns impacted hepatic metabolism. Intermittent infusions protected against increased circulating alanine aminotransferase levels and improved histopathology to more closely resemble chow controls. Transcriptomic analyses revealed 804 differentially expressed genes between PN groups, highlighting pathways related to peroxisome proliferator-activated receptor signaling, fatty acid metabolism, and peroxisomes. Relative to the continuous group, intermittent PN infusion specifically downregulated , , , and ; transcripts involved in peroxisomal lipid oxidation, dicarboxylic acid synthesis, and one-carbon metabolism. This study suggests that infusion cycling may attenuate metabolic burden induced by alternate lipid oxidation pathways. Future work can therapeutically leverage these metabolic pathways to deepen our understanding of PNALD/IFALD and guide PN treatments to improve patient outcomes. This work demonstrated that the infusion schedule, independent of nutrient and caloric concentration, is a modulator of hepatic lipid metabolism in a novel murine model of parenteral nutrition. This cyclic infusion paradigm attenuated transcripts involved in microsomal and peroxisomal lipid oxidation, which were upregulated in the continuous infusion group. These data support the clinical use of cyclic infusion to improve hepatic parameters known to be adversely affected by parenteral nutrition.
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40767846
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In a recent publication, Nieves, et. al. define the role of microbiota-derived indole metabolites in a mouse model harboring a defined microbiota. The authors observed that exogenous administration of the tryptophan met...In a recent publication, Nieves, et. al. define the role of microbiota-derived indole metabolites in a mouse model harboring a defined microbiota. The authors observed that exogenous administration of the tryptophan metabolites indole propionic acid (IPA) to colitic mice significantly enhances intestinal barrier function. Further, the authors found that IPA independently stabilized components of the defined microbiota to enhance survival in the presence of established inflammation. This commentary summarizes these findings and discusses the implications of this work at a broader level.
Autosomal recessive polycystic kidney disease (ARPKD) is associated with cysts derived from abnormal bile ducts. We focused on targeting the cysts and show that a gene therapy for ARPKD that targets the abnormal bile duc...Autosomal recessive polycystic kidney disease (ARPKD) is associated with cysts derived from abnormal bile ducts. We focused on targeting the cysts and show that a gene therapy for ARPKD that targets the abnormal bile ducts is feasible. We injected 1-mo-old, mice intraperitoneally with 2 × 10 particles/kg of adeno-associated virus (AAV1) containing either a GFP vector or a truncated cystic fibrosis transmembrane conductance regulator (CFTR) vector, Δ27-264-CFTR, or left them untreated. Two months after treatment, the cyst area and size in the liver were lower in the CFTR vector-treated mice than in mice receiving the GFP vector. We detected vector genomes and mRNA expression only in mice receiving the corresponding CFTR or GFP vector. We observed abundant GFP immunofluorescence in the cholangiocytes of the cysts and also saw expression of GFP and CFTR proteins above background levels in the corresponding treated mice. CFTR immunofluorescence was predominantly apically located in the ARPKD cholangiocytes, but after CFTR vector installation, it increased in the basolateral membrane. We stained mouse livers with lectin (MAL) or lectin (SNA), specific for α2,3- and α2,6-N-linked sialic acid, respectively, to detect the presence of sialic acid moieties contributing to AAV1 binding. Although immunofluorescent SNA was detected in the wild-type bile ducts, MAL 1 was not. MAL immunofluorescence was present in remarkably high levels on the apical surfaces of the cysts in cholangiocytes, offering a good target for AAV gene therapy. A gene therapy using an AAV1-based vector containing a truncated CFTR could be therapeutic in ARPKD. Autosomal recessive polycystic kidney disease (ARPKD) causes severe disease in babies in the womb. Those who survive the neonatal period face chronic kidney and liver disease throughout their life. The overall goal of our study here is to develop a gene therapy to treat ARPKD.
polysaccharides (ATPS) were investigated for their protective effects against 5-fluorouracil (5-FU)-induced intestinal mucositis in intestinal epithelial cell 6 (IEC-6) cells and a murine model, with a focus on the role...polysaccharides (ATPS) were investigated for their protective effects against 5-fluorouracil (5-FU)-induced intestinal mucositis in intestinal epithelial cell 6 (IEC-6) cells and a murine model, with a focus on the role of β-arrestin1 (ARRB1) in endoplasmic reticulum stress (ERS) suppression. The study evaluated cell viability, apoptosis, inflammatory cytokine secretion (interleukin-1β, interleukin-6, tumor necrosis factor-α), and lactate dehydrogenase (LDH) release in IEC-6 cells, whereas diarrhea severity, body weight loss, intestinal histopathology, and tight junction protein expression were assessed in C57BL/6 mice. Western blot, immunohistochemistry, and transmission electron microscopy were used to investigate the underlying mechanisms of ATPS-mediated ERS inhibition. ATPS significantly improved cell survival and proliferation, reduced inflammatory cytokines and apoptosis, alleviated diarrhea severity, mitigated weight loss, and preserved intestinal barrier integrity by upregulating tight junction protein. Mechanistically, ATPS suppressed ERS activation by reducing glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α subunit (p-eIF2α), and C/EBP homologous protein (CHOP) expression, effects that were significantly attenuated in ARRB1-knockdown IEC-6 cells and mice, indicating that ARRB1 is essential for ATPS-mediated ERS suppression and intestinal protection. These findings suggest that ATPS protects against 5-FU-induced intestinal mucositis by modulating ARRB1 and inhibiting ERS, highlighting its potential as a novel therapeutic strategy for chemotherapy-induced intestinal injury. This study provides new insights into the therapeutic potential of ATPS in alleviating 5-FU-induced intestinal mucositis by modulating ARRB1 and suppressing ERS. The protective effects of ATPS were validated in both IEC-6 cells and a murine model, demonstrating its ability to enhance intestinal barrier integrity, inhibit apoptosis, and reduce inflammation. These findings suggest that ARRB1-mediated ERS suppression is a critical mechanism underlying ATPS-induced intestinal protection, presenting a novel strategy for mitigating chemotherapy-induced gastrointestinal toxicity.
Am J Physiol Gastrointest Liver Physiol
· 2025 Sep · PMID 40713026
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Traditional in vitro intestinal model systems frequently fail to accurately replicate human intestinal physiology for absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments. These limitations,...Traditional in vitro intestinal model systems frequently fail to accurately replicate human intestinal physiology for absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments. These limitations, coupled with the growing demand for faster drug discovery and high-throughput screening capabilities, have refined more physiologically relevant models. Recent advancements have led to the development of cell-based intestinal systems that better reflect in vivo conditions, ranging from monolayer and coculture models to complex three-dimensional (3-D) cell culture systems, microfluidic devices, and bioengineered models. This review provides a comprehensive overview of current progress, ongoing challenges, and future directions in developing and applying human in vitro intestinal models for chemical testing.
Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phosphoethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) synthesis. Whole body knockout mi...Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phosphoethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) synthesis. Whole body knockout mice were fed a high-fat diet (HFD) containing 45% kcal fat for 10 wk. female mice were resistant to HFD-induced obesity and had decreased liver weight compared with mice. Furthermore, female mice had improved glucose sensitivity and increased energy expenditure compared with mice. Plasma triglyceride (TG) levels were elevated in female mice, although the rate of very low-density lipoprotein (VLDL) secretion was not increased. The hepatic expression of PCSK9 was elevated, indicating a possible decrease in VLDL uptake. Interestingly, both plasma and hepatic cholesterol levels were reduced in relative to mice. No difference in hepatic phosphatidylcholine, PE, or TG was detected between groups. Histopathological examination of hepatic tissues revealed decreased lipid deposition in mice that may be explained by the lower hepatic cholesterol level. Additionally, RNA sequencing analysis showed upregulation in genes related to cholesterol metabolism in female mice. In male mice, a slight decrease in weight gain was observed in mice compared with mice. No change in plasma and hepatic lipid levels was detected in male mice. To conclude, ETNPPL impacts whole body energy expenditure, weight gain, cholesterol metabolism, and hepatic lipoprotein metabolism without altering hepatic phospholipid levels. female mice resisted diet-induced obesity with enhanced energy expenditure and less adipose tissue. In addition, female mice fed an HFD showed decreased liver cholesterol deposition. RNA sequencing revealed changes in genes related to cholesterol and lipid metabolism in female mice. female mice fed an HFD supplemented with cholesterol had no difference in plasma and hepatic cholesterol levels compared with mice.
The intestinal epithelium is in continual flux. It must balance maintaining a healthy microbiota with detecting and destroying intestinal pathogens. Intestinal stem cells (ISCs), which sit in the crypts below the intesti...The intestinal epithelium is in continual flux. It must balance maintaining a healthy microbiota with detecting and destroying intestinal pathogens. Intestinal stem cells (ISCs), which sit in the crypts below the intestinal villi, control this process. Depending on the molecular signals they receive, ISCs rapidly differentiate into the different intestinal epithelial cell subsets, making the intestine a remarkably adaptable organ. However, pathogens can hijack ISC functions to their advantage and establish infections. In this review, we explore the mechanisms used by pathogens to exploit ISCs.
Suther C, Hatch-McChesney A, Allen JT
… +12 more, Chakraborty N, Lawrence A, Moyler C, Dimitrov G, Gautam A, Hammamieh R, Gwin JA, Margolis LM, Hennigar SR, McClung JP, Pasiakos SM, Karl JP
Am J Physiol Gastrointest Liver Physiol
· 2025 Aug · PMID 40637323
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Host-gut microbiota interactions may impact intestinal function during sustained periods of high energy demands. Whether energy status, reflecting the balance between energy intake and expenditure, impacts those interact...Host-gut microbiota interactions may impact intestinal function during sustained periods of high energy demands. Whether energy status, reflecting the balance between energy intake and expenditure, impacts those interactions is unknown. This study determined the effects of energy status during sustained high-energy demands on intestinal function and the gut microbiota. Ten healthy men completed a randomized, crossover study that included baseline (BL) testing and two 72-hour periods of high physical activity-induced energy demands (HPA; ∼2,300 kcal/day physical activity energy expenditure) followed by a 7-day recovery period (REC). During HPA, diets designed to elicit a ∼45% energy deficit (DEF; -2,047 ± 920 kcal/day) or maintain energy balance within ±10% total daily energy expenditure (BAL; 689 ± 852 kcal/day) were provided. Intestinal permeability and transit time, fecal microbiota composition and gene content, fecal short-chain fatty acids (SCFAs), and gastrointestinal symptoms were measured. Intestinal permeability was 17% higher during HPA-DEF vs. HPA-BAL ( = 0.02), and colonic transit time was slower during HPA-DEF vs. HPA-BAL [mean difference (95% CI) = -764 min (-1,345, -183)] and BL [-643 min (-1,178, -108)] ( ≤ 0.02). Fecal microbiota species richness [-40 species (-66, -13), = 0.01] and relative abundances of multiple species (log fold difference < -5, < 0.02) were lower during HPA-BAL vs. HPA-DEF but did not differ between conditions during REC. Small bowel transit time, gastrointestinal symptoms, fecal microbiota gene pathways, and fecal SCFAs did not differ between conditions. Findings suggest that increasing dietary intake to prevent energy deficit may benefit intestinal health and function during short-term periods of high energy demands without sustained impacts on the gut microbiota. The effect of energy status on host-gut microbiota interactions impacting intestinal function during periods of high energy demands is unknown. Herein, increasing energy intake to prevent energy deficit during three days of high physical activity-induced energy demands prevented increases in intestinal permeability and transit time, and transiently reduced gut microbiota community richness without compromising community functional potential. Results suggest minimizing energy deficits may benefit gastrointestinal function during periods of high energy demands.
Gershner GH, Golubkova A, Dalton C
… +9 more, Schlegel C, Calkins C, Reuter DN, Learner M, Papin JF, Gurung S, Jonscher KR, Myers DA, Hunter CJ
Am J Physiol Gastrointest Liver Physiol
· 2025 Aug · PMID 40637163
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The Western diet (WD) has been associated with various pathologies, largely due to chronic inflammatory responses triggered by insulin spikes and excess cholesterol. However, the effects of maternal WD on offspring are c...The Western diet (WD) has been associated with various pathologies, largely due to chronic inflammatory responses triggered by insulin spikes and excess cholesterol. However, the effects of maternal WD on offspring are currently understudied. We hypothesize that maternal WD consumption in baboons induces a hyperinflammatory state in offspring, leading to compromised intestinal barrier function. Intestinal tissue was harvested from olive baboon () 0.9 gestation fetuses and juveniles (age 2-3 yr), whose mothers were fed either a high-fat/high-sugar WD or a control diet (CD) of standard monkey chow. RNA and protein were isolated and analyzed for markers of inflammation and apoptosis. Intestinal organoids (enteroids) were generated from these bowel samples and subsequently subjected to hypoxia and LPS to simulate necrotizing enterocolitis (NEC). RNA was extracted and similarly examined for inflammatory markers and markers of apoptosis. Enteroids were plated onto TransWellTM plates to evaluate barrier function. Immunohistochemistry and immunofluorescence were used to evaluate barrier proteins. The intestinal tissue of baboon fetuses and juveniles of mothers fed a Western diet exhibited evidence of a hyperinflammatory state. Although not all cytokines reached our significance set a priori at < 0.05, interleukin-8 (IL-8) and Interferon γ (IFNγ) were significantly elevated. This trend was stable across generations. Offspring from the Western diet group exhibited decreased barrier function based on transepithelial resistance measurements. Maternal consumption of a Western diet during gestation in olive baboons leads to a generalized inflammatory state and weakened intestinal barrier function in offspring, with potential long-term health implications. Our research examines a currently understudied area of the maternal/fetal relationship. This is especially pertinent, given the rampant access to high-fat/high-sugar foods in the Western diet. It is also noteworthy due to the findings of decreased barrier function among those in the Western diet group. This decreased function and hyperinflammatory state can prime neonates for various pathologies, such as necrotizing enterocolitis.