• Fermentation
• Gene expression
• Poultry
• Short-chain fatty acids
• Sorghum

• Animals
• Sorghum/chemistry
• Chickens/growth & development
• Chickens/physiology
• Chickens/genetics
• Chickens/anatomy & histology
• Animal Feed/analysis
• Male
• Diet/veterinary
• Fermentation
• Jejunum/anatomy & histology
• Jejunum/drug effects
• Random Allocation
• Gene Expression/drug effects
• Animal Nutritional Physiological Phenomena/drug effects
• Tight Junctions/metabolism
• Dose-Response Relationship, Drug
• Fatty Acids, Volatile/metabolism
• Dietary Supplements/analysis

• Caco-2 cells
• TEER
• intestinal barrier integrity
• probiotics
• tight junctions

• 20XD1430100 Program of Shanghai Academic Technology Research Leader
• 2022013 Enterprise Innovation Development and Energy Upgrading Project of Municipal State-owned Assets Supervision and Administration Commission

• bacterial community
• chicken
• immunity
• mechanical barrier
• tannin

• microbes
• necrotizing enterocolitis (NEC)
• premature
• sepsis

• Infant
• Infant, Newborn
• Humans
• Enterocolitis, Necrotizing
• Gastrointestinal Microbiome
• Infant, Premature
• Infant, Newborn, Diseases
• Sepsis

• R35 GM141956 NIGMS NIH HHS
• T32 DK007713 NIDDK NIH HHS

• gut-brain axis
• microbiome
• necrotizing enterocolitis
• neonatal brain
• neurodevelopmental impairment
• perinatal brain injury

Older breeder chicks (OBC) are heavier and robust at hatch than younger breeder chicks (YBC). However, the implications of broiler breeder age on chick intestinal function and the role of functional feedstuffs are unexplored. We evaluated the effects of broiler breeder age and the impact of feeding YBC enzymatically treated yeast on growth, nutrient utilization, and indices of intestinal function. Fertile Ross 708 eggs: 2,250 (56.5 ± 3.4g) from 30-wk-old (YBC) and 550 (64.2 ± 4.2 g) from 47-wk-old (OBC) were hatched and placed in 48 pens (44 chicks/pen) containing equal males and females for growth and intestinal function evaluation and 36 cages (5 chicks/cage) for metabolizable energy (AME). Five corn and soybean meal-based diets were formulated to contain 0, 0.05, 0.10, 0.20, and 0.40% HY40 for a 3-phase feeding program (starter: days 0–10, grower: days 11–24, and finisher; days 25–42). Grower phase diets also contained a 0.3% TiO₂ indigestible marker. The diets were allocated within YBC in a completely randomized block design (n = 8 for pens; n = 6 for cages). The OBC were fed a 0% yeast diet. Feed and water were provided freely; BW and feed intake were monitored, and excreta samples were collected on days 17 to 21 for apparent retention (AR). Birds were necropsied for plasma, jejunal tissues, organs weight, and ceca digesta. The OBC were heavier (P < 0.01) than YBC at hatch. Final BW of OBC and YBC fed, ≥0.10% yeast, was similar (P > 0.05). The OBC had similar FCR (P > 0.05) to YBC fed 0 to 0.10% yeast but higher (P = 0.003) than for YBC fed ≥0.20% yeast. Jejunal villi height to crypt depth ratio (VCR) and IgA were higher in OBC than 0% yeast (P = 0.01). Yeast increased VCR, bursa weight, jejunal, and plasma IgA (P = 0.01). The YBC fed ≥0.10% yeast had higher (P < 0.05) AR of crude protein, and gross energy than OBC and YBC fed 0 or 0.05% yeast. In conclusion, yeast improved YBC performance to the level of OBC linked to improved intestinal function, integrity, and immunity.

The Wuji pill, also called Wuji Wan (WJW), is an effective traditional medicine for the clinical treatment of irritable bowel syndrome (IBS). It is principally composed of Rhizoma Coptidis, Fructus Evodiae Rutaecarpae, and Radix Paeoniae Alba. There have been no reports on the pharmacokinetics of WJW on IBS. Because it is more meaningful to study pharmacokinetics in relation to specific pathological conditions, our study investigated the pharmacokinetic differences of five representative components (berberine, palmatine, evodiamine, rutaecarpine, and paeoniflorin) in normal rats and chronic visceral hypersensitivity IBS (CVH-IBS) model rats after single dose and multiple doses of WJW using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Transmission electron microscopy, immunohistochemistry, and immunofluorescence were used to explore mechanisms behind the pharmacokinetic differences in terms of tight junction proteins (Occludin and ZO-1), myosin light chain kinase (MLCK), and transporters including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and multidrug resistance associated protein 2 (MRP2) in rat colons. After a single dose, for all components except rutaecarpine, significant differences were observed between normal and model groups. Compared with normal group, T_1/2 and AUC_0-t of berberine and palmatine in model group increased significantly (562.5 ± 237.2 vs. 1,384.9 ± 712.4 min, 733.8 ± 67.4 vs. 1,532.4 ± 612.7 min; 5,443.0 ± 1,405.8 vs. 9,930.8 ± 2,304.5 min·ng/ml, 2,365.5 ± 410.6 vs. 3,527.0 ± 717.8 min·ng/ml), while Cl/F decreased (840.7 ± 250.8 vs. 397.3 ± 142.7 L/h/kg, 427.7 ± 89.4 vs. 288.9 ± 114.4 L/h/kg). C_max and AUC_0-t of evodiamine in model group increased significantly (1.4 ± 0.6 vs. 2.4 ± 0.7 ng/ml; 573 ± 45.3 vs. 733.9 ± 160.2 min·ng/ml), while T_1/2, T_max, Cl/F, and Vd/F had no significant difference. T_max and AUC_0-t of paeoniflorin in model group increased significantly (21.0 ± 8.2 vs. 80.0 ± 45.8 min; 15,428.9 ± 5,063.6 vs. 33,140.6 ± 5,613.9 min·ng/ml), while Cl/F decreased (110.5 ± 48.1 vs. 43.3 ± 9.5 L/h/kg). However, after multiple doses, all five components showed significant differences between normal and model groups. Moreover, these differences were related to tight junction damage and the differential expression of transporters in the colon, suggesting that dose adjustment might be required during administration of WJW in the clinical treatment of IBS.

• National Natural Science Foundation of China

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.

• COVID
• Vitamin A
• Vitamin D
• barrier function
• claudin
• critical care
• inflammation
• micronutrient
• sepsis
• tight junction
• virus
• zinc

Heat stress (HS) alters the rumen fermentation of dairy cows thereby affecting the metabolism of rumen papillae and thus the epithelial barrier function. The aim of the present study was to investigate if HS damages the barrier function of ruminal epithelia. Eight multiparous Holstein dairy cows with rumen cannula were randomly equally allocated to two replicates (n = 4), with each replicate being subjected to heat stress or thermal neutrality and pair-feeding in four environmental chambers. Micromorphological observation showed HS aggravated the shedding of the corneum and destroyed the physical barrier of the ruminal epithelium to a certain extent. Transcriptomics analysis of the rumen papillae revealed pathways associated with DNA replication and repair and amino acid metabolism were perturbated, the biological processes including sister chromatid segregation, etc. were up-regulated by HS, while the MAPK and NF-kB cell signaling pathways were downregulated. However, no heat stress-specific change in the expression of tight junction protein or TLR4 signaling was found, suggesting that HS negatively affected the physical barrier of the ruminal epithelium to some extent but did not break the ruminal epithelium. Heat stress invoked mechanisms to maintain the integrity of the rumen epithelial barrier by upregulating the expression of heat shock protein and repairments in rumen papillae. The increase in amino acid metabolism in rumen papillae might affect the nutrient utilization of the whole body. The findings of this study may inform future research to better understand how heat stress affects the physiology and productivity of lactating cows and the development of mitigation strategies.

• dairy cow
• heat stress
• milk protein
• rumen fermentation
• ruminal epithelium

• Anti/pro-inflammatory cytokines
• Gut
• Inflammation
• Irritable bowel syndrome
• Therapy

• Anti-Inflammatory Agents/therapeutic use
• Cytokines/metabolism
• Cytokines/therapeutic use
• Humans
• Intestinal Mucosa
• Irritable Bowel Syndrome/drug therapy

Atopic dermatitis (AD) is the most common chronic skin inflammatory disease, with a profound impact on patients’ quality of life. AD varies considerably in clinical course, age of onset and degree to which it is accompanied by allergic and non-allergic comorbidities. Skin barrier impairment in both lesional and nonlesional skin is now recognized as a critical and often early feature of AD. This may be explained by a number of abnormalities identified within both the stratum corneum and stratum granulosum layers of the epidermis. The goal of this review is to provide an overview of key barrier defects in AD, starting with a historical perspective. We will also highlight some of the commonly used methods to characterize and quantify skin barrier function. There is ample opportunity for further investigative work which we call out throughout this review. These include: quantifying the relative impact of individual epidermal abnormalities and putting this in a more holistic view with physiological measures of barrier function, as well as determining whether these barrier-specific endotypes predict clinical phenotypes (e.g. age of onset, natural history, comorbidities, response to therapies, etc). Mechanistic studies with new (and in development) AD therapies that specifically target immune pathways, Staphylococcus aureus abundance and/or skin barrier will help us understand the dynamic crosstalk between these compartments and their relative importance in AD.

• Atopic dermatitis
• Skin barrier
• Stratum corneum
• Tight junctions
• Type 2 inflammation

• NF-kappaB (NF-κB)
• interleukin-1β (IL-1β)
• intestinal inflammation
• intestinal tight junction (TJ) barrier
• microRNA
• myosin light chain kinase (MLCK)

Systemic inflammatory response after cardiovascular surgery is associated with poor prognosis, to which gut barrier impairment is related. To investigate whether perioperative changes of the gut microbiome are associated with systemic and intestinal inflammatory response, we examined changes of the gut microbiome, intestinal homeostasis, and systemic inflammatory response in cardiovascular patients before (Pre) surgery and on the first defecation day [postoperative time 1 (Po1)] or a week [postoperative time 2 (Po2)] postsurgery. Markedly, the enhanced systemic inflammatory response was observed in Po1 and Po2 compared with that in Pre. In line with inflammatory response, impaired gut barrier and elevated gut local inflammation were observed in Po1 and Po2. Microbiome analysis showed a remarkable and steady decline of alpha diversity perioperatively. In addition, microbial composition in the postoperation period was characterized by significant expansion of Enterococcus along with a decrease in anaerobes (Blautia, Faecalibacterium, Bifidobacterium, Roseburia, Gemmiger, [Ruminococcus], and Coprococcus), which were typically health-associated bacteria. Spearman correlation analysis showed microbiome disorder was associated with enhanced systemic inflammatory response and intestinal dysbiosis. These results suggest that microbiome disorder was related to disturbed gut homeostatic and subsequently elevates plasma endotoxin and systemic inflammatory response after cardiovascular surgery. This study not only highlights gut microbiome would be considered in future clinical practice but also proposes a promising perspective of potential diagnostic and therapeutic options for perioperative management of cardiovascular surgery patients.

• cardiovascular diseases
• gut barrier
• gut local inflammation
• gut microbiome
• perioperation
• systemic inflammatory response

• Lactobacillus casei Zhang
• blood-milk barrier
• bovine mammary epithelial cells
• inflammatory response
• mastitis

• blood characteristics
• crude protein
• fecal score
• gene expression
• growth performance
• pigs

• NEC = necrotizing enterocolitis
• TL4 – Toll-like receptor 4
• microbiota (microorganism)
• pediatric sepsis
• prematurity and low birth weight

• Enterocolitis, Necrotizing/immunology
• Female
• Gastrointestinal Microbiome/immunology
• Humans
• Infant, Newborn
• Infant, Newborn, Diseases/immunology
• Infant, Premature/immunology
• Infant, Very Low Birth Weight/immunology
• Pregnancy
• Prenatal Exposure Delayed Effects/immunology

• R01 DK121824 NIDDK NIH HHS

Graphene oxide (GO), a novel carbon-based nanomaterial, has promising applications in biomedicine. However, it induces potential cytotoxic effects on the gastrointestinal (GI) tract cells, and these effects have been largely uncharacterized. The present study aimed to explore the toxic effects of GO on the intestinal tract especially under pre-existing inflammatory conditions, such as inflammatory bowel disease (IBD), and elucidate underlying mechanisms.

Our findings indicated that oral gavage of GO worsened acute colitis induced by 2.5% dextran sodium sulfate (DSS) in mice. In vitro, GO exacerbated DSS-induced inflammation and apoptosis in the FHC cell line, an ideal model of intestinal epithelial cells (IECs). Further, the potential mechanism underlying GO aggravated mice colitis and cell inflammation was explored. Our results revealed that GO treatment triggered apoptosis in FHC cells through the activation of reactive oxygen species (ROS)/AMP-activated protein kinase (AMPK)/p53 pathway, as evidenced by the upregulation of cytochrome c (Cytc), Bax, and cleaved caspase-3 (c-cas3) and the downregulation of Bcl-2. Interestingly, pretreatment with an antioxidant, N-acetyl-L-cysteine, and a specific inhibitor of AMPK activation, Compound C (Com.C), effectively inhibited GO-induced apoptosis in FHC cells.

Our data demonstrate that GO-induced IECs apoptosis via ROS/AMPK/p53 pathway activation accounts for the exacerbation of colitis in vivo and aggravation of inflammation in vitro. These findings provide a new insight into the pathogenesis of IBD induced by environmental factors. Furthermore, our findings enhance our understanding of GO as a potential environmental toxin, which helps delineate the risk of exposure to patients with disturbed intestinal epithelial barrier/inflammatory disorders such as IBD.

• AMP-activated protein kinase
• Apoptosis
• Colitis
• Graphene oxide
• Intestinal epithelial cell
• Reactive oxygen species

• Aging/physiology
• Animals
• Avian Proteins/biosynthesis
• Avian Proteins/genetics
• Chickens/growth & development
• Female
• Intestinal Mucosa/metabolism
• Male
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tight Junction Proteins/biosynthesis
• Tight Junction Proteins/genetics
• Tight Junctions/genetics
• Tight Junctions/metabolism

• P 30140 Austrian Science Fund FWF
• Austrian Science Fund

• Intestinal injury
• Maltodextrin
• Necrotizing enterocolitis
• Neonatal mouse model

• Animals
• Animals, Newborn
• Cytokines/metabolism
• Disease Models, Animal
• Enterocolitis, Necrotizing/chemically induced
• Enterocolitis, Necrotizing/metabolism
• Enterocolitis, Necrotizing/microbiology
• Enterocolitis, Necrotizing/pathology
• Goblet Cells/metabolism
• Goblet Cells/microbiology
• Goblet Cells/pathology
• Hypoxia/complications
• Inflammation Mediators/metabolism
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology
• Intestine, Small/metabolism
• Intestine, Small/microbiology
• Intestine, Small/pathology
• Klebsiella pneumoniae/pathogenicity
• Mice, Inbred C57BL
• Microvilli/pathology
• Mucin-2/metabolism
• Permeability
• Polysaccharides
• Tight Junction Proteins/metabolism

• R01 DK104346 NIDDK NIH HHS
• Charles H. Hood Foundation
• National Institutes of Health

Many functions of the immune system are impaired in neonates, allowing vulnerability to serious bacterial, viral and fungal infections which would otherwise not be pathogenic to mature individuals. This vulnerability is exacerbated in compromised newborns such as premature neonates and those who have undergone surgery or who require care in an intensive care unit. Higher susceptibility of preterm neonates to infections is associated with delayed immune system maturation, with deficiencies present in both the innate and adaptive immune components. Here, we review recent insights into early life immunity, and highlight features associated with compromised newborns, given the challenges of studying neonatal immunity in compromised neonates due to the transient nature of this period of life, and logistical and ethical obstacles posed by undertaking studies newborns and infants. Finally, we highlight how the unique immunological characteristics of the premature host play key roles in the pathogenesis of diseases that are unique to this population, including necrotizing enterocolitis and the associated sequalae of lung and brain injury.

• intestinal epithelial barrier
• lymphocytes
• necrotizing enterocolitis
• neonatal immunity
• regulatory lymphocytes
• sepsis
• toll like receptors

• Campylobacter spp.
• Epithelial translocation
• Gut health
• Intracellular survival
• Virulence

• Animals
• Biocompatible Materials/metabolism
• Biological Availability
• Drug Delivery Systems
• Epithelial Cells/metabolism
• Humans
• Permeability
• Tight Junctions/drug effects
• Tight Junctions/metabolism

• DP2 DK111910 NIDDK NIH HHS

• Beclin-1
• VDR
• colonoids
• enteroids
• inflammation

• blood–bile barrier (bblb)
• liver tight junction
• adherens junction
• paracellular space
• hepatocyte polarity

• Animals
• Bile Canaliculi/anatomy & histology
• Bile Canaliculi/blood supply
• Blood Vessels/anatomy & histology
• Hepatocytes/physiology
• Humans
• Intercellular Junctions
• Liver/anatomy & histology
• Liver/blood supply
• Liver/physiopathology
• Liver Diseases/blood
• Liver Diseases/pathology
• Liver Diseases/physiopathology

• R01 CA204586 NCI NIH HHS
• R01 DK062277 NIDDK NIH HHS
• R01 DK100287 NIDDK NIH HHS

• TEER
• anti-inflammatory cytokines
• eleutheroside B
• intestinal epithelial permeability
• tight junction proteins

• chronic kidney disease
• dysbiosis
• gut microbiota
• inflammation oxidative stress
• prebiotics
• probiotics
• synbiotics

• Molecular mechanism
• Permeation enhancement
• Preactivated thiomers
• Thiomers
• Tight junctions opening

• Colon epithelial barrier
• Microtus ochrogaster
• Prairie voles
• Tight junctions

• Animals
• Arvicolinae/anatomy & histology
• Arvicolinae/growth & development
• Intestinal Mucosa/growth & development
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/ultrastructure
• Permeability
• Tight Junctions/ultrastructure

Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects. There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to chronic infectious diseases. HIV-infected (HIV+) older adults show age-related co-morbidities at a younger age than their uninfected counterparts. Persistent inflammation related to the chronic viral infection and its sequelae is thought to contribute to this disparity. However, little is known about whether fish oil reduces intestinal inflammation in HIV + patients. We measure inflammation and gut barrier function in HIV + older adults (median age = 52, N = 33), following 12 weeks of fish oil supplementation (a total daily dose of 1.6 g of omega-3 fatty acids). We showed a reduction in inflammation and gut permeability as measured by CD14, inflammatory cytokines, lipopolysaccharide, and lipopolysaccharide binding protein. The results indicate that older HIV + adults may benefit from a diet supplemented with the omega-3 fatty acids found in fish oil.

• HIV
• Inflammation
• Intestinal epithelium
• LPS binding protein (LBP)
• Lipopolysaccharide (LPS)
• Omega 3 fatty acids
• Tight junctions
• Zonulin

Over the years, the scientific community has explored myriads of theories in search of the etiology and a cure for inflammatory bowel disease (IBD). The cumulative evidence has pointed to the key role of the intestinal barrier and the breakdown of these mechanisms in IBD. More and more scientists and clinicians are embracing the concept of the impaired intestinal epithelial barrier and its role in the pathogenesis and natural history of IBD. However, we are missing a key tool that bridges these scientific insights to clinical practice. Our goal is to overcome the limitations in understanding the molecular physiology of intestinal barrier function and develop a clinical tool to assess and quantify it. This review article explores the proteins in the intestinal tissue that are pivotal in regulating intestinal permeability. Understanding the molecular pathophysiology of impaired intestinal barrier function in IBD may lead to the development of a biochemical method of assessing intestinal tissue integrity which will have a significant impact on the development of novel therapies targeting the intestinal mucosa.

• inflammatory bowel disease
• intestinal barrier function

• Estrogen
• Estrogen receptors
• Gastrointestinal tumors
• Intestinal inflammation
• Mucosal barrier

• Animals
• CD11c Antigen/immunology
• Cells, Cultured
• Hyperalgesia/immunology
• Hyperalgesia/parasitology
• Hyperalgesia/pathology
• Inflammation/immunology
• Inflammation/parasitology
• Inflammation/pathology
• Intestinal Absorption
• Intestinal Mucosa/immunology
• Intestinal Mucosa/parasitology
• Intestinal Mucosa/pathology
• Irritable Bowel Syndrome/immunology
• Irritable Bowel Syndrome/parasitology
• Irritable Bowel Syndrome/pathology
• Male
• Mice
• Mononuclear Phagocyte System/immunology
• Mononuclear Phagocyte System/parasitology
• Mononuclear Phagocyte System/pathology
• Mucous Membrane/cytology
• Mucous Membrane/immunology
• Mucous Membrane/parasitology
• Mucous Membrane/pathology
• Trichinella spiralis/immunology
• Trichinellosis/immunology
• Trichinellosis/parasitology
• Trichinellosis/pathology
• Viscera/immunology
• Viscera/parasitology
• Viscera/pathology

• CK8
• TLR4
• colitis
• colitis-associated colorectal cancer
• gut microbiota

Colonization and disruption of the epithelium is a major infection mechanism of mucosal pathogens. The epithelium counteracts infection by exfoliating damaged cells while maintaining the mucosal barrier function. The sexually transmitted bacterium Neisseria gonorrhoeae (GC) infects the female reproductive tract primarily from the endocervix, causing gonorrhea. However, the mechanism by which GC overcome the mucosal barrier remains elusive. Using a new human tissue model, we demonstrate that GC can penetrate into the human endocervix by inducing the exfoliation of columnar epithelial cells. We found that GC colonization causes endocervical epithelial cells to shed. The shedding results from the disassembly of the apical junctions that seal the epithelial barrier. Apical junction disruption and epithelial exfoliation increase GC penetration into the endocervical epithelium without reducing bacterial adherence to and invasion into epithelial cells. Both epithelial exfoliation and junction disruption require the activation and accumulation of non-muscle myosin II (NMII) at the apical surface and GC adherent sites. GC inoculation activates NMII by elevating the levels of the cytoplasmic Ca²⁺ and NMII regulatory light chain phosphorylation. Piliation of GC promotes, but the expression of a GC opacity-associated protein variant, OpaH that binds to the host surface proteins CEACAMs, inhibits GC-induced NMII activation and reorganization and Ca²⁺ flux. The inhibitory effects of OpaH lead to reductions in junction disruption, epithelial exfoliation, and GC penetration. Therefore, GC phase variation can modulate infection in the human endocervix by manipulating the activity of NMII and epithelial exfoliation.

Neisseria gonorrhoeae (GC) infects human genital epithelium causing gonorrhea, a common sexually transmitted infection. Gonorrhea is a critical public health issue due to increased prevalence of antibiotic-resistant strains. Because humans are the only host for GC, a lack of a human infection model has been a major obstacle to our understanding of GC infection. Here we use a human tissue explant model to examine the mechanism by which GC infect the human endocervix, the primary site for GC infection in women. We show that GC penetrate into the human endocervix by activating the actin motor myosin and epithelial shedding. Myosin activation causes the disruption of the endocervical epithelial barrier by inducing apical junction disassembly and epithelial cell shedding, allowing GC penetration into the human endocervical tissue. GC activate myosin by inducing Ca²⁺-dependent phosphorylation of myosin light chain. We further show that GC can enhance and reduce the penetration by expressing pili and the opacity-associated protein that promotes and inhibits myosin activation, respectively. Our study is the first demonstration of GC penetration into the human endocervix. Our results provide new insights into the mechanism by which GC manipulate signaling and cytoskeletal apparatus in epithelial cells to achieve penetrating and non-penetrating infection.

• Bacterial Adhesion
• Calcium/metabolism
• Cervix Uteri/microbiology
• Cervix Uteri/pathology
• Epithelial Cells/microbiology
• Epithelial Cells/pathology
• Epithelium/microbiology
• Epithelium/pathology
• Female
• Gonorrhea/microbiology
• Humans
• Intercellular Junctions/microbiology
• Intercellular Junctions/pathology
• Mucous Membrane/microbiology
• Mucous Membrane/pathology
• Myosin Type II/metabolism
• Neisseria gonorrhoeae/pathogenicity

• R01 AI123340 NIAID NIH HHS
• National Institute of Allergy and Infectious Diseases

• BDNF
• IBS
• intestinal barrier
• tight junction proteins

• Animals
• Brain-Derived Neurotrophic Factor/pharmacology
• Dose-Response Relationship, Drug
• Gene Expression
• HT29 Cells
• Humans
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Tight Junction Proteins/biosynthesis
• Tight Junction Proteins/genetics

Estrogens are the key hormones regulating the development and function of reproductive organs in all vertebrates. Recent evidence indicates that estrogens play important roles in the immune system, cancer development, and other critical biological processes related to human well-being. Obviously, the gonads (ovary and testis) are the primary sites of estrogen synthesis, but estrogens synthesized in extra- gonadal sites play an equally important role in controlling biological activities. Understanding non-gonadal sites of estrogen synthesis and function is crucial and will lead to therapeutic interventions targeting estrogen signaling in disease prevention and treatment. Developing a rationale targeting strategy remains challenging because knowledge of extra-gonadal biosynthesis of estrogens, and the mechanism by which estrogen activity is exerted, is very limited. In this review, we will summarize recent discoveries of extra-gonadal sites of estrogen biosynthesis and their local functions and discuss the significance of the most recent novel discovery of intestinal estrogen biosynthesis. [BMB Reports 2016; 49(9): 488-496]

• Intestinal barrier function
• Necrotizing enterocolitis
• Occludin
• Tight junction

• Enterocolitis, Necrotizing/metabolism
• Enterocolitis, Necrotizing/physiopathology
• Female
• Humans
• Infant
• Infant, Newborn
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/physiopathology
• Intestine, Small/metabolism
• Intestine, Small/physiopathology
• Male
• Myosin-Light-Chain Kinase/biosynthesis
• Occludin/biosynthesis
• Permeability
• RNA, Messenger/biosynthesis
• Tight Junctions/metabolism

• K01 DK100562 NIDDK NIH HHS
• R01 DK064165 NIDDK NIH HHS

The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn's disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

• Enterobacteriaceae
• Environmental Exposure/statistics & numerical data
• Humans
• Microbiota
• Sanitation

• C. elegans apical junction
• PAR proteins
• atypical protein kinase C
• brush border
• cytokeratin
• desmosome
• endotube
• keratin
• γ-tubulin ring complex

AIM: To study whether the inflammatory bowel disease (IBD) colon which exhibits varying severity and cytokine levels across its mucosa create varying types of transepithelial leak.

METHODS: We examined the effects of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1-β (IL1β) and hydrogen peroxide (H₂O₂) - singly and in combinations - on barrier function of CACO-2 cell layers. Our focus was on the type (not simply the magnitude) of transepithelial leak generated by these agents as measured by transepithelial electrical resistance (TER) and transepithelial flux of ¹⁴C-D-mannitol, ³H-Lactulose and ¹⁴C-Polyethylene glycol as radiolabeled probe molecules. The isoquinoline alkaloid, berberine, was then examined for its ability to reduce specific types of transepithelial leak.

RESULTS: Exposure to TNF-α alone (200 ng/mL; 48 h) induced a 50% decrease in TER, i.e., increased leak of Na⁺ and Cl^- - with only a marginal but statistically significant increase in transepithelial leak of ¹⁴C-mannitol (J_m). Exposure to TNF-α + IFN-γ (200 ng/mL; 48 h) + IL1β (50 ng/mL; 48 h) did not increase the TER change (from TNF-α alone), but there was now a 100% increase in J_m. There however was no increase in transepithelial leak of two larger probe molecules, ³H-lactulose and ¹⁴C-polyethylene glycol (PEG). However, exposure to TNF-α + IFN-γ + IL1β followed by a 5 h exposure to 2 mmol/L H₂O₂ resulted in a 500% increase in ¹⁴C-PEG leak as well as leak to the luminal mitogen, epidermal growth factor.

CONCLUSION: This model of graded transepithelial leak is useful in evaluating therapeutic agents reducing IBD morbidity by reducing barrier leak to various luminal substances.

• Intestine
• Crohn’s disease
• Tight junction
• Ulcerative colitis
• CACO-2
• Berberine
• Micronutrient
• Cytokine

• Barrier function
• Enteric nervous system
• Epithelial integrity
• Intestinal permeability
• Paracellular transport
• Tight junctions
• Transport routes