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Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.

The intestine, is responsible for food digestion, nutrient absorption, endocrine secretion, food residue excretion, and immune defense. These function performances are based on the intricate composition of intestinal epithelial cells, encompassing differentiated mature cells, rapidly proliferative cells, and intestinal stem cells. Although the characteristics of these cell types are well-documented, in-depth exploration of their representative markers and transcription factors is critical for comprehensive cell fate trajectory analysis. Here, we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis. Further, the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining, and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout. Therefore, this study not only reports new markers for various intestinal epithelial cell types but also elucidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis, which facilitates the tracing and functional elucidation of intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

The intestinal epithelium comprises a dynamic single cell layer in the gut that allows segregation of luminal content from the host while executing nutrient absorption, barrier maintenance, and danger signaling. Epithelial metabolism of nutrients allows for the maintenance of epithelial cell functions and host–microbe commensalism. Dietary cues, microbes and metabolites, immune cross-talk, endocrine signals, and neuronal networks control and regulate the execution of intestinal epithelial metabolism. Rewiring of epithelial metabolism constitutes a hallmark of inflammatory and malignant diseases in the gut. Extrinsic or intrinsic perturbation of intestinal epithelial metabolism promotes experimental gut inflammation and tumorigenesis. The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host–microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future. [ABSTRACT FROM AUTHOR]

Summary: The gastrointestinal tract serves as a pivotal physical barrier that prevents the translocation of exogenous substances from the intestinal lumen into the systemic circulation. Dysfunction of intestinal barrier function has been implicated in the pathogenesis of several diseases, such as metabolic disorders. Heat shock proteins (HSPs) play a critical role in maintaining the resilience and viability of epithelial cells when exposed to stressors. Evidence suggests that dietary fibre (DF), a known inducer of HSP production, may be a promising candidate for strengthening the intestinal barrier. Understanding the regulation of intestinal HSPs and the protective effect of DF is critical to defending against environmental threats and preserving human health. To date, six DFs—pectin, chicory, psyllium, guar gum, partially hydrolysed guar gum, and xylooligosaccharide—have been reported to have promotive effects on intestinal HSP induction. DF promotes intestinal HSP induction through gut microbiota‐dependent and independent mechanisms. DF is fermented by gut microbiota to produce short‐chain fatty acids, specifically butyrate and propionate, to promote HSP production. Meanwhile, DF also promotes intestinal HSP induction through direct interaction with intestinal epithelial cells, independent of gut microbiota activity, although the precise mechanism is still unclear. Regulation of intestinal HSP occurs by transcriptional modulation through activation of heat shock transcription factors, primarily heat shock factor 1, or at the post‐transcriptional level by modulation of the translation process. This review highlights recent advances in understanding the role of DF in improving intestinal barrier function, with particular emphasis on the regulatory mechanisms of intestinal HSPs. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications. In this review, B. Stockinger and colleagues discuss physiology of the aryl hydrocarbon receptor (AHR) and development of potential therapeutic applications targeting AHR, a ligand dependent transcription factor that functions as an environmental sensor. [ABSTRACT FROM AUTHOR]

Studying viral infections necessitates well-designed cell culture models to deepen our understanding of diseases and develop effective treatments. In this study, we present a readily available ex vivo 3D co-culture model replicating the human intestinal mucosa. The model combines fully differentiated human intestinal epithelium (HIE) with human monocyte-derived macrophages (hMDMs) and faithfully mirrors the in vivo structural and organizational properties of intestinal mucosal tissues. Specifically, it mimics the lamina propria, basement membrane, and the air-exposed epithelial layer, enabling the pioneering observation of macrophage migration through the tissue to the site of viral infection. In this study, we applied the HIE-hMDMs model for the first time in viral infection studies, infecting the model with two globally significant viruses: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human norovirus GII.4. The results demonstrate the model's capability to support the replication of both viruses and show the antiviral role of macrophages, determined by their migration to the infection site and subsequent direct contact with infected epithelial cells. In addition, we evaluated the production of cytokines and chemokines in the intestinal niche, observing an increased interleukin-8 production during infection. A parallel comparison using a classical in vitro cell line model comprising Caco-2 and THP-1 cells for SARS-CoV-2 experiments confirmed the utility of the HIE-hMDMs model in viral infection studies. Our data show that the ex vivo tissue models hold important implications for advances in virology research. [ABSTRACT FROM AUTHOR]

Enteric infection is a major cause of enteric disorder in neonatal pigs during the weaning transition. Dihydromyricetin (DMY) is a natural flavanonol compound extracted from Ampelopsis grossedentata with numerous biological activities such as antioxidative and immunomodulatory functions. The objective of this study was to investigate the effects of dietary dihydromyricetin supplementation on growth performance, immunity, and intestinal functions in weaned pigs challenged by enterotoxigenic Escherichia coli (ETEC). In total, 24 weaned DLY (Duroc × Landrace × Yorkshire) pigs were allotted to 3 treatments. Pigs fed with basal diet or basal diet containing 300 mg/kg DMY were orally infused with sterilized culture or ETEC (2.5 × 1011 colony-forming units). Dietary DMY supplementation significantly elevated the final weight and average daily gain (ADG) but reduced diarrhea incidence in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Compared to the ECON group, DMY also improved the digestibility of dry matter (DM), ether extract (EE), gross energy (GE), and ash of the EDMY group (p < 0.05). Moreover, DMY not only significantly decreased the ratio of albumin/globulin but also elevated serum concentrations of immunoglobulins (e.g., IgA and IgG) in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Interestingly, the villus height, the ratio of villus height to crypt depth (V:C), and the activities of mucosal alkaline phosphatase, sucrase, and maltase in the duodenum and jejunum of the EDMY group were higher than those in the ECON group (p < 0.05). Importantly, DMY significantly elevated the expression levels of jejunal zonula occludens-1 (ZO-1), claudin-1, cationic amino acid transporter-1 (CAT-1), and fatty acid transport protein-1 (FATP-1) in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Additionally, compared to the ECON group, DMY increased the concentrations of microbial SCFA metabolites (e.g., acetic acid and propanoic acid), but reduced the abundance of Escherichia coli in the cecum of the EDMY group (p < 0.05). Dietary DMY supplementation can attenuate the ETEC--induced growth retardation and intestinal injury, which was attributed to the amelioration of intestinal nutrient digestion and transport functions as well as the improved microbiota. [ABSTRACT FROM AUTHOR]

Introduction: Benzoic acid (BA) could be added to the diets of weaned pigs to prevent diarrhea due to its antibacterial function. However, BA may be absorbed or decomposed before it can reach the hindgut. This study was conducted to explore the effect of a novel coated benzoic acid (CBA) on growth performance, immunity, and intestinal barrier functions in weaned pigs upon enterotoxigenic Escherichia coli (ETEC) challenge. Methods: In a 21d experiment, 32 piglets were randomly assigned to 4 treatments: (1) a basal diet (CON), (2) CON added with CBA at 3 g/kg (CBA); (3) CON and challenged by ETEC (ECON); (4) CON added with CBA at 3 g/kg and challenged by ETEC (ECON). On d 22, all piglets were euthanised to obtain samples. Results: Dietary CBA supplementation elevated the average daily gain (ADG) of the ETEC-challenged pigs (p < 0.05). CBA also improved the digestibility of dry matter, gross energy, and ash (p < 0.05). Moreover, CBA elevated the ratio of blood basophil and the serum concentration of total cholesterol of the ETEC challenged pigs (p < 0.05). Importantly, CBA increased the serum concentrations of immunoglobulin A (IgA), IgG, and IgM (p < 0.05). CBA not only decreased the crypt depth but also increased the ratio of villus height to crypt depth (V:C) in the jejunum and ileum (p < 0.05). Moreover, CBA increased the activities of jejunal and ileal sucrase, and the activities of duodenal and ileal maltase (p < 0.05). Importantly, CBA elevated the expression levels of critical functional genes such as the claudin-1, occluding, glucose transporter-2 (GLUT2), and sodium/glucose cotransporter-1 (SGLT-1) in the jejunal epithelium upon ETEC challenge (p < 0.05). Additionally, CBA increased the abundances of total bacteria and Bacillus, and increased the concentrations of volatile fatty acids (acetic acid, propanoic acid, and butyric acid) in cecum (p < 0.05). Discussion: These results suggested a beneficial role for CBA in alleviating intestinal injury in weaned pigs following ETEC challenge. Such effects may be tightly associated with elevated immunity and improved intestinal epithelium functions and microbiota. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known. To this end, we used IEC-specific AhR deletion coupled with a mouse model of dextran sodium sulfate (DSS)-induced colitis to understand how dietary AhR ligand 3, 3′-diindolylmethane (DIM) influenced TLT formation. DIM consumption increased the size of TLTs and decreased T-cell aggregation to TLT sites in an IEC-specific manner. In DSS-exposed female mice, DIM consumption increased the expression of genes implicated in TLT formation (Interleukin-22, Il-22; CXC motif chemokine ligand 13, CXCL13) in an IEC AhR-specific manner. Conversely, in female mice without DSS exposure, DIM significantly reduced the expression of Il-22 or CXCL13 in iAhRKO mice, but this effect was not observed in WT animals. Our findings suggest that DIM affects the immunological landscape of TLT formation during DSS-induced colitis in a manner contingent on AhR expression in IECs and biological sex. Further investigations into specific immune cell activity, IEC-specific AhR signaling pathways, and dietary AhR ligand-mediated effects on TLT formation are warranted. [ABSTRACT FROM AUTHOR]

Cryptosporidium parvum is a microscopic parasite and furthermore, an identified agent that spends its life cycle in the mammalian gastrointestinal tract causing chronic and life-threatening diarrhoea in immunocompromised individuals. In this study, the GSE2077 series were selected from the NCBI site, which examined the contamination of the HCT-8 cell line with C. parvum in three treatment groups. Each of 24, 48, and 72 hours post-infection (PI) groups was compared with the mock, and the differentially expressed genes (DEGs) were identified during the analysis. For each comparison, the |logFC|= 2 and P values <0.05 were considered. The obtained values included: 24 hours=71 DEGs, 48 hours=82 DEGs, and 72 hours=55 DEGs. For the DEGs of each group, gene ontology diagrams were drawn separately using the Funrich3.1.3 software, including cellular components, biological processes, and molecular functions. The heat map diagrams were drawn with the R software and the heat map package. Also, the networks were plotted for each comparison in the Cytoscape software, and hub genes were obtained. Finally, the commonalities between the three treatment groups were identified using the FunRich software. Five common genes were revealed in all groups: RAD23B, DKK1, CXCL8, PHLDA1, and UGT1A3. [ABSTRACT FROM AUTHOR]

Abstract The intestine, is responsible for food digestion, nutrient absorption, endocrine secretion, food residue excretion, and immune defense. These function performances are based on the intricate composition of intestinal epithelial cells, encompassing differentiated mature cells, rapidly proliferative cells, and intestinal stem cells. Although the characteristics of these cell types are well-documented, in-depth exploration of their representative markers and transcription factors is critical for comprehensive cell fate trajectory analysis. Here, we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis. Further, the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining, and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout. Therefore, this study not only reports new markers for various intestinal epithelial cell types but also elucidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis, which facilitates the tracing and functional elucidation of intestinal epithelial cells.

Abstract The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.

Cryptosporidium parvum is a microscopic parasite and furthermore, an identified agent that spends its life cycle in the mammalian gastrointestinal tract causing chronic and life-threatening diarrhoea in immunocompromised individuals. In this study, the GSE2077 series were selected from the NCBI site, which examined the contamination of the HCT-8 cell line with C. parvum in three treatment groups. Each of 24, 48, and 72 hours post-infection (PI) groups was compared with the mock, and the differentially expressed genes (DEGs) were identified during the analysis. For each comparison, the |logFC|= 2 and P values

Abstract Human milk (HM) components affect immune cell toll-like receptor 4 (TLR4) signaling. However, studies examining the immunomodulatory impacts of HM on TLR4 signaling in intestinal epithelial cells (IECs) are limited. This study utilized both a TLR4 reporter cell line and a Caco-2 IEC model to examine the effects of HM on lipopolysaccharide (LPS)-induced TLR4 activation and cytokine responses, respectively. Additionally, we performed fast protein liquid chromatography and mass spectrometry to identify a HM component that contributes to the effect of HM on LPS/TLR4 signaling. HM enhances LPS-induced TLR4 signaling as well as LPS-induced IEC gene expression of pro-inflammatory cytokines and negative regulators of NF-κB. Human serum albumin (HSA) present in HM contributes to these effects. HSA within HM synergizes with LPS to induce IEC gene expression of pro-inflammatory cytokines and negative regulators of NF-κB. Altogether, this study provides mechanistic evidence behind the immunomodulatory function of HM on IECs, which may contribute to an enhanced immune response in breast-fed neonates.

Simple Summary: The research was carried out to examine the safeguarding impact of dietary coated benzoic acid supplementation on intestinal barrier functions in weaned pigs challenged by enterotoxigenic Escherichia coli. We found that coated benzoic acid supplementation enhanced the distribution of tight junction proteins, reduced cell apoptosis and intestinal inflammation, as well as increasing immunity and antioxidant capacity in both serum and intestinal epithelium. These results suggest that coated benzoic acid can reduce the damage from enterotoxigenic Escherichia coli to intestinal epithelium by reducing inflammation, enhancing intestinal immunity and antioxidant capacity, so as to improve intestinal epithelial function. The study was designed to investigate the protective effect of dietary supplementation with coated benzoic acid (CBA) on intestinal barrier function in weaned pigs challenged with enterotoxigenic Escherichia coli (ETEC). Thirty-two pigs were randomized to four treatments and given either a basal diet or a basal diet supplemented with 3.0 g/kg CBA, followed by oral administration of ETEC or culture medium. The results showed that CBA supplementation increased the average daily weight gain (ADWG) in the ETEC-challenged pigs (p < 0.05). CBA also increased the serum activity of total superoxide dismutase (T-SOD) and the total antioxidant capacity (T-AOC), as it decreased the serum concentrations of endotoxin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the ETEC-challenged pigs (p < 0.05). Interestingly, the CBA alleviated the ETEC-induced intestinal epithelial injury, as indicated by a reversal of the decrease in D-xylose absorption and a decrease in the serum levels of D-lactate and diamine oxidase (DAO) activity, as well as a decrease in the quantity of apoptotic cells in the jejunal epithelium following ETEC challenge (p < 0.05). Moreover, CBA supplementation significantly elevated the mucosal antioxidant capacity and increased the abundance of tight junction protein ZO-1 and the quantity of sIgA-positive cells in the jejunal epithelium (p < 0.05). Notably, CBA increased the expression levels of porcine beta defensin 2 (PBD2), PBD3, and nuclear factor erythroid-2 related factor 2 (Nrf-2), while downregulating the expression of toll-like receptor 4 (TLR4) in the jejunal mucosa (p < 0.05). Moreover, CBA decreased the expression levels of interleukin-1β (IL-1β), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB) in the ileal mucosa upon ETEC challenge (p < 0.05). These results suggest that CBA may attenuate ETEC-induced damage to the intestinal epithelium, resulting in reduced inflammation, enhanced intestinal immunity and antioxidant capacity, and improved intestinal epithelial function. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease‐activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells. Experimental Approach: The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples. The ability of chymotrypsin to cleave the extracellular domain of PAR1 or PAR2 was assessed using cell lines expressing N‐terminally tagged receptors. The cleavage site of chymotrypsin on PAR1 and PAR2 was determined by HPLC–MS analysis. The chymotrypsin signalling mechanism was investigated in CMT93 intestinal epithelial cells by calcium mobilization assays and Western blot analyses of (ERK1/2) phosphorylation. The transcriptional consequences of chymotrypsin signalling were analysed on colonic organoids. Key Results: We found that chymotrypsin was present and active in the vicinity of the colonic epithelium. Molecular pharmacological studies have shown that chymotrypsin cleaves both PAR1 and PAR2 receptors. Chymotrypsin activated calcium and ERK1/2 signalling pathways through PAR2, and this pathway promoted interleukin‐10 (IL‐10) up‐regulation in colonic organoids. In contrast, chymotrypsin disarmed PAR1, preventing further activation by its canonical agonist, thrombin. Conclusion and Implications: Our results highlight the ability of chymotrypsin to signal to intestinal epithelial cells via PARs, which may have important physiological consequences in gut homeostasis. [ABSTRACT FROM AUTHOR]

After birth, the development of secondary lymphoid tissues (SLTs) in the colon is dependent on the expression of the aryl hydrocarbon receptor (AhR) in immune cells as a response to the availability of AhR ligands. However, little is known about how AhR activity from intestinal epithelial cells (IECs) may influence the development of tertiary lymphoid tissues (TLTs). As organized structures that develop at sites of inflammation or infection during adulthood, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis in the colon. Here, we investigated the effect of the conditional loss of AhR activity in IECs in the formation and immune cell composition of TLTs in a model of acute inflammation. In females, loss of AhR activity in IECs reduced the formation of TLTs without significantly changing disease outcomes or immune cell composition within TLTs. In males lacking AhR expression in IECs, increased disease activity index, lower expression of functional-IEC genes, increased number of TLTs, increased T-cell density, and lower B- to Tcell ratio were observed. These findings may represent an unfavorable prognosis when exposed to dextran sodium sulfate (DSS)-induced epithelial damage compared with females. Sex and loss of IEC AhR also resulted in changes in microbial populations in the gut. Collectively, these data suggest that the formation of TLTs in the colon is influenced by sex and AhR expression in IECs. NEW & NOTEWORTHY This is the first research of its kind to demonstrate a clear connection between biological sex and the development of tertiary lymphoid tissues (TLT) in the colon. In addition, the research finds that in a preclinical model of inflammatory bowel disease, the expression of the aryl hydrocarbon receptor (AhR) influences the development of these structures in a sex-specific manner [ABSTRACT FROM AUTHOR]

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), which is primarily produced by activated hepatic stellate cells (HSCs). However, effective therapies for hepatic fibrosis are currently lacking. Artesunate is a promising anti-fibrotic drug candidate, but its clinical application is hindered by limited absorption. Here, we present a novel oral delivery platform that enhances the HSCs uptake of artesunate and induces potent ferroptosis. The platform is vitamin A-decorated nanoparticles encapsulated with artesunate. The multifunctional ligand vitamin A interacts with retinol-binding proteins that are highly expressed on the intestinal epithelium to promote transcytosis, highly expressed on the surface of HSCs but lowly expressed in normal hepatocytes. After oral administration, this oral delivery platform enhances transepithelial transport in the intestine, improves drug accumulation in the liver, and continuously increases HSCs uptake of artesunate. Upon drug release in HSCs, artesunate depletes glutathione peroxidase 4 and glutathione, effectively initiating ferroptosis. In vivo experiments demonstrate that this strategy induces pronounced ferroptosis, efficiently relieving liver fibrosis. This work provides a proof-of-concept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for liver fibrosis treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative process responsible for almost 70% of all cases of dementia. The clinical signs consist in progressive and irreversible loss of memory, cognitive, and behavioral functions. The main histopathological hallmark is the accumulation of amyloid-ß (Aß) peptide fibrils in the brain. To date, the origin of Aß has not been determined. Recent studies have shown that the gut microbiota produces Aß, and dysbiotic states have been identified in AD patients and animal models of AD. Starting from the hypothesis that maintaining or restoring the microbiota's eubiosis is essential to control Aß's production and deposition in the brain, we used a mixture of probiotics and prebiotics (symbiotic) to treat APPPS1 male and female mice, an animal model of AD, from 2 to 8 months of age and evaluated their cognitive performances, mucus secretion, Aβ serum concentration, and microbiota composition. The results showed that the treatment was able to prevent the memory deficits, the reduced mucus secretion, the increased Aβ blood levels, and the imbalance in the gut microbiota found in APPPS1 mice. The present study demonstrates that the gut–brain axis plays a critical role in the genesis of cognitive impairment, and that modulation of the gut microbiota can ameliorate AD's symptomatology. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is lined by an epithelial monolayer responsible for selective permeability and absorption, as well as protection against harmful luminal contents. Recognition of foreign or aberrant DNA within these epithelial cells is, in part, regulated by pattern recognition receptors such as cyclic GMP-AMP synthase (cGAS). cGAS binds double-stranded DNA from exogenous and endogenous sources, resulting in the activation of stimulator of interferon genes (STING) and a type 1 interferon response. cGAS is also implicated in non-canonical pathways involving the suppression of DNA repair and the upregulation of autophagy via interactions with PARP1 and Beclin-1, respectively. The importance of cGAS activation in the development and progression of inflammatory bowel disease and gastrointestinal cancers has been and continues to be explored. This review delves into the intricacies of the complex role of cGAS in intestinal epithelial inflammation and gastrointestinal malignancies, as well as recent therapeutic advances targeting cGAS pathways. [ABSTRACT FROM AUTHOR]

Intestinal epithelial cells possess the requisite molecular machinery to initiate cell-intrinsic defensive responses against intracellular pathogens, including intracellular parasites. Interferons(IFNs) have been identified as cornerstones of epithelial cell-intrinsic defense against such pathogens in the gastrointestinal tract. Long non-coding RNAs (lncRNAs) are RNA transcripts (>200 nt) not translated into protein and represent a critical regulatory component of mucosal defense. We report here that lncRNA Nostrill facilitates IFN-γ-stimulated intestinal epithelial cell-intrinsic defense against infection by Cryptosporidium, an important opportunistic pathogen in AIDS patients and a common cause of diarrhea in young children. Nostrill promotes transcription of a panel of genes controlled by IFN-γ through facilitating Stat1 chromatin recruitment and thus, enhances expression of several genes associated with cell-intrinsic defense in intestinal epithelial cells in response to IFN-γ stimulation, including Igtp, iNos, and Gadd45g. Induction of Nostrill enhances IFN-γ-stimulated intestinal epithelial defense against Cryptosporidium infection, which is associated with an enhanced autophagy in intestinal epithelial cells. Our findings reveal that Nostrill enhances the transcription of a set of genes regulated by IFN-γ in intestinal epithelial cells. Moreover, induction of Nostrill facilitates the IFN-γ-mediated epithelial cell-intrinsic defense against cryptosporidial infections. [ABSTRACT FROM AUTHOR]

The incidence of perturbed gastrointestinal integrity, as well as resulting systemic immune responses and gastrointestinal symptoms, otherwise known as exercised-induced gastrointestinal syndrome (EIGS), is common among individuals who partake in prolonged exercise. EIGS may cause the translocation of pathogenic material, including whole bacteria and bacterial endotoxins, from the lumen into circulation, which may progress into clinical consequences such as sepsis, and potentially subsequent fatality. However, further investigation is warranted to assess the possibility of food allergen and/or digestive enzyme luminal to circulatory translocation in response to exercise, and the clinical consequences. Findings from this narrative literature review demonstrate evidence that whole bacteria and bacterial endotoxins translocation from the gastrointestinal lumen to systemic circulation occurs in response to exercise stress, with a greater propensity of translocation occurring with accompanying heat exposure. It has also been demonstrated that food allergens can translocate from the lumen to systemic circulation in response to exercise stress and initiate anaphylaxis. To date, no research investigating the effect of exercise on the translocation of digestive enzymes from the lumen into systemic circulation exists. It is evident that EIGS and consequential pathogenic translocation presents life-threatening clinical implications, warranting the development and implementation of effective management strategies in at-risk populations. [ABSTRACT FROM AUTHOR]

The complexification of in vitro models requires the compatibility of cells with the same medium. Since immune cells are the most sensitive to growth conditions, growing intestinal epithelial cells in their usual medium seems to be necessary. This work was aimed at comparing the sensitivity of these epithelial cells to pro-inflammatory stimuli but also to dietary polyphenols in both DMEM and RPMI-1640 media. Co-cultures of Caco-2 and HT29-MTX cells were grown for 21 days in the two media before their stimulation with a cocktail of TNF-α (20 ng/mL), IL-1β (1 ng/mL), and IFN-γ (10 ng/mL) or with LPS (10 ng/mL) from E. coli (O111:B4). The role of catechins (15 µM), a dietary polyphenol, was evaluated after its incubation with the cells before their stimulation for 6 h. The RPMI-1640 medium did not alter the intensity of the inflammatory response observed with the cytokines. By contrast, LPS failed to stimulate the co-culture in inserts regardless of the medium used. Lastly, catechins were unable to prevent the pro-inflammatory response observed with the cytokines in the two media. The preservation of the response of this model of intestinal epithelium in RPMI-1640 medium is promising when considering its complexification to evaluate the complex cellular crosstalk leading to intestinal homeostasis. [ABSTRACT FROM AUTHOR]

Human milk (HM) components affect immune cell toll-like receptor 4 (TLR4) signaling. However, studies examining the immunomodulatory impacts of HM on TLR4 signaling in intestinal epithelial cells (IECs) are limited. This study utilized both a TLR4 reporter cell line and a Caco-2 IEC model to examine the effects of HM on lipopolysaccharide (LPS)-induced TLR4 activation and cytokine responses, respectively. Additionally, we performed fast protein liquid chromatography and mass spectrometry to identify a HM component that contributes to the effect of HM on LPS/TLR4 signaling. HM enhances LPS-induced TLR4 signaling as well as LPS-induced IEC gene expression of pro-inflammatory cytokines and negative regulators of NF-κB. Human serum albumin (HSA) present in HM contributes to these effects. HSA within HM synergizes with LPS to induce IEC gene expression of pro-inflammatory cytokines and negative regulators of NF-κB. Altogether, this study provides mechanistic evidence behind the immunomodulatory function of HM on IECs, which may contribute to an enhanced immune response in breast-fed neonates. [ABSTRACT FROM AUTHOR]

Ernst Brücke's 1861 essay Die Elementarorganismen has often been cited as a watershed in the history of physiology as well as in the history of cell theory. In its time it was widely read as a reform of animal cell theory, shifting the concept of the cell away from Schleiden and Schwann's original cell schema of a membranous vesicle with a nucleus, and towards the protoplasm theory that had developed in botany, centered on the cell's living contents. It was also notorious for its arguments against the necessity of both the nucleus and the cell membrane. An English translation of "The Elementary Organisms" is presented for the first time in this journal issue, with annotations and illustrations, https://doi.org/10.1007/s10739-024-09773-9. Brücke's essay was not only an intervention into cell theory: historians can read it as a continuation of debates on the nature of the organism and theories of organization, and as an epistemological meditation on the microscope. In addition, although Brücke was known as a founder of the Berlin school of organic physics, "The Elementary Organisms" shows how he combined an avant-garde physicalist physiology with a much older tradition of comparative anatomy and physiology. The following introductory essay will provide a scientific biography of Ernst Brücke up to 1863, with background on debates on biological organization, cell theory, and muscle histology. [ABSTRACT FROM AUTHOR]

Recently, the bioactive potential of several functional ingredients and biomolecules has been evaluated regarding human and animal nutrition. The digestive process from food intake to absorption and metabolism are important events that induce changes in ingredients, which affect their bioactivity. Consequently, there is a need to assess the bioavailability and bioaccessibility of these compounds. The methodology for the simulation of the human gastrointestinal tract has been standardized (INFOGEST protocol), while a gastrointestinal protocol for other animals (e.g., ruminants or broilers) has yet to be established. However, INFOGEST allows us only to predict bioaccessibility, leaving a gap regarding a methodology able to assess bioavailability by mimicking intestinal permeability and absorption. Several approaches—including in vitro, ex vivo, in situ and in vivo methods—can be found in the literature, aiming to tackle transepithelial routes, but leading to different results concerning the bioefficiency of the compounds studied. Therefore, this review aims to assess the current state-of-the-art regarding monogastric intestinal dynamics, absorption, and permeability events. Moreover, it compiled methodologies for simulating intestinal absorption in several biological systems, while reasoning their advantages, disadvantages, applications in ingredient development and the existing gaps.

Objective To investigate the regulation role of sterol regulatory element binding protein 1c (SREBP1c) in intestinal gluconeogenesis. Methods After C57BL/6 mice, and SREBP1c homozygous knockout (SREBP1c-KO) and littermate wild-type (SREBP1c-WT) mice were fasted for 48 h, qPCR and Western blotting were used to detect the expression of rate-limiting gluconeogenic genes glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1) in the liver, jejunum and ileum tissues at mRNA and protein levels. After overexpression or knockdown of SREBP1c in the intestinal epithelial cell line CaCo-2, the expression levels of G6PC and PCK1 were measured. Results The expression levels of G6PC, PCK1, and SREBP1c were significantly increased in the jejunum and ileum tissues of C57BL/6 mice after fasting (P < 0.05). In SREBP1c-KO mice, fasting treatment induced obviously inhibited expression of G6PC and PCK1 in the jejunum and ileum tissues (P < 0.05). Overexpression of SREBP1c significantly upregulated the expression levels of G6PC and PCK1, and promoted the production of glucose in CaCo-2 cells (P < 0.05). Conversely, knocking SREBP1c down resulted in down-regulation of G6PC and PCK1 and suppressed production of glucose in CaCo-2 cells (P < 0.05). Conclusion Under fasting, SREBP1c is involved in regulation of G6PC and PCK1 in intestinal epithelial cells, and thus affects glucose production. It indicates that SREBP1c might be involved in the regulation of intestinal gluconeogenesis, and the mechanism needs further exploration.

Human CD81 and CD9 are members of the tetraspanin family of proteins characterized by a canonical structure of four transmembrane domains and two extracellular loop domains. Tetraspanins are known as molecular facilitators, which assemble and organize cell surface receptors and partner molecules forming clusters known as tetraspanin-enriched microdomains. They have been implicated to play various biological roles including an involvement in infections with microbial pathogens. Here, we demonstrate an important role of CD81 for the invasion of epithelial cells by Salmonella enterica. We show that the overexpression of CD81 in HepG2 cells enhances invasion of various typhoidal and non-typhoidal Salmonella serovars. Deletion of CD81 by CRISPR/Cas9 in intestinal epithelial cells (C2BBe1 and HT29-MTX-E12) reduces S. Typhimurium invasion. In addition, the effect of human CD81 is species-specific as only human but not rat CD81 facilitates Salmonella invasion. Finally, immunofluorescence microscopy and proximity ligation assay revealed that both human tetraspanins CD81 and CD9 are recruited to the entry site of S. Typhimurium during invasion but not during adhesion to the host cell surface. Overall, we demonstrate that the human tetraspanin CD81 facilitates Salmonella invasion into epithelial host cells.

Alternariol monomethyl-ether (AME), together with altenuene and alternariol, belongs to the Alternaria mycotoxins group, which can contaminate different substrates, including cereals. The aim of the present study was to obtain a deeper understanding concerning the effects of AME on pig intestinal health using epithelial intestinal cell lines as the data concerning the possible effects of Alternaria toxins on swine are scarce and insufficient for assessing the risk represented by Alternaria toxins for animal health. Our results have shown a dose-related effect on IPEC-1 cell viability, with an IC50 value of 10.5 μM. Exposure to the toxin induced an increase in total apoptotic cells, suggesting that AME induces programmed cell death through apoptosis based on caspase-3/7 activation in IPEC-1 cells. DNA and protein oxidative damage triggered by AME were associated with an alteration of the antioxidant response, as shown by a decrease in the enzymatic activity of catalase and superoxide dismutase. These effects on the oxidative response can be related to an inhibition of the Akt/Nrf2/HO-1 signaling pathway; however, further studies are needed in order to validate these in vitro data using in vivo trials in swine. [ABSTRACT FROM AUTHOR]

The recent development of single-cell transcriptomics highlighted the existence of a new lineage of mature absorptive cells in the human intestinal epithelium. This subpopulation is characterized by the specific expression of Bestrophin 4 (BEST4) and of other marker genes including OTOP2, CA7, GUCA2A, GUCA2B, and SPIB. BEST4+ cells appear early in development and are present in all regions of the small and large intestine at a low abundance (<5% of all epithelial cells). Location-specific gene expression profiles in BEST4+ cells suggest their functional specialization in each gut region, as exemplified by the small intestine-specific expression of the ion channel CFTR. The putative roles of BEST4+ cells include sensing and regulation of luminal pH, tuning of guanylyl cyclase-C signaling, transport of electrolytes, hydration of mucus, and secretion of antimicrobial peptides. However, most of these hypotheses lack functional validation, notably because BEST4+ cells are absent in mice. The presence of BEST4+ cells in human intestinal organoids indicates that this in vitro model should be suitable to study their role. Recent studies showed that BEST4+ cells are also present in the intestinal epithelium of macaque, pig, and zebrafish and, here, we report their presence in rabbits, which suggests that these species could be appropriate animal models to study BEST4+ cells during the development of diseases and their interactions with environmental factors such as diet or the microbiota. In this review, we summarize the existing literature regarding BEST4+ cells and emphasize the description of their predicted roles in the intestinal epithelium in health and disease. NEW & NOTEWORTHY: BEST4+ cells are a novel subtype of mature absorptive cells in the human intestinal epithelium highlighted by single-cell transcriptomics. The gene expression profile of BEST4+ cells suggests their role in pH regulation, electrolyte secretion, mucus hydration, and innate immune defense. The absence of BEST4+ cells in mice requires the use of alternative animal models or organoids to decipher the role of this novel type of intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

The gut represents an important site of colonization of the commensal bacterium Streptococcus agalactiae (group B Streptococcus or GBS), which can also behave as a deadly pathogen in neonates and adults. Invasion of the intestinal epithelial barrier is likely a crucial step in the pathogenesis of neonatal infections caused by GBS belonging to clonal complex 17 (CC17). We have previously shown that the prototypical CC17 BM110 strain invades polarized enterocytelike cells through their lateral surfaces using an endocytic pathway. By analyzing the cellular distribution of putative GBS receptors in human enterocyte-like Caco-2 cells, we find here that the alpha 3 (α3) and alpha 2 (α2) integrin subunits are selectively expressed on lateral enterocyte surfaces at equatorial and parabasal levels along the vertical axis of polarized cells, in an area corresponding to GBS entry sites. The α3β1 and α2β1 integrins were not readily accessible in fully dierentiated Caco-2 monolayers but could be exposed to specific antibodies after weakening of intercellular junctions in calcium-free media. Under these conditions, anti-α3β1 and anti-α2β1 antibodies significantly reduced GBS adhesion to and invasion of enterocytes. After endocytosis, α3β1 and α2β1 integrins localized to areas of actin remodeling around GBS containing vacuoles. Taken together, these data indicate that GBS can invade enterocytes by binding to α3β1 and α2β1 integrins on the lateral membrane of polarized enterocytes, resulting in cytoskeletal remodeling and bacterial internalization. Blocking integrins might represent a viable strategy to prevent GBS invasion of gut epithelial tissues. [ABSTRACT FROM AUTHOR]

Inflammatory mediators have context-dependent pro- and anti-repair effects on the intestinal epithelium. Inflammatory pro-repair effects might be impaired by anti-inflammatory therapies against inflammatory bowel disease (IBD). A detailed understanding of epithelial integration of inflammatory signals and their translation into repair responses might inform novel, more targeted treatment strategies to boost epithelial repair and promote mucosal healing in IBD. The intestinal epithelium fulfills important physiological functions and forms a physical barrier to the intestinal lumen. Barrier function is regulated by several pathways, and its impairment contributes to the pathogenesis of inflammatory bowel disease (IBD), a chronic inflammatory condition affecting more than seven million people worldwide. Current treatment options specifically target inflammatory mediators and have led to improvement of clinical outcomes; however, a significant proportion of patients experience treatment failure. Pro-repair effects of inflammatory mediators on the epithelium are emerging. In this review we summarize current knowledge on involved epithelial pathways, identify open questions, and put recent findings into clinical perspective, and pro-repair effects. A detailed understanding of epithelial pathways integrating mucosal stimuli in homeostasis and inflammation is crucial for the development of novel, more targeted therapies. The intestinal epithelium fulfills important physiological functions and forms a physical barrier to the intestinal lumen. Barrier function is regulated by several pathways, and its impairment contributes to the pathogenesis of inflammatory bowel disease (IBD), a chronic inflammatory condition affecting more than seven million people worldwide. Current treatment options specifically target inflammatory mediators and have led to improvement of clinical outcomes; however, a significant proportion of patients experience treatment failure. Pro-repair effects of inflammatory mediators on the epithelium are emerging. In this review we summarize current knowledge on involved epithelial pathways, identify open questions, and put recent findings into clinical perspective. A detailed understanding of epithelial pathways integrating mucosal stimuli in homeostasis and inflammation is crucial for the development of novel, more targeted therapies. [ABSTRACT FROM AUTHOR]

Due to the unstable chemical properties and poor water solubility of carotenoids, their processing adaptation and oral bioavailability are poor, limiting their application in hydrophilic food systems. Lipid-biomacromolecular compounds can be excellent carriers for carotenoid delivery by taking full advantage of the solubilization of lipids to non-polar nutrients and the water dispersion and gastrointestinal controlled release properties of biomacromolecules. This paper reviewed the research progress of lipid-biomacromolecular compounds as encapsulation and delivery carriers of carotenoids and summarized the material selection and preparation methods for biomacromolecular compounds. By considering the interaction between the two, this paper briefly discussed the effect of these compounds on carotenoid water solubility, stability, and bioavailability, emphasizing their delivery effect on carotenoids. Finally, various challenges and future trends of lipid-biomacromolecular compounds as carotenoid delivery carriers were discussed, providing new insight into efficient loading and delivery of carotenoids. [ABSTRACT FROM AUTHOR]

Recently, the bioactive potential of several functional ingredients and biomolecules has been evaluated regarding human and animal nutrition. The digestive process from food intake to absorption and metabolism are important events that induce changes in ingredients, which affect their bioactivity. Consequently, there is a need to assess the bioavailability and bioaccessibility of these compounds. The methodology for the simulation of the human gastrointestinal tract has been standardized (INFOGEST protocol), while a gastrointestinal protocol for other animals (e.g., ruminants or broilers) has yet to be established. However, INFOGEST allows us only to predict bioaccessibility, leaving a gap regarding a methodology able to assess bioavailability by mimicking intestinal permeability and absorption. Several approaches—including in vitro, ex vivo, in situ and in vivo methods—can be found in the literature, aiming to tackle transepithelial routes, but leading to different results concerning the bioefficiency of the compounds studied. Therefore, this review aims to assess the current state-of-the-art regarding monogastric intestinal dynamics, absorption, and permeability events. Moreover, it compiled methodologies for simulating intestinal absorption in several biological systems, while reasoning their advantages, disadvantages, applications in ingredient development and the existing gaps. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is lined by an epithelial monolayer responsible for selective permeability and absorption, as well as protection against harmful luminal contents. Recognition of foreign or aberrant DNA within these epithelial cells is, in part, regulated by pattern recognition receptors such as cyclic GMP-AMP synthase (cGAS). cGAS binds double-stranded DNA from exogenous and endogenous sources, resulting in the activation of stimulator of interferon genes (STING) and a type 1 interferon response. cGAS is also implicated in non-canonical pathways involving the suppression of DNA repair and the upregulation of autophagy via interactions with PARP1 and Beclin-1, respectively. The importance of cGAS activation in the development and progression of inflammatory bowel disease and gastrointestinal cancers has been and continues to be explored. This review delves into the intricacies of the complex role of cGAS in intestinal epithelial inflammation and gastrointestinal malignancies, as well as recent therapeutic advances targeting cGAS pathways.

Background and Aims: Glucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB1R) are expressed in these cell subpopulations; however, roles for CB1Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB1Rs control fat-induced incretin secretion. Methods: We treated mice with conditional deletion of CB1Rs in the intestinal epithelium (IntCB1−/−) or controls (IntCB1+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ9 tetrahydrocannabinol (THC), and the peripherally-restricted CB1R antagonist AM6545. Circulating incretin levels were measured in plasma. Results: Oral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB1+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB1−/− mice. In contrast, THC inhibited the secretion of incretins irrespective of CB1R expression in intestinal epithelial cells. Conclusion: These results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB1R-dependent and CB1R-independent mechanisms.

Abstract Background Adherent-invasive Escherichia coli (AIEC) is isolated from patients with Crohn’s disease (CD). AIEC can invade the intestinal epithelium, suggesting that it is involved in the development and pathogenesis of CD. However, the mechanism by which AIEC acquired the invasive phenotype remains unknown. Results This study was designed to examine the mechanisms of AIEC invasiveness. We found that the flagellin (fliC) expression in AIEC was two-fold higher than that in non-AIEC strains, and this overexpression induced the formation of long-filament flagellin. Deletion of fliC in the AIEC LF82 strain resulted in the disappearance of flagellar filaments and attenuated the motility and invasive ability of the bacterium, suggesting that the formation of long filament flagellin induced by increased fliC expression is required by AIEC to invade the intestinal epithelium. In AIEC and non-AIEC K12 strains cultured in the presence of cyclic-di-AMP (c-di-AMP), the expression of fliC was enhanced, and flagellar filaments were elongated. Stimulation with c-di-AMP enhanced the bacterial motility and ability to invade epithelial cells, even in the non-AIEC K12 strain. Conclusions Our findings show that c-di-AMP confers an AIEC-like phenotype on non-AIEC strains by enhancing the expression of fliC. The results should be useful for understanding the pathogenesis of CD.

Yunhao Yang,1,2 Fang Pang,1– 3 Min Zhou,1,2 Xiao Guo,1,2 Yan Yang,1,2 Wei Qiu,1,2 Cai Liao,1,2 Yang Chen,1,2 Chenglin Tang1,2 1College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, People’s Republic of China; 3Institute of Sports Biology, Shaanxi Normal University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Chenglin Tang, Email tangchenglin@cqmu.edu.cnBackground: Electroacupuncture (EA) is used to treat inflammatory bowel disease (IBD). Nevertheless, the precise mechanisms by which this approach safeguards against obesity-induced intestinal barrier damage has not been fully understood.Objective: This study aimed to assess whether EA could ameliorate intestinal barrier damage that had been reversed in a mouse model of obesity induced by a high-fat diet (HFD) and whether this repair is correlated with ferroptosis and gut microbiota enhancement.Methods: To assess the potential of EA to prevent obesity and restore the intestinal barrier, we divided in C57BL/6J mice into two groups; one was fed with HFD and another one with a normal diet. Samples of stool, blood, fat, and intestinal epithelium were then evaluated, along with body weight.Results: Following EA, we observed a significant reduction in body weight, fat accumulation, and serum triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels; an increase was seen in high-density lipoprotein cholesterol (HDL-C) levels. EA also activated the Nrf2 signaling pathway; upregulated the expression of GPX4, FTH1, and SLC7A11; and downregulated the expression of TFR1. In addition, the administration of EA resulted in a notable modification of the gut microbiota composition, characterized by a decrease in the Firmicutes to Bacteroidetes ratio.Conclusion: EA had beneficial effects on weight loss and showed potential ability to repair the intestinal barrier by activating the Nrf2 signaling pathway, inhibiting intestinal inflammation and ferroptosis, and regulating the intestinal microbiota to treat IBD caused by HFD-induced obesity. Keywords: ferroptosis, electrostimulation, acupuncture, Chinese medicine, obesity, intestinal epithelium

Abstract The intestinal barrier is critical in maintaining gut homeostasis and host health. The intestinal barrier dysfunction contributes to intestinal and systemic diseases like inflammatory bowel disease, colorectal cancer, and metabolic syndromes. This review summarizes the physicochemical properties of three main kinds of brown seaweed polysaccharides (BSP), laminarin, fucoidan, and alginate, along with their absorption and metabolism in the intestine and their effects on the intestinal barrier. The physicochemical properties of BSP were closely related to their beneficial effects on intestinal health. BSP were not digested directly in the upper gastrointestinal tract but could be utilized through fermentation by the gut microbiota. BSP kept the integrity of intestinal epithelium by ameliorating intestinal oxidative stress through the nuclear factor erythroid 2‐related factor 2 signaling pathway. They also reduced tight junction dysfunction and intestinal permeability and increased the expression of mucins. Moreover, BSP regulated the composition and abundance of gut microbiota and promoted the production of beneficial metabolites such as short‐chain fatty acids. This review will help to understand the gut health‐promoting functions of the natural compounds derived from brown seaweed and offer a new perspective on intestinal disease prevention and therapy with high effectiveness and safety.

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known. To this end, we used IEC-specific AhR deletion coupled with a mouse model of dextran sodium sulfate (DSS)-induced colitis to understand how dietary AhR ligand 3, 3′-diindolylmethane (DIM) influenced TLT formation. DIM consumption increased the size of TLTs and decreased T-cell aggregation to TLT sites in an IEC-specific manner. In DSS-exposed female mice, DIM consumption increased the expression of genes implicated in TLT formation (Interleukin-22, Il-22; CXC motif chemokine ligand 13, CXCL13) in an IEC AhR-specific manner. Conversely, in female mice without DSS exposure, DIM significantly reduced the expression of Il-22 or CXCL13 in iAhRKO mice, but this effect was not observed in WT animals. Our findings suggest that DIM affects the immunological landscape of TLT formation during DSS-induced colitis in a manner contingent on AhR expression in IECs and biological sex. Further investigations into specific immune cell activity, IEC-specific AhR signaling pathways, and dietary AhR ligand-mediated effects on TLT formation are warranted.

The growing incidence of human diseases involving inflammation and increased gut permeability makes the quest for protective functional foods more crucial than ever. Propionibacterium freudenreichii (P. freudenreichii) is a beneficial bacterium used in the dairy and probiotic industries. Selected strains exert anti-inflammatory effects, and the present work addresses whether the P. freudenreichii CIRM-BIA129, consumed daily in a preventive way, could protect mice from acute colitis induced by dextran sodium sulfate (DSS), and more precisely, whether it could protect from intestinal epithelial breakdown induced by inflammation. P. freudenreichii CIRM-BIA129 mitigated colitis severity and inhibited DSS-induced permeability. It limited crypt length reduction and promoted the expression of zonula occludens-1 (ZO-1), without reducing interleukin-1b mRNA (il-1b ) expression. In vitro, P. freudenreichii CIRM-BIA129 prevented the disruption of a Caco-2 monolayer induced by proinflammatory cytokines. It increased transepithelial electrical resistance (TEER) and inhibited permeability induced by inflammation, along with an increased ZO-1 expression. Extracellular vesicles (EVs) from P. freudenreichii CIRM-BIA129, carrying the surface layer protein (SlpB), reproduced the protective effect of P. freudenreichii CIRM-BIA129. A mutant strain deleted for slpB (DslpB), or EVs from this mutant strain, had lost their protective effects and worsened both DSS-induced colitis and inflammation in vivo. These results shown that P. freudenreichii CIRM-BIA129 daily consumption has the potential to greatly alleviate colitis symptoms and, particularly, to counter intestinal epithelial permeability induced by inflammation by restoring ZO-1 expression through mechanisms involving S-layer protein B. They open new avenues for the use of probiotic dairy propionibacteria and/or postbiotic fractions thereof, in the context of gut permeability. NEW & NOTEWORTHY Propionibacterium freudenreichii reduces dextran sodium sulfate (DSS)-induced intestinal permeability in vivo. P. freudenreichii does not inhibit inflammation but damages linked to inflammation. P. freudenreichii inhibits intestinal epithelial breakdown through S-layer protein B. The protective effects of P. freudenreichii depend on S-layer protein B. Extracellular vesicles from P. freudenreichii CB 129 mimic the protective effect of the probiotic. [ABSTRACT FROM AUTHOR]

Intestinal epithelium is a dynamic cellular layer that lines the small-bowel and makes a relatively impenetrable barrier to macromolecules. Intestinal epithelial cell polarity is crucial in coordinating signalling pathways within cells and mainly regulated by three conserved polarity protein complexes, the Crumbs (Crb) complex, partitioning defective (PAR) complex, and Scribble (Scrib) complex. Polarity proteins regulate the proper establishment of the intercellular junctional complexes including tight junctions (TJs), adherence junctions (AJs), and desmosomes which hold epithelial cells together and play a major role in maintaining intestinal barrier integrity. Impaired intestinal epithelial cell polarity and barrier integrity result in irreversible immune responses, the host- microbial imbalance and intestinal inflammatory disorders. Disassembling the epithelial tight junction and augmented paracellular permeability is a conspicuous hallmark of celiac disease (CD) pathogenesis. There are several dietary components that can improve intestinal integrity and function. The aim of this review article is to summarize current information about the association of polarity proteins and AJC damages with pathogenesis of CD. [ABSTRACT FROM AUTHOR]

Background: Adherent-invasive Escherichia coli (AIEC) is isolated from patients with Crohn's disease (CD). AIEC can invade the intestinal epithelium, suggesting that it is involved in the development and pathogenesis of CD. However, the mechanism by which AIEC acquired the invasive phenotype remains unknown. Results: This study was designed to examine the mechanisms of AIEC invasiveness. We found that the flagellin (fliC) expression in AIEC was two-fold higher than that in non-AIEC strains, and this overexpression induced the formation of long-filament flagellin. Deletion of fliC in the AIEC LF82 strain resulted in the disappearance of flagellar filaments and attenuated the motility and invasive ability of the bacterium, suggesting that the formation of long filament flagellin induced by increased fliC expression is required by AIEC to invade the intestinal epithelium. In AIEC and non-AIEC K12 strains cultured in the presence of cyclic-di-AMP (c-di-AMP), the expression of fliC was enhanced, and flagellar filaments were elongated. Stimulation with c-di-AMP enhanced the bacterial motility and ability to invade epithelial cells, even in the non-AIEC K12 strain. Conclusions: Our findings show that c-di-AMP confers an AIEC-like phenotype on non-AIEC strains by enhancing the expression of fliC. The results should be useful for understanding the pathogenesis of CD. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), celiac disease, and other inflammatory conditions of the gastrointestinal tract are highly prevalent in society. Due to the complexity of factors involved, detailed pathogenesis is difficult to determine and thus remains elusive in many cases. The advent of gut-on-chip devices has permitted more accurate modeling of the gut microenvironment with the inclusion of fluid flow and mechanical cues that are true to intestinal architecture and physiology. This review outlines the evolution of gut-on-chip platforms towards greater physiological relevance and elucidates how these devices have been used to model and study intestinal inflammation in humans. In addition, we identify key elements from both technological and disease standpoints that are integral for accurate gut-on-chip models of IBD and celiac disease. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are an effective tool to elucidate the bioeffect of nanomedicines. To clarify the interaction between oral nanomedicines and intestinal epithelial cells, and their bioeffects on downstream cells, polystyrene nanoparticles (PS-NPs) with different sizes were used as the model nanomedicines for EVs induction. Caco-2 monolayers were selected as the model of the intestinal epithelium and DLD-1 cells as the colorectal cancer model proximal to the gastrointestinal tract. It is found that compared with small-sized (25, 50, 100 nm) PS-NPs, the large-sized (200 and 500 nm) exhibited higher co-localization with multivesicular bodies and lysosomes, and more significant reduction of lysosomal acidification in Caco-2 cells. Proteomic and western-blotting analysis showed that the EVs remodeled by large-sized PS-NPs exhibited a higher extent of protein expression changes. The in vitro and in vivo signaling pathway detection in DLD-1 cells and DLD-1 cell xenograft nude mice showed that the remodeled EVs by large-sized PS-NPs inhibited the activation of multiple signaling pathways including Notch3, EGF/EGFR, and PI3K/Akt pathways, which resulted in the inhibition of tumor cell migration. These results primarily clarify the regulation mechanisms of nanomedicines-EVs-receptor cells chain. It provides a new perspective for the rational design and bioeffect evaluation of oral drug nanomaterials and sets up the fundamental knowledge for novel tumor therapeutics in the future. [Display omitted] • Oral nanomedicines induce a biological response cascade through extracellular vesicles derived from intestinal epithelial cells. • Polystyrene nanoparticles alter the protein contents of extracellular vesicles in a size-dependent manner. • Extracellular vesicles remodeled by large-sized polystyrene nanoparticles inhibit tumor cell migration. • The activation of Notch3, EGF/EGFR, and PI3K/Akt pathways, accounts for the inhibition of tumor metastasis. • The regulation mechanisms of nanomedicines-EVs-receptor cells chain, suggest a potential EVs-mediated tumor therapeutics in the future, and provide a theoretical basis for the rational design of oral nanomedicines. [ABSTRACT FROM AUTHOR]

The intestinal epithelium is one of the fastest renewing tissues in mammals and plays a critical role in food digestion and nutrient absorption, maintenance of mucosal barrier, immune regulation, and defense against intestinal microbiota. The diverse cell types within the intestinal epithelium provide the foundation for its multifunctional roles, and their differentiation and development are tightly controlled. Dysregulation of key regulatory signals can compromise the intestinal epithelial barrier function and contribute to the occurrence of various intestinal diseases. This review discusses the functions, cellular composition, and regulatory signals of the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) in mammalian systems are well known for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorsoventral patterning function of the original Toll receptor in Drosophila and neurogenesis in mice. Recent discoveries in flies suggested key roles for TLRs in epithelial cells in patterning of junctional cytoskeletal activity. Here, we address the function of TLRs and the downstream key signal transduction component IRAK4 in human epithelial cells. Using differentiated human Caco-2 cells as a model for the intestinal epithelium, we show that these cells exhibit baseline TLR signalling, as revealed by p-IRAK4, and that blocking IRAK4 function leads to a loss of epithelial tightness involving key changes at tight and adherens junctions, such as a loss of epithelial tension and changes in junctional actomyosin. Changes upon IRAK-4 inhibition are conserved in human bronchial epithelial cells. Knockdown of IRAK4 and certain TLRs phenocopies the inhibitor treatment. These data suggest a model whereby TLR receptors near epithelial junctions might be involved in a continuous sensing of the epithelial state to promote epithelial tightness and integrity. [ABSTRACT FROM AUTHOR]

Epithelial metabolism in the intestine is increasingly known to be important for stem cell maintenance and activity while also affecting weight gain and diseases. This review compiles studies from recent years which describe major transcription factors controlling metabolic activity across the intestinal epithelium as well as transcriptional and epigenetic networks controlling the factors themselves. Recent studies show that transcriptional regulators serve as the link between signals from the microbiota and diet and epithelial metabolism. Studies have advanced this paradigm to identify druggable targets to block weight gain or disease progression in mice. As such, there is great potential that a better understanding of these regulatory networks will improve our knowledge of intestinal physiology and promote discoveries to benefit human health. [ABSTRACT FROM AUTHOR]