Alpha-Lipoic Acid Promotes Intestinal Epithelial Injury Repair by Regulating MAPK Signaling Pathways.

Intestinal epithelial cells are an essential barrier in human gastrointestinal tract, and healing of epithelial wound is a key process in many intestinal diseases. α-Lipoic acid (ALA) was shown to have antioxidative and anti-inflammatory effects, which could be helpful in intestinal epithelial injury repair. The effects of ALA in human colonic epithelial cells NCM460 and human colorectal adenocarcinoma cells Caco-2 were studied. ALA significantly promoted NCM460 and Caco-2 migration, increased mucosal tight junction factors ZO-1 and OCLN expression, and ALA accelerated cell injury repair of both cells in wound healing assay. Western blot analysis indicated that ALA inhibited a variety of mitogen-activated protein kinase (MAPK) signaling pathways in the epithelial cells. In conclusion, ALA was beneficial to repair of intestinal epithelial injury by regulating MAPK signaling pathways.

SARS-CoV-2 infection causes intestinal cell damage: Role of interferon's imbalance.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the newly emerging lung disease pandemic COVID-19. This viral infection causes a series of respiratory disorders, and although this virus mainly infects respiratory cells, the small intestine can also be an important site of entry or interaction, as enterocytes highly express in angiotensin-2 converting enzyme (ACE) receptors. There are countless reports pointing to the importance of interferons (IFNs) with regard to the mediation of the immune system in viral infection by SARS-CoV-2. Thus, this review will focus on the main cells that make up the large intestine, their specific immunology, as well as the function of IFNs in the intestinal mucosa after the invasion of coronavirus-2.

Sodium Butyrate Ameliorates Oxidative Stress-Induced Intestinal Epithelium Barrier Injury and Mitochondrial Damage through AMPK-Mitophagy Pathway.

Sodium butyrate has gained increasing attention for its vast beneficial effects. However, whether sodium butyrate could alleviate oxidative stress-induced intestinal dysfunction and mitochondrial damage of piglets and its underlying mechanism remains unclear. The present study used a hydrogen peroxide- (H2O2-) induced oxidative stress model to study whether sodium butyrate could alleviate oxidative stress, intestinal epithelium injury, and mitochondrial dysfunction of porcine intestinal epithelial cells (IPEC-J2) in AMPK-mitophagy-dependent pathway. The results indicated that sodium butyrate alleviated the H2O2-induced oxidative stress, decreased the level of reactive oxygen species (ROS), increased mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA), and mRNA expression of genes related to mitochondrial function, and inhibited the release of mitochondrial cytochrome c (Cyt c). Sodium butyrate reduced the protein expression of recombinant NLR family, pyrin domain-containing protein 3 (NLRP3) and fluorescein isothiocyanate dextran 4 kDa (FD4) permeability and increased transepithelial resistance (TER) and the protein expression of tight junction. Sodium butyrate increased the expression of light-chain-associated protein B (LC3B) and Beclin-1, reduced the expression of P62, and enhanced mitophagy. However, the use of AMPK inhibitor or mitophagy inhibitor weakened the protective effect of sodium butyrate on mitochondrial function and intestinal epithelium barrier function and suppressed the induction effect of sodium butyrate on mitophagy. In addition, we also found that after interference with AMPKα, the protective effect of sodium butyrate on IPEC-J2 cells treated with H2O2 was suppressed, indicating that AMPKα is necessary for sodium butyrate to exert its protective effect. In summary, these results revealed that sodium butyrate induced mitophagy by activating AMPK, thereby alleviating oxidative stress, intestinal epithelium barrier injury, and mitochondrial dysfunction induced by H2O2.

Adaptive differentiation promotes intestinal villus recovery.

Loss of differentiated cells to tissue damage is a hallmark of many diseases. In slow-turnover tissues, long-lived differentiated cells can re-enter the cell cycle or transdifferentiate to another cell type to promote repair. Here, we show that in a high-turnover tissue, severe damage to the differentiated compartment induces progenitors to transiently acquire a unique transcriptional and morphological postmitotic state. We highlight this in an acute villus injury model in the mouse intestine, where we identified a population of progenitor-derived cells that covered injured villi. These atrophy-induced villus epithelial cells (aVECs) were enriched for fetal markers but were differentiated and lineage committed. We further established a role for aVECs in maintaining barrier integrity through the activation of yes-associated protein (YAP). Notably, loss of YAP activity led to impaired villus regeneration. Thus, we define a key repair mechanism involving the activation of a fetal-like program during injury-induced differentiation, a process we term "adaptive differentiation."

Protective effects of polysaccharides from Atractylodes macrocephalae Koidz. against dextran sulfate sodium induced intestinal mucosal injury on mice.

In the present research, the water-soluble polysaccharides (AMP) from Atractylodes macrocephalae Koidz. were isolated and prepared. The protective effects of AMP on intestinal mucosal barrier injury induced by dextran sulfate sodium (DSS) in mice were investigated. It was found that AMP treatment significantly alleviated the body weight decreases and shorten colon length, and ameliorated colonic damage induced by DSS. Importantly, AMP prevented the over-expression of proinflammatory cytokines TNF-α, IL-1ß and IL-6, and decreased the infiltration of neutrophils in colon. Additionally, AMP could raise expressions of Mucin 2 and tight junction protein Claudin-1. AMP also modulated the intestinal microbiota by enhancing the overall richness and diversity, greatly reducing the proportion of harmful bacteria, for instance, Clostridiumsensu stricto1 and Escherichia Shigella, however, augmenting the ratio of potential beneficial bacteria such as Faecalibaculum and Bifidobacterium. This work offers some important insights on protective effects of polysaccharides AMP against intestinal barrier dysfunction and provides underlying mechanism of health-beneficial properties of these biological macromolecules.

Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice.

BACKGROUND: Inflammation-related diseases present a significant public health problem. Ginger is a flavoring spice and medicinal herb with anti-inflammatory activity. This study investigated the preventive effects of ginger extract (GE) and its main bioactive component, 6-gingerol (6G), on lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and liver injury in mice. RESULTS: GE and 6G were orally administered to mice for seven consecutive days before LPS administration. After 24 h, the mice were sacrificed. GE and 6G were found to significantly reverse LPS-induced inflammation in the mouse ileum by modifying the NF-κB pathway. They also alleviated apoptosis in the ileum by downregulating Bax and cytochrome c gene expression and by inhibiting the caspase-3 pathway. Through the aforementioned mechanisms, GE and 6G restored the intestinal barrier by increasing ZO-1 and claudin-1 protein expressions. Gut-derived LPS induced inflammation and apoptosis in the liver; these effects were markedly reversed through GE and 6G treatment. 6G was the most abundant component in GE, as evidenced through liquid chromatography-mass spectrometry, and accounted for >50% of total gingerols and shogaols in GE. CONCLUSION: The current results support the use of GE and 6G as dietary supplements to protect against gut-derived endotoxemia-associated inflammatory response and disorders. © 2021 Society of Chemical Industry.

Gastrointestinal tissue as a "new" target of pollution exposure.

Airborne pollution has become a leading cause of global death in industrialized cities and the exposure to environmental pollutants has been demonstrated to have adverse effects on human health. Among the pollutants, particulate matter (PM) is one of the most toxic and although its exposure has been more commonly correlated with respiratory diseases, gastrointestinal (GI) complications have also been reported as a consequence to PM exposure. Due to its composition, PM is able to exert on intestinal mucosa both direct damaging effects, (by reaching it either via direct ingestion of contaminated food and water or indirect inhalation and consequent macrophagic mucociliary clearance) and indirect ones via generation of systemic inflammation. The relationship between respiratory and GI conditions is well described by the lung-gut axis and more recently, has become even clearer during coronavirus disease 2019 (COVID-19) pandemic, when respiratory symptoms were associated with gastrointestinal conditions. This review aims at pointing out the mechanisms and the models used to evaluate PM induced GI tract damage.

The Role of lncRNAs in Regulating the Intestinal Mucosal Mechanical Barrier.

lncRNA is a transcript that is more than 200 bp in length. Currently, evidence has shown that lncRNA is of great significance in cell activity, involved in epigenetics, gene transcription, chromatin regulation, etc. The existence of an intestinal mucosal mechanical barrier hinders the invasion of pathogenic bacteria and toxins, maintaining the stability of the intestinal environment. Serious destruction or dysfunction of the mechanical barrier often leads to intestinal diseases. This review first summarizes the ability of lncRNAs to regulate the intestinal mucosal mechanical barrier. We then discussed how lncRNAs participate in various intestinal diseases by regulating the intestinal mucosal mechanical barrier. Finally, we envision its potential as a new marker for diagnosing and treating intestinal inflammatory diseases.

Protection by microRNA-7a-5p Antagomir Against Intestinal Mucosal Injury Related to the JNK Pathway in TNBS-Induced Experimental Colitis.

BACKGROUND: Increasing evidence shows that microRNA-7a-5p (miR-7a-5p) plays an important role in regulating the inflammatory process in inflammatory bowel disease (IBD). How miR-7a-5p contributes to this process is poorly defined. The purpose of this study was to examine whether miR-7a-5p regulates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammatory responses via the JNK pathway. METHODS: Colitis was induced in male mice by intracolonic administration of TNBS; mice were divided into 3 groups: normal control (NC), TNBS, and miR-7a-5p antagomir-treated group. Inflammatory responses were estimated by disease activity index (DAI) and histological scores. The relative expressions of miR-7a-5p and tight junction protein, ZO-1, were detected by RT-qPCR. Western blot assays were used to estimate the level of JNK pathway proteins and ZO-1. After miRNA-antagomir injection, the extent of colonic tissue injury and expression levels of ZO-1 and JNK in intestinal tissue were compared. RESULTS: miR-7a-5p and p-JNK expression were higher in the intestinal tissue of the TNBS group as compared to NC. Inhibition of the expression of miR-7a-5p resulted in significantly decreased expression of p-JNK but increased expression of ZO-1 and promoted the recovery of intestinal mucosa. CONCLUSION: This work demonstrates a correlation between the JNK pathway and miR-7a-5p in TNBS-induced experimental colitis in mice, which may provide a new research direction for the treatment of IBD.

Small Intestinal Adenocarcinomas Arising in Enteritis Cystica Profunda With Metaplasia: A Report of 2 Cases.

Enteritis cystica profunda (ECP) is an uncommon benign condition arising after mucosal damage. We describe 2 cases of small intestinal adenocarcinomas associated with ECP at the distal ileum, one in a background of active Crohn ileitis (case 1), the other 22 years after pelvic radiation therapy (case 2). Both patients presented with small bowel obstruction and received ileocectomy. Macroscopic examination identified an indurated/strictured area in the distal ileum. Histologically, both cases showed a low-grade tubuloglandular adenocarcinoma arising in a background of chronic ischemic stricture and ECP lined by flat cuboidal cells with mild cytologic atypia resembling pancreatobiliary-type epithelium. There was no conventional dysplasia in the surface or adjacent mucosa. Immunohistochemically, both ECP with metaplasia and invasive carcinomas were diffusely positive for CK7 and CK19, while focally positive for CDX2 or CK20. Both cases showed normal wild-type p53 expression. Case 2 was also mismatch repair protein proficient, with membranous ß-catenin staining, and retained nuclear SMAD4 expression. In summary, the 2 cases uniquely exhibits "enteritis-metaplasia-carcinoma" sequence, which has not been reported before. This process appears to bypass conventional dysplasia, be slow and indolent, independent of p53, APC/ß-catenin, and SMAD4/TGFß signaling pathways.

Efficacy of Liangxue Guyuan decoction on radiation-induced intestinal injury in rats via the toll-like receptor 4/myeloid differentiation primary response 88/ nuclear factor-kappa B pathway.

OBJECTIVE: To evaluate the efficacy of Liangxue Guyuan decoction ( LGD) on radiation-induced intestinal injury in rats, and the possible underlying mechanism of action. METHODS: A total of 255 male Sprague-Dawley rats were used. 15 rats were assigned to the control group and the remaining 240 rats were exposed to a 60Co source at a dose of 11 Gy. Irradiated rats were randomly divided into model, dexamethasone (DXM), low-dose LGD (LGDl), and high-dose LGD (LGDh) groups and treated for 11 d. The survival rate, weight of body, intestinal pathology and the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF-κB) were recorded. RESULTS: Radiation reduced the survival rate and weight of rats, destroyed the intestinal structure, induced an inflammatory reaction, and increased both protein and mRNA expression of TLR4, MyD88, and NF-κB in ileum. However, LGDh increased the survival rate, inhibited weight loss, alleviated inflammation and improve the expression of TLR4 pathway. CONCLUSION: LGD increased the survival rate and inhibit weight loss of irradiated rats, and reduced inflammation and intestinal injury. The underlying mechanism may involve regulation of the TLR4/MyD88/NF-κB pathway.

Polysaccharides in natural products that repair the damage to intestinal mucosa caused by cyclophosphamide and their mechanisms: A review.

Cyclophosphamide (CTX) is a commonly used antitumor drug in clinical practice, and intestinal mucosal injury is one of its main toxic side effects, which seriously affects the treatment tolerance and prognosis of patients. Therefore, the prevention of intestinal mucosal injury is a research hotspot. Studies have shown that polysaccharides can effectively prevent and improve CTX-induced intestinal mucosal injury and immune system disorders. Recent research has elucidated the structure, biological function, and physicochemical properties of polysaccharides that prevent intestinal mucosal injury, and the potential mechanisms whereby they have this effect. In this paper, we review the recent progress made in understanding the effects of polysaccharides on intestinal mucosal injury and their protective mechanism in order to provide a reference for further research on the prevention of intestinal mucosal injury and the mechanisms involved in nutritional intervention.

ZINC40099027 activates human focal adhesion kinase by accelerating the enzymatic activity of the FAK kinase domain.

Focal adhesion kinase (FAK) regulates gastrointestinal epithelial restitution and healing. ZINC40099027 (Zn27) activates cellular FAK and promotes intestinal epithelial wound closure in vitro and in mice. However, whether Zn27 activates FAK directly or indirectly remains unknown. We evaluated Zn27 potential modulation of the key phosphatases, PTP-PEST, PTP1B, and SHP2, that inactivate FAK, and performed in vitro kinase assays with purified FAK to assess direct Zn27-FAK interaction. In human Caco-2 cells, Zn27-stimulated FAK-Tyr-397 phosphorylation despite PTP-PEST inhibition and did not affect PTP1B-FAK interaction or SHP2 activity. Conversely, in vitro kinase assays demonstrated that Zn27 directly activates both full-length 125 kDa FAK and its 35 kDa kinase domain. The ATP-competitive FAK inhibitor PF573228 reduced basal and ZN27-stimulated FAK phosphorylation in Caco-2 cells, but Zn27 increased FAK phosphorylation even in cells treated with PF573228. Increasing PF573228 concentrations completely prevented activation of 35 kDa FAK in vitro by a normally effective Zn27 concentration. Conversely, increasing Zn27 concentrations dose-dependently activated kinase activity and overcame PF573228 inhibition of FAK, suggesting the direct interactions of Zn27 with FAK may be competitive. Zn27 increased the maximal activity (Vmax ) of FAK. The apparent Km of the substrate also increased under laboratory conditions less relevant to intracellular ATP concentrations. These results suggest that Zn27 is highly potent and enhances FAK activity via allosteric interaction with the FAK kinase domain to increase the Vmax of FAK for ATP. Understanding Zn27 enhancement of FAK activity will be important to redesign and develop a clinical drug that can promote mucosal wound healing.

Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration.

The capacity of 3D organoids to mimic physiological tissue organization and functionality has provided an invaluable tool to model development and disease in vitro. However, conventional organoid cultures primarily represent the homeostasis of self-organizing stem cells and their derivatives. Here, we established a novel intestinal organoid culture system composed of 8 components, mainly including VPA, EPZ6438, LDN193189, and R-Spondin 1 conditioned medium, which mimics the gut epithelium regeneration that produces hyperplastic crypts following injury; therefore, these organoids were designated hyperplastic intestinal organoids (Hyper-organoids). Single-cell RNA sequencing identified different regenerative stem cell populations in our Hyper-organoids that shared molecular features with in vivo injury-responsive Lgr5+ stem cells or Clu+ revival stem cells. Further analysis revealed that VPA and EPZ6438 were indispensable for epigenome reprogramming and regeneration in Hyper-organoids, which functioned through epigenetically regulating YAP signaling. Furthermore, VPA and EPZ6438 synergistically promoted regenerative response in gut upon damage in vivo. In summary, our results demonstrated a new in vitro organoid model to study epithelial regeneration, highlighting the importance of epigenetic reprogramming that pioneers tissue repair.

Effects of Qing Hua Chang Yin on lipopolysaccharide­induced intestinal epithelial tight junction injury in Caco­2 cells.

Disruption of the intestinal mucosal barrier integrity is a pathogenic process in inflammatory bowel disease (IBD) development, and is therefore considered a drug discovery target for IBD. The well­known traditional Chinese formulation Qing Hua Chang Yin (QHCY) has been suggested as a potential therapeutic agent for the treatment of ulcerative colitis. However, the possible underlying molecular mechanisms regarding its therapeutic effect remain unclear. Consequently, the present study investigated the effects of QHCY on lipopolysaccharide (LPS)­induced loss of intestinal epithelial barrier integrity in vitro using the Caco­2 cell model of intestinal epithelium. QHCY reversed the LPS­induced decrease in transepithelial electrical resistance and significantly alleviated the increased fluorescently­labeled dextran 4 flux caused by LPS. Moreover, QHCY upregulated the mRNA and protein expression levels of occludin, zona occludens­1 and claudin­1 in LPS­exposed Caco­2 cells. In conclusion, QHCY was able to protect intestinal epithelial barrier integrity following an inflammatory insult; the protective effects of QHCY may be mediated by modulation of the expression of tight junction proteins.

Mesenteric Lymph Duct Ligation Alleviates Acute Lung Injury Caused by Severe Acute Pancreatitis Through Inhibition of High Mobility Group Box 1-Induced Inflammation in Rats.

BACKGROUND: Acute lung injury (ALI) is the most common complication and one of the leading causes of mortality of severe acute pancreatitis (SAP). Nevertheless, no effective therapeutic schemes are presently available. AIMS: To investigate the effect and potential mechanism of mesenteric lymph duct ligation (MLDL) on experimental SAP-induced ALI. METHODS: Immediately following MLDL, rats were subjected to SAP by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. At 24 h after modeling, tissues were collected for morphological examination. The levels of TNF-α, IL-6, intercellular adhesion molecule-1 (ICAM1), diamine oxidase (DAO), and D-lactic acid (D-LA) in serum, and the myeloperoxidase (MPO) activity in lung tissues were determined. Moreover, the expressions of high mobility group box 1 (HMGB1), receptor of advanced glycation endproducts (RAGE), and NF-κB p65 at the mRNA and protein levels in lung tissues, and the expressions of HMGB1, RAGE, and TNF-α at the mRNA level in intestinal lymphoid tissues were evaluated. RESULTS: MLDL significantly attenuated the histological injury of the pancreas and lung and reduced the production of TNF-α, IL-6, and ICAM1. Besides, MLDL repressed the activity of MPO in the lung. However, the levels of serum DAO and D-LA were decreased without obvious morphological improvement in intestinal injury. Moreover, MLDL apparently reduced the up-regulation of HMGB1, RAGE, and NF-κB p65 in lung tissues, as well as the expressions of HMGB1, RAGE, and TNF-α in intestinal lymphoid tissues. CONCLUSIONS: Mesenteric lymph was a source of harmful factors leading to SAP-ALI. MLDL could alleviate SAP-ALI probably by inhibiting HMGB1-induced production of inflammation factors.

Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease.

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-ß, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

Glucagon-like peptide 2 attenuates intestinal mucosal barrier injury through the MLCK/pMLC signaling pathway in a piglet model.

Glucagon-like peptide-2 (GLP-2), an intestinotrophic hormone, has drawn considerable attention worldwide due to its potential to promote intestinal development. We investigated the effects and mechanisms of GLP-2 against lipopolysaccharide (LPS)-induced intestinal inflammation and injury both in vitro and in vivo. Forty healthy piglets weaned at the age of 28 days with similar body weight (BW) were assigned to four in vivo treatments with ten piglets each: (i) nonchallenged control; (ii) LPS-challenged control; (iii) LPS + low dose GLP-2; and (iv) LPS + high dose GLP-2. Piglets were subcutaneously injected with phosphate-buffered saline supplemented with GLP-2 at doses of 0, 0, 2, and 10 nmol/kg BW per day for seven consecutive days. The piglets were challenged with an intraperitoneal injection with 100 µg/kg LPS on day 14 to induce intestinal damage. After that, the gene and protein expression levels of representative tight junction proteins and myosin light-chain kinase (MLCK)/phosphorylated myosin light chain (pMLC), as well as proinflammatory cytokine levels were determined using quantitative reverse transcription polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay methods. A high dose of GLP-2 pretreatment increased intestinal permeability by downregulating and redistributing tight junction proteins (p < .05), for example, zona occluden-1 (ZO-1) and occludin. GLP-2 decreased the transcription of proinflammatory cytokines genes including interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor-α in small intestines (p < .05). GLP-2 prevented the LPS-induced increase in the expression of MLCK dose-dependently and the increase in pMLC levels in the duodenum, jejunum, and ileum. To assess further the protective effect of GLP-2 on LPS-induced intestinal barrier injury after weaning and its possible mechanism, an in vitro intestinal epithelial barrier model was established with IPEC-J2 monolayers and treated with 100 µg/ml LPS with or without 1 × 10-8 mol/L GLP-2 pretreatment. The in vitro analysis included control, LPS, and GLP-2 + LPS treatments. GLP-2 treatment alleviated the destructive effect of LPS on barrier permeability by restoring the expression and ultrastructure of ZO-1 and occludin (p < .05). In addition, GLP-2 reversed the LPS-induced MLCK hyperexpression and pMLC hyperphosphorylation (p < .05). Taken together, our findings revealed a mechanism by which GLP-2 alleviated LPS-challenged intestinal barrier injury and inflammation in weaned piglets and IPEC-J2 cells via the MLCK/pMLC signaling pathway.

Hydrogel-based 3D bioprints repair rat small intestine injuries and integrate into native intestinal tissue.

3D Printing has become a mainstay of industry, with several applications in the medical field. One area that could benefit from 3D printing is intestinal failure due to injury or genetic malformations. We bioprinted cylindrical tubes from rat vascular cells that were sized to form biopatches. 2 mm enterotomies were made in the small intestine of male Sprague-Dawley rats, and sealed with biopatches. These intestinal segments were connected to an ex vivo perfusion device that provided independent extraluminal and intraluminal perfusion. The fluorescence signal of fluorescein isothiocyanate (FITC)-inulin in the intraluminal perfusate, a non-absorbable fluorescent marker of intestinal integrity, was measured every 15 min over 90 min, and used to assess the integrity of the segments under both continuous perfusion and alternate-flow perfusion. Enterotomies were made an inch away from the ileocecal junction in male Wistar rats and sealed with biopatches. The animals were monitored daily and euthanized at post-operative days 7, 14, 21, and 30. Blinded histopathological analysis was conducted to compare the patch segments to native intestine. Biopatch-sealed intestinal segments withstood both continuous and pulsatile flow rates without leakage of FITC-inulin above the control baseline. 21 of 26 animals survived with normal activity, weight gain, and stool output. Histopathology of the explanted segments showed progressive villi and crypt formation over the enterotomies, with complete restoration of the epithelium by 30 days. This study presents a novel application of 3D bioprinting to develop a universal repair patch that can seal lesions in vivo, and fully integrate into the native intestine.

Trauma results in immune cell-induced intestinal epithelial damage with subsequently increased sepsis rate.

BACKGROUND: The detrimental effect of trauma on the immune system has been a subject of interest for decades. The gut-associated lymphoid tissue (GALT) of the bowel that encompasses different lymphocyte subpopulations may be an important pillar of human immunity in the context of trauma. Neither the short-term histological trauma-induced changes in the GALT nor its impact on the outcome after trauma surgery has been investigated. METHODS: This prospective, longitudinal proof-of-concept study included patients who required damage-control surgery after abdominal gunshot wounds with small bowel involvement. Bowel specimens were obtained during the index and relook operations, and the T-lymphocytic quantity therein was analyzed via immunohistochemistry. We scrutinized how the lymphocyte structure and numbers of the GALT altered, and whether the extent and nature of these changes had an impact on the postoperative outcome with regard to septic and surgical complications. RESULTS: A total of 31 damage-control patients were recruited for the study. The main histological changes between the index and relook specimen was a shift of CD8+ T cells from the lamina propria (LP) into the epithelium and a decrease of T lymphocytes in the LP. The significant increase of the intraepithelial CD8+ T cells was associated with a more extensive enterocyte apoptosis, and correlated significantly, positively with the number of postoperative septic complications. CONCLUSION: Our data support that trauma induces an immune cell-driven impairment of the intestinal epithelium, as well as an increased apoptosis of lymphocytes in the LP, which is associated with a worse clinical outcome. The underlying mechanism suggests that a therapeutic approach to minimize apoptosis in the intestine may impact the outcome of severely injured trauma patients. LEVEL OF EVIDENCE: Therapeutic/care/management, level lV.