High-dose radiation exposure results in gastrointestinal (GI) acute radiation syndrome identified by the destruction of mucosal layer, intestinal growth barrier dysfunction, and aberrant inflammatory responses. Further, radiation causes gut microbiome dysbiosis characterized by diminished microbial diversity, mostly commensal bacteria, and the spread of bacterial pathogens that trigger the recruitment of immune cells and the production of pro-inflammatory factors that lead to further GI tissue damage. Currently, there are no U.S. Food and Drug Administration (FDA) approved countermeasures that can treat radiation-induced GI injuries. To meet this critical need, Synedgen Inc. has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract, which acts by intercalating into the mucus layer and the glycocalyx of intestinal epithelial cells that could potentially ameliorate the deleterious effects of radiation. Male C57BL/6J adult mice were exposed to 13 Gy partial body X-irradiation with 5% bone marrow shielding and MIIST305 was administered on days 1, 3, and 5 post-irradiation. Approximately 85% of the animals survived the irradiation exposure and were apparently healthy until the end of the 30-day study period. In contrast, no control, Vehicle-treated animals survived past day 10 at this radiation dose. We show that MIIST305 improved intestinal epithelial barrier function and suppressed systemic inflammatory responses mediated by radiation-induced pro-inflammatory cytokines. Taxonomic profiling and community structure of the fecal and colonic mucosa microbiota demonstrated that MIIST305 treatment increased microbial diversity and restored abundance of beneficial commensal bacteria, including Lactobacillus and Bifidobacterium genera while suppressing potentially pathogenic bacteria Enterococcus and Staphylococcus compared with Vehicle-treated animals. In summary, MIIST305 is a novel GI-targeted therapeutic that greatly enhances survival in mice exposed to lethal radiation and protects the GI tract from injury by restoring a balanced gut microbiota and reducing pro-inflammatory responses. Further development of this drug as an FDA-approved medical countermeasure is of critical importance.

Mammalian carboxylesterases play an important role in the hydrolysis of both endogenous substrates and xenobiotics bearing ester or amide bond(s). We previously reported that bysspectin A and its derivative LC-20W were potent reversible hCES2A inhibitors. Here, a series of bysspectin A derivatives were designed and synthesized using LC-20W as the leading compound. Compound 9d was identified as a potent serine-targeting covalent inhibitor of hCES2A (IC50 = 0.12 nM), which was much more potent than that of LC-20W. Further chemoproteomics and docking simulations showed that 9d could selectively modify hCES2A at the catalytic serine (Ser228), thereby blocking its catalytic activity. Notably, 9d showed good cell-membrane permeability and was capable of inhibiting intracellular hCES2A in living cells. In vivo tests showed that 9d significantly alleviates irinotecan-induced diarrhea and dextran sulfate sodium-induced colitis. Collectively, a novel serine-targeting covalent inhibitor against hCES2A was developed, offering a promising candidate for treating drug-induced diarrhea and ulcerative colitis.

Maintaining the integrity of the structure and function of piglet intestines is crucial for their growth and health. This study aims to evaluate the effects of an antibiotic free diet supplemented with bile acid on gut health and growth performance of weaned piglets, and to explore their regulatory mechanisms.

Thirty-two weaned piglets were randomly divided into two groups and fed either a basal diet or a basal diet supplemented with 350 mg/kg bile acid.

Dietary supplementation with bile acid increased the average daily gain (ADG) and final weight of piglets, and reduced the diarrhea incidence (P < 0.05), which was verified to be related to the improvement of lipid absorption, amino acid transport, and intestinal barrier function. Bile acid increased the concentration of lipase and decreased the concentration of total cholesterol, total glyceride, low-density lipoprotein, and urea nitrogen in serum (P < 0.05). Meanwhile, bile acid improved the mRNA expression of amino acid transporters in the intestine. On the other hand, bile acid decreased the pH values of the stomach, jejunum, and colon, and improved intestinal morphology (P < 0.05). The real-time quantitative PCR results showed that bile acid increased the mRNA expression of Occludin and ZO-1 in the duodenum and ileum (P < 0.05). Moreover, dietary bile acid supplementation altered the composition of the ileal microbiota in piglets and increased the relative abundance of Ligilactobacillus. In vitro, bile acid improved the repair of IPEC-J2 cells after injury and was shown to be associated with the activation of farnesoid X receptors (FXR) and increased expression of tight junction proteins and aquaporins (AQPs) proteins.

This study found that dietary bile acid supplementation promotes the intestinal health and nutrient absorption partially through the FXR/AQPs pathway, ultimately improving growth performance of piglets.

Previous studies have demonstrated the beneficial effects of 2'-fucosyllactose (2'-FL) and osteopontin (OPN) in modulating intestinal mucosal immunity. Nevertheless, the potential synergistic interactions and underlying mechanisms of 2'-FL and OPN have not been fully elucidated. To address this question, this study employed Sprague-Dawley (SD) rats to establish a lipopolysaccharide (LPS)-induced model simulating human microbiota-associated intestinal barrier damage. The findings indicate that the combined administration of 2'-FL and OPN exerts a considerable protective effect on the intestinal barrier, surpassing the individual efficacy of 2'-FL or OPN alone. The administration of 2'-FL and OPN mitigated body weight loss, attenuated disease activity index (DAI) scores, reduced serum myeloperoxidase (MPO) activity, and improved intestinal histopathology. In addition, 2'-FL and OPN significantly increased the mRNA expression of MUC2, ZO-1, and claudin-2, and reduced serum diamine oxidase (DAO) and D-lactate levels. 2'-FL and OPN reduced the levels of pro-inflammatory cytokines IL-6, and IL-1β, and elevated the levels of anti-inflammatory cytokines IL-10, IL-4, and secretory immunoglobulin A (sIgA) in the intestine. 2'-FL and OPN significantly improved the balance in CD4+/CD8+, Th1/Th2, and Th17/Treg cells. Moreover, 2'-FL and OPN regulated LPS-induced dysbiosis of the intestinal microbiota, increased the abundance of Lactobacillus and Romboutsia, and reduced the abundance of Escherichia-Shigella and Alloprevotella. Overall, 2'-FL and OPN synergistically protected against LPS-induced intestinal mucosal barrier damage in rats by regulating intestinal permeability, attenuating the inflammatory response, balancing intestinal immune cells, and modulating intestinal microbiota composition.

This study investigates the effect and underlying mechanism of targeting SLC7A11 in mitigating dextran sulfate sodium (DSS)-induced intestinal inflammation and injury in colitis.

We utilized wild-type and SLC7A11-/+ mice to assess the inflammatory damage in DSS-induced colitis in vivo. In vitro, colon tissues from patients with ulcerative colitis were analyzed to compare SLC7A11 expression between inflamed and non-inflamed regions. Further mechanistic insights were obtained using Caco-2 cells and bone marrow-derived dendritic cells (BMDCs).

In human colon tissues, SLC7A11 expression was significantly elevated in inflamed regions compared to non-inflamed areas, particularly in dendritic cells. In vivo inhibition of SLC7A11 markedly alleviated DSS-induced colitis symptoms. In vitro, suppressing SLC7A11 restored the integrity of the Caco-2 monolayer intestinal epithelial model. Both knockout and inhibition of SLC7A11 enhanced ERK1/2 phosphorylation and increased efferocytosis in BMDCs.

Targeting SLC7A11 augments dendritic cell efferocytosis and preserves intestinal epithelial barrier function, potentially offering a therapeutic avenue for alleviating ulcerative colitis.

Ulcerative colitis (UC) brings inconvenience to many patients with inflammatory bowel disease (IBD). Although colonic pathology is widely investigated, little attention has been paid to the disorders in small intestine of UC. In this study, we investigated the impairments of UC to small intestine and further explored how iron metabolism regulated epithelial integrity and the activity of intestinal stem cells (ISCs).

Mice were treated by 2.5% dextran sulfate sodium (DSS) for 7 days to established acute experimental colitis. Small intestinal tissues were collected at different time points in the process of DSS-induced colitis. Histological analysis was used to evaluate the changes of small intestine, including H&E, Alcian blue and PAS staining, immunostaining, and qRT-PCR. Iron content was modulated by the supplementation of ferric citrate or depletion by deferoxamine (DFO). The influence of iron on the barrier integrity and stem cell function was further determined by histology, IEC-6 cell, and enteroid culture. ROS content was demonstrated by DHE staining. The proliferation of intestinal stem cells (ISCs) was shown by BrdU and Olfm4 staining, and Lgr5-tdTomato mice were used for lineage tracing study.

It was shown that during DSS-induced colitis, small intestine underwent a serious injury process, including dysregulated integrity and decreased proliferation of ISCs. Iron overload significantly exacerbated intestinal injury in tissues, epithelial cell line, and intestinal organoids. However, iron chelation by deferoxamine (DFO) would greatly suppress small intestinal injury. Mechanistically, iron overload exacerbated the generation of ROS and enhanced the infiltration of immune cells. In addition, STAT3 and ERK pathways in intestinal epithelium were impaired during experimental colitis, and iron content significantly interrupted the expression of p-STAT3 and p-ERK1/2 within small intestine.

In summary, this study proved that small intestine was also impaired in experimental colitis, and iron content could affect DSS-induced small intestinal damage and regeneration, indicating the strategy of iron supplementation in clinical practice needs to be more cautious and consider more factors.

Diarrheal diseases remain a major public health concern, particularly in regions with poor sanitation. Polysaccharides extracted from natural gums have been investigated as functional agents for intestinal health, and their fractionation enables the production of oligosaccharides with potential prebiotic activity. This study aimed to produce cashew gum (CG) fractions through Smith degradation (CGD48) and partial hydrolysis (CGD24) and to evaluate their ability to modulate and protect the intestinal microbiota. Balb/c mice were administered CG (1200 mg/kg), CGD24 (800 mg/kg), or CGD48 (800 mg/kg) for 10 and 26 days, followed by infection with Shiga toxin-producing Escherichia coli (STEC) (5 × 1010 CFU/mL) for three days. Characterization assays confirmed the fragmentation of CG. Both CGD24 and CGD48 promoted the growth of beneficial bacteria with and without infection and reduced STEC colonization. Furthermore, they preserved mucin levels in the cecum and large intestine and maintained baseline levels of superoxide dismutase (SOD), suggesting protection of the intestinal mucosa. These findings indicate that CG fractions exhibit microbiota-modulating and protective effects against STEC, highlighting their therapeutic potential and the need for further studies to elucidate the underlying mechanisms.

In Nature, bacterial clustering by host-released peptides or nucleic acids is an evolutionarily conserved immune defense strategy employed to prevent adhesion of pathogenic microbes, which is prerequisite for most infections. Synthetic anti-adhesion strategies present as non-lethal means of targeting bacteria and may potentially be used to avoid resistance against antimicrobial therapies. From bacteria-agglutinating biomolecules discovered in nature to synthetic designs involving peptides, cationic polymers and nanoparticles, the modes of actions appear broad and unconsolidated. Herein, we present a critical review and update of the state-of-the-art in synthetic bacteria-clustering designs with proposition of a more streamlined nomenclature and classification. Overall, this review aims to consolidate the conceptual framework in the field of bacterial clustering and highlight its potentials as an avenue for discovering novel antibacterial biomaterials.

Dahuang Mudan Decoction is a classic Chinese medicine prescription for treating ulcerative colitis (UC). Previous studies have shown that Dahuang Mudan Decoction has preventive and therapeutic effects on mice with dextran sulfate sodium (DSS) induced colitis.

The objective of this research endeavor was to ascertain the most efficacious synergistic blend of Emodin, Luteolin, and Paeonol, the main active ingredients in Dahuang Mudan Decoction, in alleviating UC. Additionally, it sought to elucidate the underlying therapeutic mechanisms and evaluate the safety of the combined components.

Employing Emodin, Luteolin, and Paeonol as starting materials, the optimal combination was selected by orthogonal design. Basic pharmacodynamics was observed in mouse model of UC induced by DSS. The pathological changes of the colon were observed using hematoxylin and eosin (H&E) staining. The changes of cytokines and proteins related to inflammation and intestinal barrier function were detected by WB, Alcian blue staining, immunofluorescence, immunohistochemistry and related kits. Subsequently, 16S rRNA sequencing was used to observe changes in the intestinal flora. To evaluate the therapeutic effect and potential mechanism of the optimal monomer composition on UC mouse model. Finally, we performed toxicity tests as part of the safety assessment of the combination of the three monomers.

The different combinations of Emodin, Luteolin, and Paeonol alleviated DSS-induced colitis to varying degrees. The ELP5 group (Emodin 5 mg/kg + Luteolin 5 mg/kg + Paeonol 15 mg/kg) and ELP9 group (Emodin 15 mg/kg + Luteolin 15 mg/kg + Paeonol 75 mg/kg) had the most significant mitigation effect on UC mice. Mechanistically, the monomeric composition provides a comprehensive treatment for UC by addressing multiple aspects, including anti-inflammatory and antioxidant effects, repairing the damaged intestinal barrier, restoring the intestinal flora structure, and regulating short-chain fatty acid levels. In addition, the combination of Emodin, Luteolin and Paeonol exhibited a more significant effect on DSS-induced colitis compared to the individual components, indicating a synergistic effect among them. In the single-dose toxicity test, no obvious abnormalities were found in the general state or major organs of the mice. In repeated toxicity tests, it was found that the combined use of three monomers had less effect on organ index, hematology and serum biochemical indexes than that of a single compound. Pathological examination showed that the three monomers had certain toxicity to mouse liver, kidney and lung when used alone and in large doses for a long time, and the toxicity was significantly reduced after combined use.

We have determined the optimal combination of three active ingredients in Dahuang Mudan Decoction to alleviate DSS induced colitis in mice by inhibiting intestinal inflammation and oxidative stress, repairing impaired intestinal barrier function, and regulating intestinal flora disturbance. The results of single administration toxicity test proved the safety of the three monomers combined, and repeated administration toxicity test clarified the safe dose range of the combined administration, and also revealed that the combined therapy exhibited superior safety compared to monotherapy.

The gut contains a diverse array of commensal microorganisms, forming a vital biological barrier within the intestine that contributes to the overall intestinal mucosal barrier. However, research on the rectal barrier during early development remains limited. This study aims to investigate the relationship between intestinal microbiota and rectal barrier function in young rats.

We evaluated the rectal barrier structure and function in rats at 2-, 4-, and 10-week-old. Methodology included histological analysis, Muc2 expression quantification, immunofluorescence localization of tight junction proteins (ZO-1, Occludin, Claudins), blood glucose monitoring after rectal insulin administration, and 16S rDNA sequencing of rectal microbiota. Spearman correlation analysis was used to explore mechanisms linking age-dependent changes in rectal permeability to microbiota dynamics.

Physiological rectal permeability was significantly higher in 2-week-old rats compared to 4- and 10-week-old rats (p < 0.01), although systemic biomarkers (LPS, D-LA, and LBP) showed no significant differences. The rectal microbiota exhibited marked age-dependent shifts in composition, α/β-diversity, and metabolic pathways, with increased abundance of beneficial taxa (e.g., Muribaculaceae, Akkermansia) in older rats. Correlation analysis revealed strong associations between reduced permeability, elevated Occludin expression, and microbiota maturation (R = 0.65, p < 0.001).

This study demonstrates that age-dependent maturation of the rectal barrier is closely linked to microbiota composition and tight junction protein expression, providing insights into developmental mechanisms and potential strategies for pediatric rectal drug delivery.

Chemotherapy-induced intestinal mucositis is a major side effect of cancer treatment. Statins are 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitors used to treat hypercholesterolemia and atherosclerotic diseases. Recent studies have demonstrated that atorvastatin (ATV) has antioxidant, anti-inflammatory, and resulting from the regulation of different molecular pathways. In the present study, we investigated the effects of ATV on intestinal homeostasis in 5-fluorouracil (5-FU)-induced mucositis. Our results showed that ATV protected the intestinal mucosa from epithelial damage caused by 5-FU mainly due to inflammatory infiltrate and intestinal permeability reduction, downregulation of inflammatory markers, such as Tlr4, MyD88, NF-κB, Tnf-a, Il1β, and Il6 dose-dependent. ATV also improved epithelial barrier function by upregulating the mRNA transcript levels of mucin 2 (MUC2), and ZO-1 and occludin tight junction proteins. The results suggest that the ATV anti-inflammatory and protective effects on 5-FU-induced mice mucositis involve the inhibition of the TLR4/MYD88/NPRL3/NF-κB, iNos, and caspase 3.

Nonsteroidal anti-inflammatory drug (NSAID) enteropathy is a serious clinical complication with no effective treatments available. Modulating the intestinal microbiota through dietary and nutritional targets is a promising strategy for preventing NSAID enteropathy. This study aimed to investigate the protective effect and underlying mechanisms of the probiotic Clostridium butyricum (CB) on indomethacin (IND)-induced enteropathy. C57BL/6J mice received CB treatment for 14 days along with concurrent IND gavage for the final 7 days. Caco2 cells were stimulated with IND to evaluate the effect of CB supernatant (CBS) on the intestinal barrier function, and LS174T cells were used to validate the modulatory action of CBS on the Notch signaling pathway. Our findings revealed that CB treatment prevented anorexia and weight loss, reduced the severity of enteropathy, and decreased the inflammatory response of the small intestine. CB also increased the expression of tight junction proteins and reduced permeability in mice and Caco2 cells. Additionally, CB suppressed apoptosis and promoted proliferation in the small intestine. Further research found that CB increased the number of goblet cells and MUC2 secretion. Mechanistically, CB may promote MUC2 secretion by suppressing the Notch signaling pathway, consistent with the results of intervention in LS174T cells with CBS. In conclusion, CB might prevent NSAID enteropathy by increasing MUC2 secretion through the inhibition of the Notch pathway. Our study identified the potential efficacy of CB as a preventive strategy against NSAID enteropathy and showed promising prospects for CB as a food supplement.

The variation of the integrity of the intestinal barrier is closely related to the occurrence and progression of various diseases, making its accurate detection and monitoring essential to provide reliable information for guiding the refinement of treatment scenarios. Herein, we developed a strategy utilizing glutathione-capped gold clusters (Au-GSH) to achieve simultaneous in vivo second near-infrared (NIR-II) fluorescence imaging and in vitro colorimetric urinalysis for noninvasive detection and monitoring of intestinal barrier integrity. After oral administration, Au-GSH can demonstrate different distribution behaviors in terms of the variation of intestinal barrier integrity. Specifically, Au-GSH could selectively permeate through compromised intestinal barrier to be distributed into the bladder in view of its ultrasmall size below the glomerular filtration cutoff, leading to the rapid excretion through urine. Such process can be visually profiled by collecting NIR-II fluorescence (>1100 nm) emitting from Au-GSH in a noninvasive real-time manner. By virtue of the peroxidase-like activity of Au-GSH, the simple colorimetric urinalysis was further established for evaluating the integrity of the intestinal barrier, advancing the detection and monitoring performance. As a result, our developed strategy successfully detected the damage of intestinal barrier integrity in ulcerative colitis (UC) mice, a common disease characterized by compromised intestinal barrier integrity. Excitingly, the monitoring of restoration of intestinal barrier integrity in both therapeutic and preventative modes for UC mice was also realized by our strategy, making it a promising diagnosis scenario for diseases related to the variation of intestinal barrier integrity.

The intestinal barrier, held together by epithelial cells and intercellular tight junction (TJ) proteins, prevents the penetration of microbial pathogens. Concurrently, intestinal epithelial cells secrete antimicrobial peptides, including cathelicidin. Cathelicidin has direct antibacterial and immunomodulatory functions, although its role in intestinal integrity remains elusive. In this study, we demonstrate that direct stimulation of human colonic epithelial (T84) cells with human cathelicidin, LL-37, resulted in a rapid and transient increase in epithelial cell permeability. This increased permeability was associated with the TJ proteins occludin and claudin-2 degradation, mediated by these specific proteins' endocytosis and lysosomal degradation. While murine cathelicidin (CRAMP) failed to modify T84 cell permeability, LL-37 degraded TJ proteins in murine rectal epithelial (CMT-93) cells. The stimulus of (CMT-93) cells with LL-37 aggravated the cell permeability and furthered TJ degradation provoked by the intestinal pathogen, attaching/effacing (A/E) Citrobacter rodentium (C. rodentium). The number of C. rodentium that colonized CMT-93 cells was not severely impacted by the presence of LL-37. While a temporary disruption of tight junctions by LL-37 may lead to a 'leaky gut,' this study demonstrates that LL-37 increases epithelial cell permeability by degrading TJ proteins occludin and claudin-2 through endocytosis and lysosomal degradation. These immunomodulatory actions occurring at concentrations lower than those microbicidal uncover a new guise for cathelicidin modulating the epithelial barrier against A/E pathogens. Recognizing native cathelicidin's functions in a specified disease setting (e.g., colitis) will help establish it as an anti-infectious immunomodulator.

Disrupted cholesterol homeostasis plays a critical role in the development of multiple diseases, such as cardiovascular disease and cancer. However, the role of cholesterol in inflammatory bowel disease (IBD) remains unclear. In the present study, we investigated whether and how high levels of cholesterol in the diet affect experimental colitis in mice. A normal diet supplemented with 1.25% cholesterol (high cholesterol diet) caused more severe colitis and aggravated the disruption of intestinal tight junction structure, accompanied by higher colonic tissue total cholesterol (TC) levels in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Cholesterol aggravated DSS-induced intestinal epithelial barrier impairment and nuclear sterol regulatory element-binding protein 2 (nSREBP2) inhibition both in vivo and in vitro. In addition, nSREBP2 overexpression ameliorated cholesterol-induced intestinal epithelial barrier disruption in Caco2 cells. Interestingly, inhibition of SREBP2 disrupted intestinal epithelial barrier in the absence of cholesterol. Furthermore, SREBP2 regulated the protein expression of tight junction proteins (occludin/Zo-1) via modulating caveolin-1-mediated endocytosis and lysosomal degradation. Analysis of UK Biobank data indicated that, in fully adjusted models, higher serum TC concentrations were an independent protective factor for IBD incidence. The sterol regulatory element-binding factor 2 (SREBF2) gene rs2228313 (G/C) genetic variant was associated with the incidence of IBD and the CC genotype of SREBF2 rs2228313 was associated with higher serum TC levels and decreased the risk of IBD. In summary, a high cholesterol diet aggravates DSS-induced colitis in mice by down-regulating nSREBP2 expression, thereby promoting the endocytic degradation of tight junction proteins. In humans, SREBF2 gene single nucleotide polymorphism rs2228313 and serum TC levels are associated with IBD incidence.

Mare milk (MM) and fermented mare milk (FM) are specialized animal milks with high nutritional value, containing a variety of functionally active substances that are capable of resisting inflammatory responses and oxidative stress. However, little relevant research on the maintenance of intestinal homeostasis has been performed. This study aimed to investigate the effects of MM and FM on the prevention of dextran sulfate sodium salt (DSS)-induced ulcerative colitis in a mouse model and to preliminarily elucidate the underlying mechanisms. The results showed that MM and FM had different degrees of protective effects against the damage caused by DSS and alleviated ulcerative colitis by inhibiting weight loss, reducing colon length shortening, and restoring intestinal structure. Additionally, MM and FM maintained intestinal tight junction protein levels to repair barrier function, downregulated inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6, and iNOS) and bolstered the body's antioxidant defense system. Moreover, MM and FM regulated dysregulation of the intestinal microenvironment by improving the diversity of the gut microbiota and reshaping its structure, including increasing the proportion of Firmicutes and Bacteroidetes and the relative abundance of beneficial bacterial genera (e.g., Akkermansia). In summary, MM and FMM can serve as dietary resources for preventing ulcerative colitis and maintaining intestinal homeostasis.

The aim of this study is to assess the impact of moxibustion on the colonic mucosal barrier and gut microbiota in a rat model of cerebral ischemic stroke (CIS).

The CIS rat model was established using the modified Zea Longa suture method. Successfully modeled rats were randomly allocated into a model group and a moxibustion group, with a sham surgery group serving as the control. The moxibustion group received suspended moxibustion at Dazhui (GV 14), Baihui (GV 20), Fengfu (GV 16), and bilateral Tianshu (ST 25) and Shangjuxu (ST 37) acupoints. Neurological function was assessed using the Longa score, and brain infarct size was assessed through 2,3,5-triphenyl tetrazolium chloride staining. Gut microbiota composition was analyzed using 16S rDNA amplification sequencing. Intestinal mucosal permeability was evaluated using the FITC-Dextran tracer method. The serum ET-1 levels and the expression of Occludin and ZO-1 proteins in colonic tissues were also measured.

The model group exhibited significantly higher Longa scores, larger brain infarct size, and higher serum FITC-Dextran levels and ET-1 levels when compared with the sham surgery group (p < 0.01). The model group demonstrated decreased expression of Occludin and ZO-1 in colonic tissues (p < 0.01) and changes in gut microbiota structure. When compared to the model group, the moxibustion group demonstrated significantly lower Longa scores, smaller brain infarct size, and lower serum FITC-Dextran levels and ET-1 levels (p < 0.05). Furthermore, the moxibustion group demonstrated decreased inflammatory cell infiltration in colonic tissues, increased expression of Occludin and ZO-1 proteins in colonic tissues (p < 0.05), enhanced gut microbiota structure, and a decreased Simpson index (p < 0.05).

Moxibustion can improve the neurological dysfunction in CIS model rats. The mechanism may be associated with the improvement in gut microbiota dysbiosis, reduction in colonic mucosal permeability, and restoration of intestinal mucosal barrier damage.

Glutamine (Gln) plays a pivotal role in maintaining the integrity of the rumen epithelial barrier in mammals. This study aimed to investigate the effects of Gln on histamine-induced barrier damage in yak rumen epithelial cells (YRECs).

RT-qPCR analysis revealed a significant decrease in the mRNA expression of tight junction proteins (ZO-1, JAM-A, Claudin-1, and Claudin-4) following 24-hour exposure to 20 µM histamine (HIS group) (P < 0.05). In the subsequent experiment, YRECs were first treated with 20 µM histamine for 24 h, followed by 8 mM glutamine for 12 h (HG group). Gln treatment reversed the histamine-induced downregulation of both mRNA and protein levels of tight junction proteins and restored the distribution of ZO-1 at the cell membrane. Transcriptome analysis revealed that co-regulated differentially expressed genes were primarily involved in the mitogen-activated protein kinase (MAPK) signaling pathway and apoptosis. These findings were further corroborated by RT-qPCR, Western blot, and flow cytometry analyses. To determine whether glutamine regulates cell barrier function through the p38 MAPK signaling pathway, 20 µM Skatole, a p38 MAPK agonist, was introduced (SK group). The results showed a significant increase in the p-p38/p38 ratio and a marked decrease in the mRNA and protein expression of tight junction proteins in the SK group compared to the HG group (P < 0.05).

Glutamine mitigates histamine-induced barrier damage in YRECs through the p38 MAPK signaling pathway and apoptosis regulation.

This study is to demonstrate the protection of atractylenolide III (AT III) on intestinal barrier dysfunction in ulcerative colitis (UC). UC model was established by 3% dextran sulfate sodium (DSS), and TNF-α was used to induce dysfunction in the intestinal epithelial barrier. TEER, FD-4 transmembrane flux and DAI were measured. Histopathological changes was identified by H&E staining, TJ structure changes were observed by TEM, IL-1β and TNF-α contents were measured by ELISA, bacterial translocation was investigated by FISH. The expressions of ZO-1, occludin, and the proteins in the MLCK/p-MLC and NF-κB pathways were analyzed by Western blotting or immunofluorescence. The results indicated that AT III alleviate the symptoms of DSS-induced colitis, reduce the disruption of intestinal epithelial barrier, and decrease FD4. Moreover, AT III inhibited the destruction of intestinal epithelial TJ structure and bacterial translocation in UC mice. AT III reversed the high levels of IL-1β and TNF-α, the decrease of occludin, ZO-1 expressions. Furthermore, AT III showed similar effects to PDTC (pyrrolidinedithiocarbamate) in ameliorating the disruption of the TNF-α-induced TEER and FD-4 disruption, MLCK protein expression, and MLC2 phosphorylation. In conclusion, AT III mitigates the dysfunction of intestinal epithelial barrier in UC through the NF-κB-mediated MLCK/p-MLC signaling pathway.

To explore a potential link between resistance exercise and the gut-brain axis, this study examined the impact of resistance exercise on intestinal permeability, as indicated by lipopolysaccharide binding protein (LBP), and mood state in healthy adults. Sedentary participants (n = 20; 39.5 ± 12.1 y; 27.4 ± 5.3 kg/m2) were randomly assigned to the resistance exercise (REX) or wait-listed control (CON) groups. REX participants strength trained 3× weekly (advancing from 45%-55% to 70%-80% 1RM for 3-4 sets over 8 weeks). Strength testing, evaluation of mood states, and collection of fasting blood occurred at baseline and weeks 4 and 8. At baseline, LBP concentrations were inversely correlated to all strength measures (r range: -0.48 to -0.57; p < 0.05). The gain in total strength [(split squat left + right)/2 + bench press] was 45% higher for REX versus CON participants (p = 0.019), and serum LBP concentrations fell 16% for REX participants and rose 9% in CON participants (p = 0.014). Mood was significantly improved by resistance training versus control (but this improvement was not related to changes in LBP; r = -0.001). These findings support a role for resistance exercise in improving mood state and intestinal barrier function, but more research is warranted to further explore the effects of resistance training on the gut-brain axis.

Ulcerative colitis (UC) is a global gastrointestinal disease, which is mainly caused by both dysfunctional epithelial barrier and inflammation response. Iron is a critical fundamental element for both the maintenance of homeostasis and the mediation of inflammation in many tissues. However, the role and mechanism of iron in the phase of enteritis and the subsequent repairing phase of intestinal stem cells has not been elucidated. In this study, we aimed to explore whether and how iron depletion would affect the occurrence and outcome of experimental colitis.

Iron depletion was realized by deferoxamine (DFO) at either the early stage or late stage of dextran sulfate sodium (DSS) induced experimental colitis in mice. The gross images of colons, general health, histology, barrier integrity, and qRT-PCR were performed. Meanwhile, cell culture and colonic organoids were used to examine the influence of iron depletion in vitro. Signaling pathway and inflammatory infiltration were investigated by immunostaining.

Iron depletion within the early stage of DSS treatment significantly inhibited the onset of the inflammatory response, maintained the integrity of the colonic epithelium, and preserved the activity of intestinal stem cells (ISCs) both in vivo and in vitro. However, both continuous iron depletion by DFO and late DFO treatment aggravated colonic injury and postponed the recovery from colitis. Early DFO-induced iron depletion was able to maintain the p-STAT3 and p-ERK1/2 signaling pathways within the colonic epithelium at the early phase of colitis, but late DFO treatment inhibited the activity of these two pathways.

Our study demonstrated that the manipulation of iron depletion by DFO might greatly affect the outcomes of experimental colitis in a phase-dependent manner, which suggests that the balance of iron metabolism might be an effective therapeutic target for the clinical treatment of IBD patients.

Inflammatory Bowel Diseases (IDB) are chronic disorders characterized by gut inflammation, mucosal damage, increased epithelial permeability and altered mucus layer. No accurate in vitro model exists to simulate these characteristics. In this context, drug development for IBD or intestinal inflammation requires in vivo evaluations to verify treatments efficacy. A new model with altered mucus layer composition; altered epithelial permeability and pro-inflammatory crosstalk between immune and epithelial cells will be developed to enhance in vitro models for studying IBD treatments. The effects of dextran sulfate sodium and/or lipopolysaccharides on intestinal permeability, cytokines synthesis (IL-6, IL-8, TNF-α and IL-1β), mucins (MUC2, MUC5AC) and tight junction proteins expression (Claudin-1, ZO-1 and Occludin) were investigated in a tri-coculture model combining differentiated Caco-2/HT29-MTX cells and THP-1 cells. Two anti-inflammatory agents were evaluated to assess the model's therapeutic strategy applicability (corticoids and pro-resolving factors). Two in vitro models have been developed. The first model, characterized by increased permeability of the epithelial layer and subsequent secretion of inflammatory cytokines, can reproduce the different phases of inflammation, and enables the evaluation of preventive treatments. The second model simulates the acute phase of inflammation and allows for the assessment of curative treatments. Both models demonstrated reversibility when treated with betamethasone and pro-resolving factors. These in vitro models are valuable for selecting therapeutic agents prior to their application in in vivo models. They enable the assessment of agents' anti-inflammatory effects and their ability to permeate the inflamed epithelial layer and interact with immune cells.

Salmonella Enteritidis is one of the main pathogens of foodborne diseases and an important pathogen causing diarrhea in yaks. Antibiotics are the mainstay of treatment for salmonellosis, but the widespread use of antibiotics has increased Salmonella resistance. Probiotics have been shown to antagonize Salmonella and reduce Salmonella infection. Bacillus pumilus is one of the microbial feed additives approved by the Chinese Ministry of Agriculture for use in animal breeding, which has the effect of improving animal growth performance and immunity, among others. Therefore, this paper explored the anti-infective effect of Bacillus pumilus against Salmonella.

Bacillus pumilus SMU5927 significantly enhances the intestinal mechanical barrier and reduces the number of Salmonella transferred to the organs. Bacillus pumilus SMU5927 ameliorated intestinal tissue damage and attenuated intestinal inflammatory responses in mice. In addition, Bacillus pumilus increased the ratio of the Firmicutes/Bacteroidetes in the intestinal flora, increased the abundance of beneficial bacteria such as Lactobacillus, and decreased the abundance of harmful bacteria.

This study confirmed the role of Bacillus pumilus SMU5927 in preventing and attenuating Salmonella damage and provided ideas for the development of novel antimicrobial drugs.

Ulcerative colitis (UC) is a chronic inflammatory bowel condition that significantly impairs patient quality of life and remains incurable. Effective dietary management is crucial for both prevention and treatment. This study investigates the effects and mechanisms of Eurotium cristatum-fermented black tea (FBT) in a dextran sulfate sodium (DSS)-induced UC mouse model using transcriptome sequencing, immunofluorescence, and flow cytometry. Our results demonstrate that FBT significantly protects intestinal integrity by suppressing NF-κB-dependent inflammatory genes through the activation of peroxisome proliferator-activated receptor gamma (PPARγ) and modulation of the NF-κB signaling pathway. FBT enhances intestinal barrier integrity by limiting microbial penetration and metabolite translocation into systemic circulation, thereby reducing systemic inflammation risk. Additionally, FBT promotes intestinal mucosa repair and maintains microecological homeostasis by regulating intestinal flora and enhancing the biosynthesis of short-chain fatty acids and amino acids. These findings suggest that FBT has promising prophylactic potential for preventing and alleviating UC by modulating multiple biological pathways, including reducing inflammation, mitigating oxidative stress, and strengthening intestinal barrier integrity. This study lays the groundwork for future research on dietary interventions for UC prevention and management.

Biofilms are structured microbial communities that adhere to various abiotic and biotic surfaces, where organisms are encased in an exo-polysaccharide matrix. Organisms within biofilms use various mechanisms that help them resist external challenges, such as antibiotics, rendering them more resistant to drugs. Therefore, researchers have attempted to develop suitable laboratory models to study the physical features of biofilms, their resistance mechanisms against antimicrobial agents, and their gene and protein expression profiles. However, current laboratory models suffer from various limitations. In this comprehensive review, we have summarized the various designs that have been used for laboratory biofilm models, presenting their strengths and limitations. Additionally, we have provided insight into improving these models to more closely simulate real-life scenarios, using newly developed techniques in additive manufacturing, synthetic biology, and bioengineering.

Inflammatory bowel disorders (IBD) can lead to severe complications like perforation, bleeding, and colon cancer, posing life-threatening risks. Lycium ruthenicum Murray (L. ruthenicum Murr.), rich in polysaccharides, has been utilized in traditional diets for thousands of years. This study explores the protective effects of the polysaccharide of L. ruthenicum on mice with dextran sulfate sodium (DSS)-induced colitis. In the present study, a pectic polysaccharide (LRWP-Ap) containing arabinogalactan (AG) and homogalacturonic acid (HG) structural domains with a Mw of 4.34 kDa was obtained from L. ruthenicum Murr. Fruit. The gavage administration of LRWP-Ap significantly alleviated symptoms of DSS-induced colitis in mice. In this process, LRWP-Ap modulated the balance of Arg-1/iNOS to regulate the metabolism of arginine, and the levels of intestinal tight junction (TJ) (ZO-1, Occludin, and Claudin 1) were increased by LRWP-Ap treatment, which promoted intestinal barrier function. In addition, LRWP-Ap alleviated the inflammatory response while increasing the anti-inflammatory response by reducing the level of proinflammatory factors, enhancing the level of anti-inflammatory factors (IL-10) and improving the balance of Treg/Th17 cells. These effects resulted in the maintenance of intestinal immune homeostasis. Moreover, LRWP-Ap modulated the gut microbiota composition and short-chain fatty acid (SCFA) content, which may maintain relatively favorable intestinal homeostasis. In general, LRWP-Ap has the potential to alleviate IBD, and the use of L. ruthenicum Murr. As a natural functional food to improve gut health in the context of DSS-induced colitis.

Hirsutella sinensis (H. sinensis), a non-sexual form of the valuable Chinese medicinal herb, demonstrates various biological activities, such as immune modulation and antioxidative capabilities. Nonetheless, the effects of bioactive polysaccharides derived from H. sinensis on colitis have yet to be investigated. In our prior research, we extracted a mannoglucan (HSWP-1d) from H. sinensis and found that it attenuates TGF-β1-induced epithelial-mesenchymal transition. The present study investigated the protective effects of HSWP-1d against colitis induced by dextran sulfate sodium (DSS) in mice. The results demonstrate that HSWP-1d effectively ameliorates symptoms of colitis and preserves the intestinal barrier's stability by enhancing the expression of tight junction proteins. The administration of HSWP-1d results in a reduction in oxidative stress through the augmentation of antioxidative enzyme activities, concomitant with the suppression of oxidative product generation. Simultaneously, HSWP-1d reduced the levels of pro-inflammatory cytokines while elevating the levels of anti-inflammatory cytokines, effectively mitigating the inflammatory response. Furthermore, HSWP-1d influences and alters short-chain-fatty-acid (SCFA) levels, thereby enhancing the intestinal microenvironment. In conclusion, HSWP-1d contributes to intestinal well-being and holds potential as both a therapeutic choice and a supplier of essential nutrients for the amelioration of colitis.

Complex respiratory diseases are a significant challenge for the livestock industry worldwide. These diseases considerably impact animal health and welfare and cause severe economic losses. One of the first lines of pathogen defense combines the respiratory tract mucus, a highly viscous material primarily composed of mucins, and a thriving multi-kingdom microbial ecosystem. The microbiome-mucin interplay protects from unwanted substances and organisms, but its dysfunction may enable pathogenic infections and the onset of respiratory disease. Emerging evidence also shows that noncoding regulatory RNAs might modulate the structure and function of the microbiome-mucin relationship. This opinion paper unearths the current understanding of the triangular relationship between mucins, the microbiome, and noncoding RNAs in the context of respiratory infections in animals of veterinary interest. There is a need to look at these molecular underpinnings that dictate distinct health and disease outcomes to implement effective prevention, surveillance, and timely intervention strategies tailored to the different epidemiological contexts.

High energy diets are a risk factor for intestinal barrier damage. Butyrate, a major energy source for intestinal epithelial cells, has been shown to improve barrier dysfunction and modulate the gut microbiota. In this trial, we examined the preventative effect of coated sodium butyrate (CSB) on high-energy and low-protein (HELP)-induced intestinal barrier injury in laying hens, and also worked to determine the underlying mechanisms by an integrative analysis of gut microbiota and the metabolome. A total of 216 healthy 28-week-old Huafeng laying hens were randomly assigned to 3 groups with 6 replicates each: the CON group (normal diet), HELP group (HELP diet) and CH500 group (500 mg/kg CSB added to HELP diet). The duration of the trial encompassed a period of 10 weeks. The results revealed that CSB treatment improved the laying rate and mitigated the detrimental effects on intestinal barrier function and the inflammatory response induced by the HELP diet in laying hens (P < 0.05). Microbial profiling analysis revealed that the CSB treatment reshaped the HELP-perturbed gut microbiota and promoted the growth of beneficial bacteria (P < 0.05). Untargeted metabolomics analysis revealed that CSB reduced the metabolites associated with intestinal inflammation (P < 0.05). In conclusion, CSB did not merely modulate alterations in the gut microbiota composition and microbial metabolites but also yielded increased egg production, while mitigating intestinal barrier dysfunction and inflammatory responses induced by HELP in laying hens.

The global epidemic of type 2 diabetes mellitus (T2DM) imposes a substantial burden on public health and healthcare expenditures, thereby driving the pursuit of cost-effective preventive and therapeutic strategies. Emerging evidence suggests a potential association between dysbiosis of gut microbiota and its metabolites with T2DM, indicating that targeted interventions aimed at modulating gut microbiota may represent a promising therapeutic approach for the management of T2DM. In this review, we concentrated on the multifaceted interactions between the gut microbiota and the intestinal barrier in the context of T2DM. We systematically summarized that the imbalance of beneficial gut microbiota and its metabolites may constitute a viable therapeutic approach for the management of T2DM. Meanwhile, the mechanisms by which gut microbiota interventions, such as probiotics, prebiotics, postbiotics, and synbiotics, synergistically improve insulin resistance in T2DM are summarized. These mechanisms include the restoration of gut microbiota structure, upregulation of intestinal epithelial cell proliferation and differentiation, enhancement of tight junction protein expression, promotion of mucin secretion by goblet cells, and the immunosuppressive functions of regulatory T cells (Treg) and M2 macrophages. Collectively, these actions contribute to the amelioration of the body's metabolic inflammatory status. Our objective is to furnish evidence that supports the clinical application of probiotics, prebiotics, and postbiotics in the management of T2DM.

Damage to intestinal epithelial cells is present in obesity and other diseases because of inflammatory and oxidative processes. This damage compromises the gastrointestinal barrier, killing enterocytes, altering intestinal permeability, and eliciting abnormal immune responses that promote chronic inflammation. Recent evidence shows that spirulina is a potent natural agent with antioxidant and anti-inflammatory properties.

This study was conducted to evaluate the effect of spirulina aqueous extract (SPAE) on the alterations of the intestinal epithelium induced by lipid micelles (LMs) and/or inflammation induced by lipopolysaccharides (LPSs) in the Caco-2 cell line.

In the current research, we assessed the protective actions of SPAE against cytotoxicity, oxidative stress, inflammation, and epithelial barrier perturbation by using an in vitro model, the intestinal Caco-2 cells, treated with LPSs and/or LMs. We also performed an in silico molecular docking analysis with spirulina's bioactive compound, phycocyanobilin.

Our results showed that SPAE has no cytotoxic effect on Caco-2 cells. On the contrary, it improved cell viability and exhibited anti-inflammatory and antioxidant actions. SPAE also protected against endoplasmic reticulum stress and tight junction proteins, thus improving the epithelial barrier. The in silico study revealed a strong binding affinity of the phycocyanobilin compound with human SOD and NADPH oxidase and a good binding affinity towards COX-2 and iNOS.

Taken together, these findings demonstrate the beneficial actions of SPAE on Caco-2 cells, suggesting it may be useful in preserving the epithelial intestinal barrier in human conditions involving oxidative stress and inflammation such as obesity.

Previous reviews have focused on the effects of probiotics on colitis, but there is a need to understand their impact on barrier integrity and tight junction protein improvement in colitis.

This study aimed to systematically examine the effects of probiotic use on barrier integrity in colitis disease. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

A systematic search in PubMed, Web of Science, Scopus, and Cochrane databases identified 2537 articles.

As a result of the search, 2537 articles were accessed. Study results were summarized descriptively through discussions by intervention conditions, study population, measurement methods, and key findings. The included studies were independently reviewed and all authors reached consensus on the quality and major findings from the included articles. Forty-six studies that met the inclusion criteria were analyzed within the scope of the systematic review.

Although the study primarily utilized probiotics from the Lactobacillaceae family (notably, L casei, L reuteri, L rhamnosus, L plantarum, and L pentosus) and the Bifidobacteriaceae family (notably, B breve, B animalis, and B dentium), other probiotics also demonstrated positive effects on tight junction proteins. These effects are attributed to the production of bioactive and metabolic compounds, as well as short-chain fatty acids, which combat pathogens and reduce anti-inflammatory agents. However, it was observed that the effects of these probiotics on tight junction proteins varied depending on the strain and dose.

The beneficial effects of probiotics on remission in inflammatory bowel disease are well documented. Studies show that probiotics generally improve intestinal barrier function, but factors such as dose, duration, and bacterial species combinations need further clarification. Additionally, comprehensive studies are needed to understand how improved barrier function affects absorption in individuals.

PROSPERO registration no. CRD42023452774.

Infection by pathogenic bacteria during weaning is a common cause of diarrhea and intestinal inflammation in piglets. Supplementing the diet with synbiotics is beneficial for animal health. The strain of Lactiplantibacillus plantarum L47 (L47) isolated in our lab exhibited good probiotic properties when combined with inulin. Here, the effectiveness of combining L47 and inulin (CLN) in protecting against enterotoxigenic Escherichia coli (ETEC) induced colon and liver inflammation in weaned piglets was evaluated.

Twenty-eight piglets aged 21 days were randomly assigned into 4 groups: CON (control), LI47 (oral CLN culture fluid, 1010 CFU/d of L47 and 1 g/d of inulin), ECON (oral ETEC culture fluid, 1010 CFU/d), and ELI47 (oral CLN and ETEC culture fluid). After 24 days, the colon and liver samples were collected for further analysis.

CLN alleviated colon damage caused by ETEC challenge, as evidenced by an increase of colonic crypt depth, mRNA expression of tight junction Claudin-1 and Occludin, GPX activity, the concentration of IL-10 and sIgA (p < 0.05). Moreover, there was a decrease in MDA activity, the load of E. coli, the concentration of LPS, gene expression of TLR4, and the concentration of TNF-α and IL-6 (p < 0.05) in colonic mucosa. Additionally, CLN counteracted liver damage caused by ETEC challenge by modulating pathways associated with immunity and disease occurrence (p < 0.05).

Supplementing with CLN alleviated colon inflammation induced by ETEC challenge by decreasing the E. coli/LPS/TLR4 pathway and regulating hepatic immune response and disease-related pathways, suggesting that CLN could protect intestinal and liver health in animals.

Injection of lipopolysaccharides (LPS) in experimental models induces a systemic inflammatory response that is associated with deleterious effects on intestinal morphology and physiology. In this study, we have studied in female mice the effects of dietary supplementation with bovine lactoferrin (bLF) given before intraperitoneal injection of LPS on jejunum and colon.

The first study evaluated the efficiency of different bLF and LPS concentrations to determine the optimal experimental conditions. For the second study mice were fed with 1% bLF before the LPS challenge (3 mg/kg body weight). Plasmatic markers of inflammation, intestinal morphology, permeability, and expression of genes related to epithelial differentiation, epithelial barrier function and intestinal inflammation in both small intestine and colon were evaluated.

bLF ingestion before the LPS challenge reduced the TNF-α circulating concentration, compared to control animals. This decrease in plasma TNF-α was correlated with improved intestinal permeability. The morphology of jejunal epithelium, which was affected by LPS challenge, was partly maintained by bLF. Measurement of the expression of genes encoding proteins involved in epithelial differentiation, intestinal inflammation, and epithelial barrier function suggests an overall protective effect of bLF against the adverse effects of LPS in the jejunum. In the colon, the effects of bLF ingestion on the subsequent LPS challenge, although protective, remain different when compared with those observed on jejunum.

Taken together, our data indicate that bLF dietary supplementation does have a protective effect on the deleterious intestinal alterations induced by LPS systemic inflammation.

Bioactive peptides hold significant potential for enhancing human health, however, their limited oral bioavailability poses a substantial barrier to their widespread use in the food and pharmaceutical industries. This article reviews the key factors influencing the absorption efficiency of oral bioactive peptides, including issues related to bitter taste perception, challenges in gastrointestinal environmental stability, and limitations in transmembrane transport. Furthermore, it highlights the latest technologies, such as osmotic technology, chemical modification, and advanced delivery systems, and discusses their advantages in enhancing the stability of bioactive peptides and facilitating intestinal absorption. In addition, the application and challenges of common delivery systems such as liposomes, emulsions, polymer nanoparticles, and hydrogels in oral bioactive peptide delivery are also discussed. This paper aims to provide a theoretical foundation for scientific research and practical applications of oral delivery of bioactive peptides, thereby promoting the further development of bioactive peptides in the context of human health.

Inflammatory bowel disease (IBD) is a chronic, systemic gastrointestinal disorder characterized by episodic inflammation that requires life-long management. Although the etiology of IBD is not fully understood, it is hypothesized to involve a multifaceted interplay among genetic susceptibility, the host immune response, and environmental factors. Previous studies have largely concluded that IBD is associated with this complex interplay; however, more recent evidence underscores the significant role of dietary habits as risk factors for the development of IBD. In this review, we review the molecular mechanisms of high-sugar and high-fat diets in the progression of IBD and specifically address the impacts of these diets on the gut microbiome, immune system regulation, and integrity of the intestinal barrier, thereby highlighting their roles in the pathogenesis and exacerbation of IBD.

For clinical translation of oral nanocarriers, simulation of the intestinal microenvironment during in vitro testing is crucial to evaluate interactions with the intestinal mucosa. However, studies are often conducted using simplistic cell culture models, overlooking key physiological factors, and potentially leading to an overestimation of nanocarrier permeation. In this study, we systematically investigate different tissue models of the human intestine under static cultivation and dynamic flow conditions and analyze the impact of altered tissue characteristics on nanocarrier permeation. Our results reveal that the selection of cell types as well as the respective culture condition have a notable impact on the physiological characteristics of the resulting tissues. Tissue layer thickness, mucus secretion, and barrier impairment, all increase with increasing amounts of goblet cells and the application of dynamic flow conditions. Permeation studies with poly(lactic-co-glycolic acid) (PLGA) nanocarriers with and without polyethylene glycol (PEG) coating elucidate that the amount of mucus present in the respective model is the limiting factor for the permeation of PLGA nanocarriers, while tissue topography presents the key factor influencing PEG-PLGA nanocarrier permeation. Furthermore, both nanocarriers exhibit diametrically opposite permeation kinetics compared to soluble compounds. In summary, these findings reveal the critical role of the implemented test systems on permeation assessment and emphasize that, in the context of preclinical nanocarrier testing, the choice of in vitro model matters.

High-dose radiation exposure results in gastrointestinal (GI) acute radiation syndrome identified by the destruction of mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses. In addition, radiation causes gut microbiome dysbiosis characterized by diminished microbial diversity, reduction in the abundance of beneficial commensal bacteria, and the spread of bacterial pathogens that trigger the recruitment of immune cells and the production of pro-inflammatory factors that lead to further GI tissue damage. Currently, there are no FDA-approved countermeasures that can treat radiation-induced GI injury. To meet this critical need, Synedgen Inc., has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract which acts by intercalating into the mucus layer and the glycocalyx of intestinal epithelial cells that could potentially ameliorate the deleterious effects of radiation. Male C57BL/6J adult mice were exposed to 13 Gy total body X-irradiation with 5% bone marrow shielding and MIIST305 was administered on days 1, 3, and 5 post-irradiation. Approximately 85% of the animals survived the irradiation exposure and were apparently healthy until the end of the 30-day study period. In contrast, no control, vehicle-treated animals survived past day 10 at this radiation dose. We show that MIIST305 improved intestinal epithelial barrier function and suppressed systemic inflammatory response mediated by radiation-induced pro-inflammatory cytokines. Taxonomic profiling and community structure of the fecal and colonic mucosa microbiota demonstrated that MIIST305 treatment increased microbial diversity and restored abundance of beneficial commensal bacteria, including Lactobacillus and Bifidobacterium genera, while suppressing potentially pathogenic bacteria compared with vehicle-treated animals. In summary, MIIST305 is a novel GI-targeted therapeutic that greatly enhances survival in mice exposed to lethal radiation and protects the GI tract from injury by restoring a balanced gut microbiota and effectively reducing proinflammatory responses. Further development of this drug as an FDA-approved medical countermeasure will be of critical importance in the event of a radiation public health emergency.

Epidemiological studies have shown that subnormal levels of vitamin D (25[OH]D) are associated with a more aggravated clinical course of ulcerative colitis [UC]. Despite an increased focus on the therapeutic importance of vitamin D and vitamin D receptor [VDR] signalling, the mechanisms underlying the effects of the vitamin D-VDR axis on UC remain elusive. Therefore, we aimed to investigate whether exposure to active vitamin D (1,25[OH]2D3/VDR) signalling in human organoids could influence the maintenance of the colonic epithelium.

Intestinal VDR expression was studied by immunohistochemistry, RNA expression arrays, and single-cell RNA sequencing of colonic biopsy specimens obtained from patients with UC and healthy individuals. To characterise the functional and transcriptional effects of 1,25[OH]2D3, we used patient-derived colonic organoids. The dependency of VDR was assessed by knocking out the receptor with CRISPR/Cas9.

Our results suggest that 1,25[OH]2D3/VDR stimulation supports differentiation of the colonic epithelium and that impaired 1,25[OH]2D3/VDR signalling thereby may compromise the structure of the intestinal epithelial barrier, leading to flares of UC. Furthermore, a transcriptional response to VDR activity was observed primarily in fully differentiated cells at the top of the colonic crypt, and this response was reduced during flares of UC.

We identified an important role of vitamin D signalling in supporting differentiated cell states in the human colonic epithelium, and thereby maintenance of the intestinal barrier integrity. This makes the vitamin D-VDR signalling axis an interesting target for therapeutic efforts to achieve and maintain remission in patients with UC.