Impaired Intestinal Barrier Research Articles

Weaning causes imbalanced T lymphocyte distribution and impaired intestinal immune barrier function in piglets

Context The immune system of piglets is not fully developed at weaning. The immature adaptive immune system along with the change in the feed types and the living conditions make piglets susceptible to pathogenic infections, and result in diarrhoea and decreased growth. However, the underlying mechanisms require further research. Aims This study was conducted to investigate the effects of weaning on the growth performance and intestinal immune function of piglets. Methods In total, 40 piglets with similar bodyweights were selected in pairs at 21 days old and divided into the suckling group (SG, breastfed by their mothers) and weaning group (WG, weaned at 21 days old). Eight piglets from each group were randomly selected and sacrificed at 24 days (SG3 and WG3) and 28 days of age (SG7 and WG7). The growth performance, T lymphocyte subpopulations, the concentration of cytokines and immunoglobulins, and the expression of Notch2 signalling proteins were determined. Key results The weaning caused a decrease in bodyweight (P < 0.01) and the ratio of CD3+CD4+/CD3+CD8+ T cells in the thymus (P < 0.05). Compared with SG3, the concentration of secretory immunoglobulin A (sIgA) in the jejunum was decreased, and that of interleukin 2 (IL-2) in serum and ileum, IL-1β and IL-2 in jejunum were upregulated (P < 0.01), while IL-10 in the small intestine was downregulated (P < 0.05) in WG3. Weaning downregulated gene expression of IL-4 and upregulated gene expression of IL-1β, IL-12, and interferon γ (IFN-γ) in small intestine (P < 0.05). Weaning downregulated protein expression of Notch2 and Hes1 but upregulated Jagged1 expression in small intestine of piglets (P < 0.05). Conclusions Weaning caused an imbalance in T lymphocyte distribution, thus impairing the intestinal immune function of piglets, which might be associated with the Notch2 signalling. Furthermore, weaning caused adverse effects on piglets especially on the first 3 days, which were partly recovered after 3 days, but still existed at 7 days after weaning. Implications The results of this study may guide the pig-raising industry, especially for the management of piglets shortly after weaning.

Involvement of gut microbiota recovery and autophagy induction in Youhua Kuijie formula's protection against experimental ulcerative colitis.

Ulcerative colitis (UC) is characterized by overactive inflammatory response, impaired intestinal mucosal barrier and disrupted gut microbiota. Youhua Kuijie formula is a classic empirical prescription based on the pathogenesis of UC. The present study was designed to verify the protective effect of Youhua Kuijie formula on DSS-induced UC in mice and uncover the related mechanism. Youhua Kuijie formula were orally administrated to UC mice induced by DSS dissolved in drinking water for ten days. The protective effect of Youhua Kuijie formula was evidenced by reduced pathological symptoms accompanied by palliative inflammatory response and relatively intact intestinal barrier. The data from 16S rRNA gene sequencing and GC-MS untargeted metabolomics indicated that the supplement of Youhua Kuijie formula restructured gut microbiota community structure, and thereby modulated the metabolic profiles in UC mice. The analysis of pathway enrichment analysis suggested the major alterations in metabolic pathway were related to protein digestion and absorption. Besides, the results of the following experiments suggested that Youhua Kuijie formula treatment increased adenosine monophosphate-activated protein kinase (AMPK) activation, decreased mechanistic target of rapamycin (mTOR) phosphorylation, and thereby reversing autophagy deficiency in the intestinal tract of UC mice. Collectively, our results demonstrated that the regulation of AMPK/mTOR was involved in Youhua Kuijie formula administration mediated protective effect on UC.

Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway.

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.

Гастроинтестинальные расстройства, ассоциированные с расстройством аутистического спектра

Aim. A synthesis of scientific literature data on the association of autism spectrum disorders (ASD) with gastrointestinal dysfunction and disturbances of the intestinal microbiota. Key points. ASDs belong to a group of neurodevelopmental disorders associated with genetic, epigenetic and environmental factors, and include conditions that are heterogeneous in clinical presentation and severity of psychopathological symptoms. ASD is often comes with various symptoms of gastrointestinal tract dysfunction referred to impaired intestinal barrier permeability. The consequence is the pervasion of external agents (food antigens, toxins, bacterial metabolites) into the blood and initiation or maintenance of the inflammatory process, which is the most important pathophysiological link in ASD. Particular attention is paid to the analysis of the mechanisms of impaired intestinal barrier permeability. It is necessary to develop strategies aimed at reducing the level of inflammation in complex therapy of patients with ASD. Conclusion. Patients with ASD, in addition to psychoneurological symptoms, often present somatic problems, which, however, may not be timely recognized due to their nonspecificity and the difficulty of differentiating behavioral reactions either associated with the disorder or being just a reaction to somatic ill-being.Moreover, the whole complex of clinical manifestations is mediated by a single systemic dysregulation of immunological and metabolic reactions and is inherently a different reflection of one process, requiring profound multidisciplinary treatment and the use of various therapy approaches. Keywords: autism spectrum disorders, neuroinflammation, microbiome, intestinal permeability.

P-hydroxy benzaldehyde attenuates intestinal epithelial barrier dysfunction caused by colitis via activating the HNF-1β/SLC26A3 pathway.

Intestinal epithelial barrier dysfunction is intricately linked to the pathogenesis of ulcerative colitis (UC). Dietary interventions that bolster intestinal epithelial barrier function can effectively thwart UC onset. Our prior research revealed that p-Hydroxy benzaldehyde (HD), a phenolic compound from Nostoc commune (an edible cyanobacterium), markedly upregulated the expression of E-cadherin, a pivotal protein in intestinal mucosa, thereby mitigating mucosal damage in mice afflicted with dextran sulfate sodium (DSS)-induced colitis. Nevertheless, the precise molecular mechanisms underpinning HD's ameliorative effects on intestinal epithelial barrier dysfunction remain elusive. Dextran sodium sulfate (DSS)-induced colitis mouse model was established, and the successful establishment of the model was determined by evaluating the changes in body weight, disease activity index (DAI), colonic histopathology, and white blood cell count. Transmission electron microscopy (TEM) observed the ultrastructural changes of intestinal villi. The levels of inflammatory factors ( IFN-γ IL-13 ) and intestinal permeability indicators (FITC-Dextran, DAO, ET, and D-LA ) were detected by Enzyme-linked immunosorbent assay (ELISA). Western blotting (WB) and immunohistochemistry (IHC) were used to detect the expression of intestinal barrier integrity-related factors such as tight junction protein TJs (ZO-1, occludin) and adhesion junction protein AJs (E-cadherin). Furthermore, WB, Pull-down assay, drug affinity reaction target stability (DARTS) assay, molecular docking and molecular dynamics (MD) simulation were used to determine the potential target and molecular mechanism of HD. HD intervention significantly alleviated the symptoms of colitis mice, inhibited the weight loss and colon shortening, reduced DAI score and colon pathological score, maintained the ultrastructure of intestinal villi in colon tissue, and significantly reduced the inflammatory factors IFN-γ, IL-13 and the number of white blood cells in colon tissue of colitis mice. HD could also reduce the levels of FITC-Dextran, DAO, ET, and D-LA and increase the expression of ZO-1, occludin, and E-cadherin in the colonic tissues of colitis mice, thereby maintaining the impaired intestinal barrier function caused by colitis. Mechanically, HD augmented the expression of hepatocyte nuclear factor 1β (HNF-1β) and DRA. Adeno-associated virus (AAV)-HNF-1β shRNA or Lentivirus-mediated HNF-1β knockdown effectively abolished HD-induced intestinal barrier protection, as well as the promotion of solute carrier family 26 member 3 (SLC26A3) expression levels. SLC26A3 siRNA effectively reversed the inhibition of intestinal permeability by HD. Pull-down assay, DARTS analysis, molecular docking, and MD results showed high binding strength, interaction efficiency and remarkable stability between HNF-1β and HD. This study elucidates HD's role in forestalling intestinal epithelial barrier disruption under colitis conditions. Mechanistic investigations revealed that HD fortifies TJs and AJs expression via the HNF-1β/SLC26A3 pathway, thus preserving the lower intestinal epithelial barrier's integrity in UC.

The PI3K/Akt-Nrf2 Signaling Pathway and Mitophagy Synergistically Mediate Hydroxytyrosol to Alleviate Intestinal Oxidative Damage.

Oxidative stress is a major pathogenic factor in many intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The Nrf2 signaling pathway and mitophagy can reduce reactive oxygen species (ROS) and alleviate oxidative stress, but their relationship is unclear. Hydroxytyrosol (HT), a polyphenolic compound abundant in olive oil, has strong antioxidant activity and may help treat these diseases. We used pigs as a model to investigate HT's effect on intestinal oxidative damage and its mechanisms. Diquat (DQ) induced oxidative stress and impaired intestinal barrier function, which HT mitigated. Mechanistic studies in IPEC-J2 cells showed that HT protected against oxidative damage by activating the PI3K/Akt-Nrf2 signaling pathway and promoting mitophagy. Our study highlighted the synergistic relationship between Nrf2 and mitophagy in mediating HT's antioxidant effects. Inhibition studies confirmed that disrupting either pathway compromised HT's protective effects. Maintaining redox balance through Nrf2 and mitophagy is important for eliminating excess ROS. Nrf2 increases antioxidant enzymes to clear existing ROS, while mitophagy removes damaged mitochondria and reduces ROS generation. This study demonstrates that these pathways collaboratively modulate the antioxidant effects of HT, with neither being dispensable. Targeting Nrf2 and mitophagy could be a promising strategy for treating oxidative stress-related intestinal diseases, with HT as a potential treatment.

New insights into the intestinal barrier through "gut-organ" axes and a glimpse of the microgravity's effects on intestinal barrier.

Gut serves as the largest interface between humans and the environment, playing a crucial role in nutrient absorption and protection against harmful substances. The intestinal barrier acts as the initial defense mechanism against non-specific infections, with its integrity directly impacting the homeostasis and health of the human body. The primary factor attributed to the impairment of the intestinal barrier in previous studies has always centered on the gastrointestinal tract itself. In recent years, the concept of the "gut-organ" axis has gained significant popularity, revealing a profound interconnection between the gut and other organs. It speculates that disruption of these axes plays a crucial role in the pathogenesis and progression of intestinal barrier damage. The evaluation of intestinal barrier function and detection of enterogenic endotoxins can serve as "detecting agents" for identifying early functional alterations in the heart, kidney, and liver, thereby facilitating timely intervention in the disorders. Simultaneously, consolidating intestinal barrier integrity may also present a potential therapeutic approach to attenuate damage in other organs. Studies have demonstrated that diverse signaling pathways and their corresponding key molecules are extensively involved in the pathophysiological regulation of the intestinal barrier. Aberrant activation of these signaling pathways and dysregulated expression of key molecules play a pivotal role in the process of intestinal barrier impairment. Microgravity, being the predominant characteristic of space, can potentially exert a significant influence on diverse intestinal barriers. We will discuss the interaction between the "gut-organ" axes and intestinal barrier damage, further elucidate the signaling pathways underlying intestinal barrier damage, and summarize alterations in various components of the intestinal barrier under microgravity. This review aims to offer a novel perspective for comprehending the etiology and molecular mechanisms of intestinal barrier injury as well as the prevention and management of intestinal barrier injury under microgravity environment.

Moringa oleifera leaf alleviates functional constipation via regulating the gut microbiota and the enteric nervous system in mice.

Moringa oleifera Lam. leaf is not only a new food resource in China, but also a traditional medicinal plant. It is commonly used in the folk to alleviate constipation, but its laxative mechanism is not fully understood. Hence we investigated it in loperamide-induced functional constipation (FC) mice. The results showed that MOAE significantly regulated not only gastrointestinal hormones and neurotransmitters in serum but also important gastrointestinal motility factors in the enteric nervous system (ENS)-interstitial cells of Cajal (ICCs)-smooth muscle cell (SMC) network. Meanwhile, MOAE attenuated intestinal inflammation, increased cecal short-chain fatty acid levels and colonic antimicrobial peptide expression, and improved the impaired intestinal barrier function in loperamide-induced FC mice. In addition, MOAE also increased fecal water content by inhibiting the mRNA expression of colonic aquaporins (Aqp3 and Aqp4) in FC mice. Interestingly and importantly, MOAE affected the intestinal microbiota by inhibiting some key "constipation-causing" microbiota, such as Bacteroidaceae, Clostridiaceae, Bacteroides, and Ruminococcus, and promoting the growth of other important "constipation-curing" microbiota, such as Butyricoccus, Tyzzerella, and Desulfovibrio. These important taxa are significantly associated with a variety of indicators of constipation. These findings suggest that MOAE can promote defecation through its rich chemical composition to modulate the ENS-ICCs-SMCs network and the gut microecosystem.

Curcumin suppresses the Wnt/β-catenin signaling pathway by inhibiting NKD2 methylation to ameliorate intestinal ischemia/reperfusion injury.

Intestinal ischemia/reperfusion (I/R) injury is a life-threatening condition with no effective treatment currently available. Curcumin (CCM), a polyphenol compound in Curcuma Longa, reportedly has positive effects against intestinal I/R injury. However, the mechanism underlying the protective effect of CCM against intestinal I/R injury has not been fully clarified. To determine whether the protective effect of CCM was mediated by epigenetic effects on Wnt/β-catenin signaling, the effect of CCM was examined in vivo and in vitro. An intestinal I/R model was established in Sprague-Dawley (SD) rats with superior mesenteric artery occlusion, and Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) for in vivo simulation of I/R. The results showed that CCM significantly reduced inflammatory, cell apoptosis, and oxidative stress induced by I/R insult in vivo and in vitro. Western blot analysis showed that CCM preconditioning reduced the protein levels of β-catenin, p-GSK3β, and cyclin-D1 and increased the protein level of GSK3β compared with the I/R group. Overexpressing β-catenin aggravated H/R injury, and knocking down β-catenin relieved H/R injury by improving intestinal permeability and reducing the cell apoptosis. Moreover, Naked cuticle homolog 2(NKD2) mRNA and protein levels were upregulated in the CCM-pretreated group. 5-aza-2'-deoxycytidine (5-AZA) treatment improved intestinal epithelial barrier impairment induced by H/R. Besides, the protein levels of total β-catenin, phosphor-β-catenin and cyclin-D1 were reduced after overexpressing NKD2 in Caco-2 cells following H/R insult. In conclusion, Our study suggests that CCM could attenuate intestinal I/R injury in vitro and in vivo by suppressing the Wnt/β-catenin signaling pathway via inhibition of NKD2 methylation.

Maternal polysorbate 80 intake promotes offspring metabolic syndrome through vertical microbial transmission in mice

Polysorbate 80 (P80) is an emulsifier extensively produced, consumed and discharged into the environment, consequently making human exposure inevitable. Despite evidence suggesting that P80 intake causes metabolic syndrome (MS) in mammals via microbial perturbation, limited data exist on its transgenerational impacts on offspring. In this study, we found that maternal P80 treatment impaired intestinal barrier integrity, leading to metabolic endotoxemia, low-grade inflammation and MS-related symptoms in C57BL/6J female offspring. Further analysis of the gut microbiome revealed MS-related changes in the offspring of P80-treated dams. Fecal microbiota transplantation experiment confirmed the crucial role of the altered microbiome in offspring in the transgenerational impacts of P80. Furthermore, we found that the P80-induced microbial alterations were directly transmitted from P80-treated mothers to their offspring and that interrupting vertical microbial transmission through cesarean section and foster nursing blocked the transgenerational impacts of P80 on the offspring microbiome and metabolic health. Moreover, maternal pectin supplementation also effectively mitigated P80-induced microbial alterations and MS-associated phenotypes in offspring. Together, our results indicated that maternal P80 intake could impair offspring metabolic health through the mother-to-offspring transmission of the microbiome, and maternal pectin supplementation might be a promising strategy for reducing the adverse effects of P80.

Intestinal epithelial barrier protective effect of nut oils (walnut, almond, pistachio, and pine nut) on TNF-α/IFN-γ induced damage in Caco-2 cell monolayers

Damage to the intestinal barrier causes intestinal inflammation, which could lead to the development of gastrointestinal diseases. Nut oils contain an abundance of unsaturated fatty acids, which are responsible for most of the bioactivities of nut oils. Here, the protective effect of four nut oils on the intestinal epithelial barrier was confirmed using Caco-2 cells damaged by tumor necrosis factor-α/interferon-γ treatment. Nut oils effectively increased transepithelial electronic resistance and lowered paracellular fluorescein isothiocyanate-dextran permeability in damaged Caco-2 cells. Furthermore, the nut oils inhibited the pro-inflammatory cytokine production of interleukin-6, which was induced by the inflammatory response. In particular, walnut oil effectively improved tight junction protein (occludin and zonula occludens-1) expression and distribution in damaged Caco-2 cells. In conclusion, our findings suggest that nut oils are promising candidates for impaired intestinal barrier protection.

Intestinal homeostasis in the gut-lung-kidney axis: a prospective therapeutic target in immune-related chronic kidney diseases.

In recent years, the role of intestinal homeostasis in health has received increasing interest, significantly improving our understanding of the complex pathophysiological interactions of the gut with other organs. Microbiota dysbiosis, impaired intestinal barrier, and aberrant intestinal immunity appear to contribute to the pathogenesis of immune-related chronic kidney diseases (CKD). Meanwhile, the relationship between the pathological changes in the respiratory tract (e.g., infection, fibrosis, granuloma) and immune-related CKD cannot be ignored. The present review aimed to elucidate the new underlying mechanism of immune-related CKD. The lungs may affect kidney function through intestinal mediation. Communication is believed to exist between the gut and lung microbiota across long physiological distances. Following the inhalation of various pathogenic factors (e.g., particulate matter 2.5 mum or less in diameter, pathogen) in the air through the mouth and nose, considering the anatomical connection between the nasopharynx and lungs, gut microbiome regulates oxidative stress and inflammatory states in the lungs and kidneys. Meanwhile, the intestine participates in the differentiation of T cells and promotes the migration of various immune cells to specific organs. This better explain the occurrence and progression of CKD caused by upper respiratory tract precursor infection and suggests the relationship between the lungs and kidney complications in some autoimmune diseases (e.g., anti-neutrophil cytoplasm antibodies -associated vasculitis, systemic lupus erythematosus). CKD can also affect the progression of lung diseases (e.g., acute respiratory distress syndrome and chronic obstructive pulmonary disease). We conclude that damage to the gut barrier appears to contribute to the development of immune-related CKD through gut-lung-kidney interplay, leading us to establish the gut-lung-kidney axis hypothesis. Further, we discuss possible therapeutic interventions and targets. For example, using prebiotics, probiotics, and laxatives (e.g., Rhubarb officinale) to regulate the gut ecology to alleviate oxidative stress, as well as improve the local immune system of the intestine and immune communication with the lungs and kidneys.

Polysaccharide from Sparassis latifolia alleviates intestinal barrier dysfunction in mice exposed to lead

Exposure to lead can have harmful effects on the intestines and gut microbiota, leading to toxicity. This study aimed to explore the protective role of Sparassis latifolia polysaccharide (SLP) in safeguarding the intestinal barrier of Kunming mice exposed to lead. The findings indicated that SLP effectively alleviates intestinal lesions, increases the density of cupped cells in the intestine, and reduces inflammation in both serum and the small intestine. Furthermore, SLP maintains the expression of key genes such as ZO-1, Occludin, Claudin-1, Lyz, Ang4, and ZO-2, as well as proteins like claudin-1 and Occludin-1. Furthermore, SLP positively impacts the diversity and richness of microorganisms in the mouse gut microbiota at both the genus and gate levels. It also increases the levels of short-chain fatty acids (SCFAs), including acetic acid, butyric acid, and propionic acid, to varying degrees. In summary, SLP plays a role in alleviating the impaired small intestinal barrier in lead-exposed mice by modulating the intestinal flora, which is consistent with reduced lead absorption. This modulation enhances the integrity of the intestinal barrier, suppresses inflammation, and facilitates the excretion of lead.

Intensive care in severe acute bowel obstruction (clinical lecture)

Most patients with severe acute small bowel obstruction in the early postoperative period require treatment in the intensive care unit. The main principles of intensive care are identifying major vital function disorders, their rapid correction, as well as supporting the functions of the affected organs and systems. The leading pathophysiological disorders that require intensive correction during small bowel obstruction are impaired intestinal barrier function (for bacteria and toxins), hypovolemia, hypotension and microcirculation disorders, primarily in the abdominal organs, fluid and electrolyte and acid-base disorders. Such disorders, in turn, could cause repeated development of intra-abdominal hypertension with impaired perfusion of the abdominal organs. Thus, the efficiency of intensive care for dynamic acute bowel obstruction primarily depends on the speed of correction of fluid and electrolyte disorders and restoration of intestinal blood flow, normalization of gut parietal digestion rather than on the quantity of the drugs that stimulate bowel movement. The primary method of gut microcirculation restoration is the ROSE approach to fluid resuscitation. The main criteria of the intensive care efficiency should be control of intra-abdominal pressure and timely treatment of intra-abdominal hypertension.

Neuropeptide Y-Mediated Gut Microbiota Alterations Aggravate Postmenopausal Osteoporosis.

Postmenopausal osteoporosis (PMO) is often accompanied by neuroendocrine changes in the hypothalamus, which closely associates with the microbial diversity, community composition, and intestinal metabolites of gut microbiota (GM). With the emerging role of GM in bone metabolism, a potential neuroendocrine signal neuropeptide Y (NPY) mediated brain-gut-bone axis has come to light. Herein, it is reported that exogenous overexpression of NPY reduced bone formation, damaged bone microstructure, and up-regulated the expressions of pyroptosis-related proteins in subchondral cancellous bone in ovariectomized (OVX) rats, but Y1 receptor antagonist (Y1Ra) reversed these changes. In addition, it is found that exogenous overexpression of NPY aggravated colonic inflammation, impaired intestinal barrier integrity, enhanced intestinal permeability, and increased serum lipopolysaccharide (LPS) in OVX rats, and Y1Ra also reversed these changes. Most importantly, NPY and Y1Ra modulated the microbial diversity and changed the community composition of GM in OVX rats, and thereby affecting the metabolites of GM (e.g., LPS) entering the blood circulation. Moreover, fecal microbiota transplantation further testified the effect of NPY-mediated GM changes on bone. In vitro, LPS induced pyroptosis, reduced viability, and inhibited differentiation of osteoblasts. The study demonstrated the existence of NPY-mediated brain-gut-bone axis and it might be a novel emerging target to treat PMO.

Effect of Cordyceps militaris Powder Prophylactic Supplementation on Intestinal Mucosal Barrier Impairment and Microbiota-Metabolites Axis in DSS-Injured Mice.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease with an unknown pathogenesis and increasing incidence. The objective of this study is to investigate the impact of prophylactic treatment with Cordyceps militaris on UC. The findings demonstrate that prophylactic supplementation of C. militaris powder effectively mitigates disease symptoms in DSS-injured mice, while also reducing the secretion of pro-inflammatory cytokines. Furthermore, C. militaris powder enhances the integrity of the intestinal mucosal barrier by up-regulating MUC2 protein expression and improving tight junction proteins (ZO-1, occludin, and claudin 1) in DSS-injured mice. Multiomics integration analyses revealed that C. militaris powder not only reshaped gut microbiota composition, with an increase in Lactobacillus, Odoribacter, and Mucispirillum, but also exerted regulatory effects on various metabolic pathways including amino acid, glyoxylates, dicarboxylates, glycerophospholipids, and arachidonic acid. Subsequent analysis further elucidated the intricate interplay of gut microbiota, the intestinal mucosal barrier, and metabolites, suggesting that the microbiota-metabolite axis may involve the effect of C. militaris on intestinal mucosal barrier repair in UC. Moreover, in vitro experiments demonstrated that peptides and polysaccharides, derived from C. militaris, exerted an ability to change the gut microbiota structure of UC patients' feces, particularly by promoting the growth of Lactobacillus. These findings suggest that regulatory properties of C. militaris on gut microbiota may underlie the potential mechanism responsible for the protective effect of C. militaris in UC. Consequently, our study will provide support for the utilization of C. militaris as a whole food-based ingredient against the occurrence and development of UC.

Intestinal immunological events of acute and resolved SARS-CoV-2 infection in non-human primates

SARS-CoV-2 infection has been associated with intestinal mucosal barrier damage, leading to microbial and endotoxin translocation, heightened inflammatory responses, and aggravated disease outcomes. This study aimed to investigate the immunological mechanisms associated with impaired intestinal barrier function. We conducted a comprehensive analysis of gut damage and inflammation markers and phenotypic characterization of myeloid and lymphoid populations in the ileum and colon of SARS-CoV-2-exposed macaques during both the acute and resolved infection phases. Our findings revealed a significant accumulation of terminally differentiated and activated CD4+ and CD8+ T cells, along with memory B cells, within the gastrointestinal tract up to 43 days after exposure to SARS-CoV-2. This robust infection-induced immune response was accompanied by a notable depletion of plasmacytoid dendritic cells, myeloid dendritic cells, and macrophages, particularly affecting the colon during the resolved infection phase. Additionally, we identified a population of CX3CR1Low inflammatory macrophages associated with intestinal damage during active viral replication. Elevated levels of immune activation and gut damage markers, and perturbation of macrophage homeostasis, persisted even after the resolution of the infection, suggesting potential long-term clinical sequelae. These findings enhance our understanding of gastrointestinal immune pathology following SARS-CoV-2 infection and provide valuable information for developing and testing medical countermeasures.

Lactobacillus intestinalis/Lactobacillus rhamnosus protects against AFB1-induced liver damage: involvement of intestinal mucosal barrier

Aflatoxin B1 (AFB1) is a widely spread mycotoxin that poses a threat to the healthy to human and animals. The liver is the main target organ for AFB1-induced damage, primarily causing inflammatory injury and oxidative stress. When AFB1 enters the body, it can damage the intestinal barrier function, and its metabolites are transported to the liver. Therefore, the damage to the liver is closely associated with intestinal barrier impairment. Lactobacillus plays a crucial role in mitigating liver damage by improving the intestinal barrier function. In our previous report, we reported that Lactobacillus reduces liver damage caused by AFB1. However, it is still unclear how the intestinal barrier contributes to the protective effects of Lactobacillus against AFB1. To investigate the protective effects and intestinal barrier mechanisms of Lactobacillus intestinals /rhamnosus against AFB1-induced liver damage, we orally administered AFB1 and Lactobacillus intestinals/rhamnosus to male SD rats. Then the body weight, organ index, histopathological changes in the liver and gut, liver and kidney function indicators, intestinal mucosal barrier indicators, serum AFB1 content and inflammatory factors, liver oxidative stress index, and short-chain fatty acids content were analyzed. Our findings demonstrate that exposure to AFB1 resulted in changes in liver histopathology and biochemical functions, altered inflammatory response and oxidative stress, compromised the intestinal mucosal barrier, and induced the accumulation of inflammatory factor and inflammation in the liver. However, supplementation with Lactobacillus intestinals or Lactobacillus rhamnosus significantly prevented AFB1-induced liver injury, alleviated histopathological changes and hepatic injury by the maintenance of intestinal mucosal barrier integrity.

Ammonia nitrogen stress damages the intestinal mucosal barrier of yellow catfish (Pelteobagrus fulvidraco) and induces intestinal inflammation.

Nitrogen from ammonia is one of the most common pollutants toxics to aquatic species in aquatic environment. The intestinal mucosa is one of the key mucosal defenses of aquatic species, and the accumulation of ammonia nitrogen in water environment will cause irreversible damage to intestinal function. In this study, histology, immunohistochemistry, ultrastructural pathology, enzyme activity analysis and qRT-PCR were performed to reveal the toxic effect of ammonia nitrogen stress on the intestine of Pelteobagrus fulvidraco. According to histological findings, ammonia nitrogen stress caused structural damage to the intestine and reduced the number of mucous cells. Enzyme activity analysis revealed that the activity of bactericidal substances (Lysozyme, alkaline phosphatase, and ACP) had decreased. The ultrastructure revealed sparse and shortened microvilli as well as badly degraded tight junctions. Immunohistochemistry for ZO-1 demonstrated an impaired intestinal mucosal barrier. Furthermore, qRT-PCR revealed that tight junction related genes (ZO-1, Occludin, Claudin-1) were downregulated, while the pore-forming protein Claudin-2 was upregulated. Furthermore, as ammonia nitrogen concentration grew, so did the positive signal of Zap-70 (T/NK cell) and the expression of inflammation-related genes (TNF, IL-1β, IL-8, IL-10). In light of the above findings, we conclude that ammonia nitrogen stress damages intestinal mucosal barrier of Pelteobagrus fulvidraco and induces intestinal inflammation.

Loss of polarity protein Par3 in the intestinal epithelium promotes colitis-associated colorectal cancer progression by damaging tight junction assembly.

Partitioning defective 3 (Par3) is a polarity protein critical in establishing epithelial cell polarity and tight junctions (TJs). Impaired intestinal epithelial barrier integrity is closely associated with colitis-associated colorectal cancer (CRC) progression. According to the GEO and TCGA database analyses, we first observed that the expression of Par3 was reduced in CRC patients. To understand how Par3 is related to CRC, we investigated the role of Par3 in the development of CRC using an in vivo genetic approach. Our results show that the intestinal epithelium-specific PAR3 deletion mice demonstrated a more severe CRC phenotype in the context of azoxymethane/dextran sodium sulfate (AOM/DSS) treatment, with a corresponding increase in tumor number and inflammatory cytokines profile. Mechanistically, loss of Par3 disrupts the TJs of the intestinal epithelium and increases mucosal barrier permeability. The interaction of Par3 with ZO-1 prevents intramolecular interactions within ZO-1 protein and facilitates the binding of occludin to ZO-1, hence preserving TJs integrity. Our results suggest that Par3 deficiency permits pathogenic bacteria and their endotoxins to penetrate the intestinal submucosa and activate TLR4/MyD88/NF-κB signaling, promoting inflammation-driven CRC development and that Par3 may be a novel potential molecular marker for the diagnosis of early-stage CRC.