Mucosal Integrity Research Articles

5S-Heudelotinone alleviates experimental colitis by shaping the immune system and enhancing the intestinal barrier in a gut microbiota-dependent manner

Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5S-heudelotinone (an enantiomer) as a potent agent against experimental colitis that acts by modulating the gut microbiota. 5S-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids (SCFAs); thus, it regulates the intestinal immune system by reducing proinflammatory immune cell numbers, and maintains intestinal mucosal integrity by modulating tight junctions (TJs). Moreover, 5S-heudelotinone (2) ameliorates colitis-associated colorectal cancer (CAC) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced in situ carcinoma model. Together, these findings reveal the potential of a novel natural product, namely, 5S-heudelotinone, to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.

Nutritional effects on mucosal integrity and immune function

The intestinal mucosal barrier plays a critical role in maintaining the integrity of the gastrointestinal (GI) tract and protecting the body from harmful toxins and pathogens. Nutrition additionally serves as a vital component in maintaining bodily homeostasis. Macronutrients, micronutrients, and specific dietary habits exert profound effects on the immune system. The complex interactions of the immune system reflect a multifaceted, integrated epithelial and immune cell-mediated regulatory system. While several factors can influence the intestinal mucosal barrier and its pro- and anti-inflammatory processes, such as myeloid cell, regulatory T cell (Treg), or intraepithelial lymphocyte populations, there is growing evidence that macronutrients play an essential role in regulating its function. Herein this is a review of the peer-reviewed literature pertaining to dietary effects on mucosal integrity, including intraepithelial lymphocyte populations and immune function. This review is intended to explore the underlying mechanisms by which macronutrients impact and modulate the mucosal immune system.

The Interaction between Stress and Inflammatory Bowel Disease in Pediatric and Adult Patients.

Background: Inflammatory bowel diseases (IBDs) have seen an exponential increase in incidence, particularly among pediatric patients. Psychological stress is a significant risk factor influencing the disease course. This review assesses the interaction between stress and disease progression, focusing on articles that quantified inflammatory markers in IBD patients exposed to varying degrees of psychological stress. Methods: A systematic narrative literature review was conducted, focusing on the interaction between IBD and stress among adult and pediatric patients, as well as animal subjects. The research involved searching PubMed, Scopus, Medline, and Cochrane Library databases from 2000 to December 2023. Results: The interplay between the intestinal immunity response, the nervous system, and psychological disorders, known as the gut-brain axis, plays a major role in IBD pathophysiology. Various types of stressors alter gut mucosal integrity through different pathways, increasing gut mucosa permeability and promoting bacterial translocation. A denser microbial load in the gut wall emphasizes cytokine production, worsening the disease course. The risk of developing depression and anxiety is higher in IBD patients compared with the general population, and stress is a significant trigger for inducing acute flares of the disease. Conclusions: Further large studies should be conducted to assess the relationship between stressors, psychological disorders, and their impact on the course of IBD. Clinicians involved in the medical care of IBD patients should aim to implement stress reduction practices in addition to pharmacological therapies.

Dietary Protein Quality Affects the Interplay between Gut Microbiota and Host Performance in Nile Tilapia.

Dietary protein quality plays a key role in maintaining intestinal mucosal integrity, but also modulates the growth of luminal microorganisms. This work assessed the effect of dietary protein sources on the performance, gut morphology, and microbiome in Nile tilapia. Four isonitrogenous and isolipidic diets comprising equivalent amounts of the protein supply derived from either PLANT, ANIMAL, INSECT, or BACTERIAL (bacterial biomass) sources were fed to triplicate groups of fish (IBW: 12 g) for 46 days. Fish fed the ANIMAL and BACTERIAL diets showed significantly higher weight gains than those fed the PLANT and INSECT diets (p < 0.05). Relative abundance at the phylum level showed that Bacteroidetes, Fusobacteria, and Proteobacteria were the more abundant phyla in tilapia's intestine, while Cetobacterium was the most representative genus in all treatments. Interesting patterns were observed in the correlation between amino acid intake and genus and species abundance. Metabolism prediction analysis showed that BACTERIAL amine and polyamine degradation pathways are modulated depending on diets. In conclusion, different protein sources modulate the relationship between bacteria functional pathways and amino acid intake.

Structural and functional abnormalities of the tongue: An epidemiological study from a tertiary care center in India.

The tongue is a prominent muscular organ of the oral cavity and the integrity of the tongue mucosa frequently can reflect the overall health of an individual. Many notable structural and functional alterations can affect the tongue. These changes may be symptomatic or asymptomatic. Hence, the aim of the study was to determine the prevalence of structural and functional abnormalities of the tongue in a population reporting to a tertiary care center. We also assessed the prevalence of the normal variants and evaluated the normal tongue protrusion measurement in the study population. The cross-sectional study included 1,143 dental outpatients above 18 years of age who visited the Department of Oral Medicine and Radiology between October 2021 to February 2022. Demographic details of the patients were noted. Participants were asked questions regarding any symptoms or abnormalities noticed on the tongue. The tongue was examined thoroughly for any structural/ functional abnormalities. The maximal tongue protrusion for each participant was measured by asking them to extend their tongue out. Medical history, drug history, and social history were recorded. The study included 564 male and 579 female participants; tongue lesions were positive in 66.5% of the study population. Coated tongue (26.2%) was the most frequent structural abnormality that was noted in the present study. Taste dysfunction (4.6%) was the most frequent functional abnormality. The lesions were mostly in the anterior two-thirds (4.2%) of the tongue. Functional abnormalities of the tongue were noted in 8.7% of the study participants. The results of the present study showed that structural and functional abnormalities of the tongue were present in 66.5% of the population. Careful and detailed evaluation of the tongue examination is mandated in routine dental checkups. This shall help in the prompt identification of various etiological factors causing structural and functional abnormalities of the tongue.

Antiulcer activity of Mauritia flexuosa L.f. (Arecaceae) pulp oil: An edible Amazonian species with functional properties

Mauritia flexuosa, known as buriti in Brazil, is a widespread palm tree in Amazonia. It has many ethnobotanical uses, including food, oil, and medicine. The oil obtained from buriti's fruit pulp has high levels of monounsaturated fatty acids, carotenoids, and tocopherols, and is used in the food, cosmetic, and pharmaceutical industries for its antioxidant properties. Many biological activities have been reported for buriti oil, such as antioxidant, antimicrobial, chemopreventive, and immunomodulatory. Due to its high content of bioactive compounds, buriti oil is considered a functional ingredient with possible benefits in preventing oxidative stress and chronic diseases, particularly in the gastrointestinal tract. Peptic ulcer disease is a multifactorial disorder, involving lesions in the stomach and duodenum mucosa, which has a complex healing process. In this context, some nutrients and bioactive compounds help the maintenance of gastrointestinal mucosal integrity and function, such as carotenoids, tocopherols, and unsaturated fatty acids, which makes buriti oil an interesting candidate to be used in the prevention and management of gastrointestinal diseases. This study aimed to evaluate the gastroprotective and antiulcer effects of buriti oil and its possible mechanisms of action. Buriti oil reduced the ulcerative area and lipid peroxidation induced by ethanol. The gastroprotective activity of buriti oil partially depends on nitric oxide and sulfhydryl compounds. In acetic acid-induced gastric ulcers, buriti oil accelerated healing and stimulated the formation of new gastric glands. These results demonstrated the potential of buriti oil as a functional ingredient to promote health benefits in the gastrointestinal tract.

Alpha-Linolenic Acid Ameliorates Cognitive Impairment and Liver Damage Caused by Obesity.

Obesity is a growing global problem that causes various complications such as diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease. Alpha-linolenic acid (ALA) has been reported to exhibit multiple pharmaceutical effects. This study aimed to explore the effects of ALA on obesity-induced adipose tissue accumulation, cognitive impairment, inflammation, and colonic mucosal barrier integrity. Mice were fed with high-fat diet (HFD) and were treated with ALA (60 or 100 mg/kg). Body weight, adipose tissue, serum glucose and lipid levels, glucose resistance, and insulin resistance were measured. Cognitive ability was analyzed using the behavior tests. PTP1B and IRS/p-AKT/p-GSK3β/p-Tau signaling were examined to evaluate inflammation and synaptogenesis. Colon mucosal barrier integrity was examined by Alcian blue staining and expression of the tight junction proteins. The production of pro-inflammatory cytokines and liver damages were evaluated. 3T3-L1 cells were used for in vitro experiments. Cell viability, migration and invasion were detected. The levels of ROS, iron, and ferrous ions were measured to assess ferroptosis. Metabolomic analysis of adipose tissues was performed. ALA treatment prevented HFD-induced adipose tissue accumulation, improved glucose and lipid homeostasis and metabolism. Administration of ALA repressed the HFD-induced increase in insulin levels and insulin resistance index. Serum and colon levels of pro-inflammatory cytokines were decreased after ALA treatment. ALA elevated mitochondrial content in brown adipose tissues. ALA ameliorated obesity-induced cognitive impairment and hippocampal inflammation, enhanced colon mucosa integrity. ALA treatment ameliorated HFD-induced liver damage and lipid accumulation and inhibited differentiation of preadipocyte 3T3-L1 cells into mature adipocytes and induces ferroptosis. Metabolomic analysis suggested that ALA may target the glycerolipid metabolism pathway to ameliorate obesity. Knockdown of AGPAT2 abolished the protective effects of ALA. ALA treatment suppressed adipose accumulation in adipocytes, improved cognitive ability and colon integrity, and alleviated liver damage by modulating the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2).

Influence of zinc sulfate and threonine supplementation on mucin 5ac gene expression in the small intestine and intestinal mucosal morphology in broiler chickens

ABSTRACT A 42-day feeding trial was carried out to evaluate the effect of dietary supplementation of zinc and threonine on the integrity of intestinal mucosa and expression of intestinal mucin 5ac (MUC5AC) gene in broiler chickens. A total of 640-day-old Arbor Acres broiler chicks were allocated to four dietary treatments with eight replicates of 20 birds in a completely randomized design. The experimental diets included T0: control (standard diet), T1: standard diet + 40 mg/kg Zinc Sulfate (ZnSO4), T2: standard diet + 2% L-Threonine (L-Thr) and T3: standard diet + (40 mg/kg ZnSO4 + 0.2% L-Threonine (L-Thr)). During the starter phase, the average daily gain and body weight of birds fed the T1 diet was lower (p < 0.05) than T2 and T0. The villus height (VH) of the jejunum in T2 was longer (p < 0.05) than in T0 and T3. In the ileum, VH for T1 was longer (p < 0.05) than for T0. The MUC5AC mRNA expression in the duodenum at the starter phase was lower (p < 0.05) in T3 than in T2 while in the jejunum, T1 was higher (p < 0.05) than the other treatment groups. The supplementation of zinc and threonine in the diet can improve the intestinal integrity of broiler chickens.

Gene-environment interaction in the pathophysiology of type 1 diabetes.

Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as "epidrugs", which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.

THE FUNCTION OF THE CYSTATHIONINE-GAMMA-LYASE/HYDROGEN SULFIDE AXIS IN THE PATHOGENESIS OF ULCERATIVE COLITIS

Abstract INTRODUCTION Current combination therapies in ulcerative colitis (UC) target different inflammatory cascades, including tumor necrosis factor-alpha (TNF-alpha) signaling. However, most patients do not achieve long-term remission, suggesting that the molecular pathophysiology of UC is still poorly understood. Endogenously produced hydrogen sulfide (H2S) has emerged as a critical physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to epithelial injury. Inhibition of cystathionine-gamma-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. Our research group has strong evidence revealing that the CSE/H2S axis regulates TNF-alpha signaling in colonic epithelial cells. Therefore, we hypothesize that decreased CSE/H2S pathway activity in colonic mucosa cells leads to dysregulation of TNF-alpha signaling and uncontrolled inflammatory/immune responses with aberrant wound repair mechanisms contributing to the pathogenesis of UC. RESULTS We found a significant decrease in CSE mRNA and protein expression in colonic biopsies from patients with UC. Using a preclinical animal model of epithelium injury-induced chronic colitis (DSS), we confirmed a sustained downregulation of CSE, as well as upregulation of TNF-alpha and tumor necrosis receptor 2 expressions in colonic mucosa samples. Treatment with the slow-releasing H2S-donor GYY4137 significantly reduced the severity of DSS-induced inflammation and improved mucosal integrity and restitution responses. In epithelial cell and colonoid cultures, the inhibition of CSE-dependent H2S synthesis decreased the activation of extracellular-signal-regulated-kinase-1/2 (ERK1/2), increased IL-6 and TNF-alpha mRNA levels and suppressed basic and TNF-alpha–mediated colonocyte migration. CONCLUSION These studies demonstrate that CSE regulates mucosal TNF-alpha signaling, pro- and anti-inflammatory responses as well as colonic epithelial repair. Adding the H2S donor GYY4137 reduces inflammation, suggesting the restoration of normal TNF-alpha signaling function. Acknowledgments: KM is supported by the DoD Career Development Award (W81XWH2010641) and ACS Research Scholar Grant (RSG–21–027–01–CSM).

P1208 MH002, an optimized live biotherapeutic product, for the treatment of inflammatory bowel diseases, has mode-of-actions linked to restoration of intestinal dysbiosis, mucosal integrity, and immune homeostasis

Abstract Background MH002 is a live biotherapeutic product consisting of 6 well-characterized commensal strains, that is in clinical development for the treatment of Ulcerative Colitis (UC) and acute Pouchitis. Both are multifactorial disorders which occur through a combination of dysregulated host inflammatory mechanisms and interactions with gut microbiota. Methods Faecal slurries of 6 UC patients with active disease were prepared to inoculate a standardized in vitro gut model (SHIME®) which mimics the colon microbiome of patients. A total of 24 simulators were run for 8d, with a single dose administration of MH002 (human equivalent dose [HED] ~1) or vehicle on Day0. Butyrate production in the simulators was quantified daily and host response effects were assessed in in vitro cell-based assays using samples from Day1. Caco-2 cells were co-cultured with human peripheral blood mononuclear cells and treated for 48h with Day1 samples, followed by transepithelial electrical resistance (TEER) and cytokine measurements. Wound healing was assessed by imaging of monolayers of T84 cells, scratched and treated with Day1 samples. Furthermore, the effects of MH002 (daily, 24d, HED ~30) on disease activity index (DAI; body weight [BW], stool consistency, occult blood), local inflammation, and mucosal damage were evaluated in acute dextran sulfate sodium (DSS) induced colitis, when administered to C57BL/6 mice (15/group) as from 14d prior to DSS intake, and compared to 5-aminosalicylate (5-ASA; daily, 24d, 150mg/kg) and vehicle. Animals were euthanized in the acute (Day7; 10/group) and recovery phase (Day11; 5/group). Results In vitro administration of MH002 to patient-derived colonic microbiomes restored within 1d butyrate production and increased efficiency to improve epithelial barrier integrity, modulate T-cell-mediated immune responses, and promote mucosal wound healing in in vitro cell cultures (Table 1). DSS intake induced a significant decrease in relative BW and an increase in DAI. A significant recovery (BW, DAI, stool consistency) was observed at Day11 for MH002 and 5-ASA. Moreover, at Day11, macroscopic inflammation (colon weight/length ratio) and histologic scores were lower with MH002 and 5-ASA as compared to vehicle (Figure 1). Conclusion By restoring intestinal dysbiosis and epithelial integrity, and attenuating local inflammation, MH002 treatment should lead to lower disease activity and, ultimately, to clinical remission without immune suppression. Indeed, study MH002-UC-201 in mild-to-moderate UC was completed with favourable treatment effects (endoscopic improvement, faecal calprotectin normalization, improved stool consistency) and no safety concerns (Abstract Vermeire et al.; EudraCT 2020-004355-33).

Gasotransmitters do not prevent changes in transepithelial ion transport induced by hypoxia followed by reoxygenation.

How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still needs to be clarified. The objective of the present study was to characterize the impact of gaseous signalling molecules on parameters of colonic ion transport during a hypoxia/reoxygenation cycle and the remaining secretory capacity of the epithelium after such a cycle. Short-circuit current (Isc) and tissue conductance (Gt) recordings in Ussing chamber experiments were performed on rat colon samples using CORM-2 (putative CO donor; 35 and 350 µM), sodium nitroprusside (NO donor; 100 µM), NaHS (fast H2S donor; 10- 1,000 µM), GYY 4137 (slowH2S donor; 50 µM) and Angeli's salt (HNO donor; 100 µM) as donors for gasotransmitters. Inhibition of endogenous synthesis of H2S was operated by inhibitors of cystathionin-γ-lyase, i.e.dl-propargylglycine (1 mM) or β-cyano-l-alanine (5 mM), and the inhibitor of cystathionine-β-synthase, amino-oxyacetate (5 mM). The fast gasotransmitter donors NaHS, sodium nitroprusside and Angeli's salt, administered 5 min before the onset of hypoxia, induced an increase in Isc. The response to the subsequently applied hypoxia was characterized by a decrease in Isc, which tended to be reduced only in the presence of the lowest concentration of NaHS (10 µM) tested. Reoxygenation resulted in a slow increase in Isc, which was unaffected by all donors or inhibitors tested. The stable acetylcholine derivative carbachol (50 µM) was administered at the end of each hypoxia/reoxygenation cycle to test the secretory capacity of the epithelium. Pretreatment of thetissue with the putative CO donor CORM-2 suppressed thesecretory response induced by carbachol. The same wasobserved when cystathionin-γ-lyase and cystathionin-γ-synthase were inhibited simultaneously. Under both conditions, Gt drastically increased suggesting an impaired tissue integrity. The present results demonstrate that none of the exogenous gasotransmitter releasing drugs significantly ameliorated the changes in epithelial ion transport during the hypoxia/reoxygenation cycle exvivo. In contrast, the putative CO donor CORM-2 exerted a toxic effect on the epithelium. The endogenous production of H2S, however, seems to have a protective effect on the mucosal integrity and the epithelial transport functions, which- when inhibited- leads to a loss of the secretory ability of the mucosa. This observation together with the trend for improvement observed with a low concentration of the H2S donor NaHS suggests a moderate protective role of low concentrations of H2S under hypoxic conditions.

Sevelamer-Induced Gastrointestinal Disease in 12 Patients with End-Stage Renal Disease: A Case Series.

Isolated case reports and case series have linked the use of sevelamer to severe gastrointestinal (GI) inflammation and perforation among patients with end-stage renal disease. In this study, we identified 12 cases of biopsy-proven sevelamer-induced gastrointestinal disease from a large urban community hospital over the course of 5 years. We described baseline characteristics, sites and types of injury, histological findings, timing and dosing of sevelamer initiation compared with symptom onset, and in a smaller subset, endoscopic resolution post drug cessation. We also reviewed preexisting conditions to identify trends in populations at risk. Several of the patients reviewed had preexisting conditions of decreased motility and/or impaired mucosal integrity. The presentation of disease was broad and included both upper-GI and lower-GI pathologies and in varying severity. There is a broad phenotypic range of sevelamer-induced gastrointestinal disease. As this becomes a more frequently recognized pathology, clinicians should be aware of how it may present and which populations may be more susceptible.

Effects of Branched-Chain Amino Acids on the Inflammatory Response Induced by LPS in Caco-2 Cells.

Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.

Macleaya cordata isoquinoline alkaloids attenuate Escherichia coli lipopolysaccharide-induced intestinal epithelium injury in broiler chickens by co-regulating the TLR4/MyD88/NF-κB and Nrf2 signaling pathways.

This study sought to explore the effects and potential mechanisms of dietary supplementation with isoquinoline alkaloids (IA) from Macleaya cordata to alleviate lipopolysaccharide (LPS)-induced intestinal epithelium injury in broilers. A total of 486 1-day-old broilers were assigned at random to a control (CON) group, LPS group, and LPS+IA group in a 21-d study. The CON and LPS groups received a basal diet, while the LPS+IA group received a basal diet supplemented with 0.6 mg/kg IA. At 17, 19, and 21 days of age, the LPS and LPS+BP groups were injected intraperitoneally with LPS, and the CON group was intraperitoneally injected equivalent amount of saline solution. The results manifested that LPS injection caused intestinal inflammation and lipid peroxidation, disrupted intestinal barrier and function, and increased the abundance of harmful microorganisms. However, dietary IA supplementation alleviated LPS-induced adverse changes in intestinal morphology, apoptosis, mucosal barrier integrity, cecum microorganisms, and homeostasis disorder by decreasing inflammatory cytokines and enhancing antioxidant-related genes expressions; inhibited LPS-induced increases in TLR4 and NF-κB expressions and decreases in Nrf2 and GPX1 genes expressions. Our findings indicated that Macleaya cordata IA addition attenuated LPS-induced intestinal epithelium injury and disorder of intestinal homeostasis by enhancing the anti-inflammatory and antioxidant capacity of broiler chickens possibly via co-regulating TLR4/MyD88/NF-κB and Nrf2 signaling pathways.

MicroRNA expression profile of chicken jejunum in different time points Eimeria maxima infection.

Coccidiosis stands as a protozoan disease of notable economic impact, characterized by an intracellular parasite that exerts substantial influence over poultry production. This invasion disrupts the integrity of the enteric mucosa, leading to the emergence of severe lesions and diminishing the efficiency of feed utilization in chickens. MicroRNA (miRNA) are short, non-coding RNA molecules with approximately 21-24 nucleotides long in size that play essential roles in various infectious diseases and inflammatory responses. However, the miRNA's expression patterns and roles in the context of Eimeria maxima infection of chicken intestines remain unclear. miRNA sequencing was employed to assess the miRNA expression profile in chicken jejunum during E. maxima infection. In this study, we analyzed miRNA expression profiles related to the host's immune response in the chicken jejunum during E. maxima infection. At 4 days infection and control (J4I versus J4C), 21 differentially expressed miRNAs in the jejunum were identified, comprising 9 upregulated and 12 downregulated miRNAs. Furthermore, in the jejunum, at 7 days infection and control (J7I versus J7C) groups, a total of 35 significantly differentially expressed miRNAs were observed, with 13 upregulated and 22 downregulated miRNAs. The regulatory networks were constructed between differentially expressed miRNA and mRNAs to offer insight into the interaction mechanisms between chickens and E. maxima coccidian infection. Furthermore, within the comparison group, we obtained 946, 897, and 281 GO terms that exhibited significant enrichment associated with host immunity in the following scenarios, J4I vs. J4C, J7I vs. J7C, and J4I vs. J7I, respectively. The KEGG pathway analysis indicated notable enrichment of differentially expressed miRNAs in the jejunum, particularly in J4I vs. J4C; enriched pathways included metabolic pathways, endocytosis, MAPK signaling pathway, regulation of actin cytoskeleton, and cytokine-cytokine receptor interaction. Moreover, in J7I vs. J7C, the KEGG pathway was significantly enriched, including metabolic pathways, protein processing in the endoplasmic reticulum, ubiquitin-mediated proteolysis, and FoxO signaling pathway. A comprehensive understanding of the host genetic basis of resistance with a combination of time-dependent infection to the Eimeria parasite is crucial for pinpointing resistance biomarkers for poultry production.

Pepsin Inhibitors Prevent Inflammation and Loss of Laryngeal Barrier Function in Mice with Gastroesophageal Reflux.

This study aimed to evaluate the role of pepsin inhibitors in the inflammatory response and their effects on laryngeal mucosal integrity during gastroesophageal reflux (GERD) under in vivo conditions. A surgical model of GERD was used, in which mice were treated with pepstatin (0.3 mg/kg) or darunavir (8.6 mg/kg) for 3 days. On the third day after the experimental protocol, the laryngeal samples were collected to assess the severity of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and paracellular epithelial permeability to fluorescein). The surgical GERD model was reproduced. It showed features of inflammation and loss of barrier function in the laryngeal mucosa. Pepstatin and darunavir administration suppressed laryngeal inflammation and preserved laryngeal mucosal integrity. Pepsin inhibition by the administration of pepstatin and darunavir improved inflammation and protected the laryngeal mucosa in a mouse experimental model of GERD. NA Laryngoscope, 134:3080-3085, 2024.

Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy.

Degenerative Cervical Myelopathy (DCM) is a progressive neurological condition characterized by structural alterations in the cervical spine, resulting in compression of the spinal cord. While clinical manifestations of DCM are well-documented, numerous unanswered questions persist at the molecular and cellular levels. In this study, we sought to investigate the neuromotor axis during DCM. We use a clinically relevant mouse model, where after 3 months of DCM induction, the sensorimotor tests revealed a significant reduction in both locomotor activity and muscle strength compared to the control group. Immunohistochemical analyses showed alterations in the gross anatomy of the cervical spinal cord segment after DCM. These changes were concomitant with the loss of motoneurons and a decrease in the number of excitatory synaptic inputs within the spinal cord. Additionally, the DCM group exhibited a reduction in the endplate surface, which correlated with diminished presynaptic axon endings in the supraspinous muscles. Furthermore, the biceps brachii (BB) muscle exhibited signs of atrophy and impaired regenerative capacity, which inversely correlated with the transversal area of remnants of muscle fibers. Additionally, metabolic assessments in BB muscle indicated an increased proportion of oxidative skeletal muscle fibers. In line with the link between neuromotor disorders and gut alterations, DCM mice displayed smaller mucin granules in the mucosa layer without damage to the epithelial barrier in the colon. Notably, a shift in the abundance of microbiota phylum profiles reveals an elevated Firmicutes-to-Bacteroidetes ratio-a consistent hallmark of dysbiosis that correlates with alterations in gut microbiota-derived metabolites. Additionally, treatment with short-chain fatty acids stimulated the differentiation of the motoneuron-like NSC34 cell line. These findings shed light on the multifaceted nature of DCM, resembling a synaptopathy that disrupts cellular communication within the neuromotor axis while concurrently exerting influence on other systems. Notably, the colon emerges as a focal point, experiencing substantial perturbations in both mucosal barrier integrity and the delicate balance of intestinal microbiota.

TSP50 Attenuates DSS-Induced Colitis by Regulating TGF-β Signaling Mediated Maintenance of Intestinal Mucosal Barrier Integrity.

The integrity of the intestinal mucosal barrier is crucial for protecting the intestinal epithelium against invasion by commensal bacteria and pathogens, thereby combating colitis. The investigation revealed that the absence of TSP50 compromised the integrity of the intestinal mucosal barrier in murine subjects. This disruption facilitated direct contact between intestinal bacteria and the intestinal epithelium, thereby increasing susceptibility to colitis. Mechanistic analysis indicated that TSP50 deficiency in intestinal stem cells (ISCs) triggered aberrant activation of the TGF-β signaling pathway and impeded the differentiation of goblet cells in mice, leading to impairment of mucosal permeability. By inhibiting the TGF-β pathway, the functionality of the intestinal mucosal barrier is successfully restored and mitigated colitis in TSP50-deficient mice. In conclusion, TSP50 played a crucial role in maintaining the intestinal mucosal barrier function and exhibited the preventive effect against the development of colitis by regulating the TGF-β signaling pathway.

Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management.

Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder in which retrograde flow of gastric content into the oesophagus causes uncomfortable symptoms and/or complications. It has a multifactorial and partially understood pathophysiology. GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or extra-oesophageal symptoms. Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. The intensity of the symptoms is affected by peripheral and central neural and psychological mechanisms. In this Review, we describe an updated understanding of the complex and multifactorial pathophysiology of GERD. It is now recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. These variations are probably due to the occurrence of a predominant pathophysiological mechanism in each patient. We also describe the main pathophysiological mechanisms of GERD and their implications for personalized diagnosis and management.