Small Intestinal Barrier Research Articles

Isoleucine Enhanced the Function of the Small Intestinal Mucosal Barrier in Weaned Piglets to Alleviate Rotavirus Infection.

Rotavirus (RV) is a major cause of diarrhea in young children and animals, especially piglets, leading to substantial economic losses in the global pig industry. Isoleucine (Ile), a branched-chain amino acid, plays an important role in regulating nutrient metabolism and has been shown to improve diarrhea. This study aimed to evaluate the effects of Ile supplementation on the mucosal immune barrier of the small intestine in RV-infected weaned piglets. Forty-eight 21-day-old weaned piglets were randomly divided into three dietary treatments (each treatment was subdivided into two groups, eight replicates per group), with 0%, 0.5%, or 1% Ile added for 15 days, and then, one group from each treatment was challenged with RV. The results showed that 1% Ile added to the diet promoted the healthy development of the intestinal mucosa. Ile could restore the reduced villus height in the ileum and the goblet cell number in the duodenum and ileum to normal levels, improving the intestinal epithelial tight junctions in RV-infected piglets. Additionally, Ile increased the activity of lipase, amylase, and sucrase, as well as superoxide dismutase (SOD) and glutathione (GSH), along with the expression of SIgA, DEFβ1, and DEFβ2 in parts of the small intestine. The addition of Ile to the diet mitigated the effects of RV infection on intestinal morphology and mucosal barrier function, as well as the physiological functions of weaned piglets, and improved the antioxidant and immune functions of the piglets to some extent. These findings offer valuable insights, contributing to a deeper understanding of the role of Ile in supporting intestinal health.

Aging by autodigestion.

The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.

Tsg101 knockout in the mammary gland leads to a decrease in small extracellular vesicles in milk from C57BL/6J dams and contributes to leakiness of the gut mucosa and reduced postnatal weight gain in suckling pups

Human milk contains 2.2 ± 1.5×1011 small extracellular vesicles (sEVs) per milliliter and human infants consume 1.7×1014 milk sEVs (sMEVs) daily in 800 mL milk. Infant formula contains trace amounts of sMEVs. To date, eight adverse effects of milk depletion and five beneficial effects of sMEV supplementation have been reported including studies in infants and neonate mice. Formula-fed infants do not realize the benefits of sMEVs. Most of the phenotyping studies reported to date have the limitation that sMEV depletion and supplementation were initiated after mice were weaned. Here, we used a genetics approach for assessing effects of sMEV depletion on the development of suckling mice. Newborn C57BL/6J pups were fostered to Tumor Susceptibility Gene 101 (Tsg101) mammary-specific knockout (KO) dams or C57BL/6J dams (controls) in synchronized pregnancies. Tsg101 KO was associated with an 80% decrease of sMEVs. Postnatal weight gain and gut health (histology, morphology, and barrier function) were assessed until weaning at age three weeks. We observed a significant decrease in weight gain, length of small intestine, villi height, crypt depth, and intestinal barrier function in male and female pups fostered to Tsg101 dams compared to pups fostered to control dams. The effect size varied between 11 and 32 percent. Maternal Tsg101 KO did not affect the dams’ health, content of macronutrients and dry mass of milk and had no effect on the amount of milk consumed by pups. We conclude that sMEVs are important for growth and gut health in neonate mice.

Understanding the role of the human gut microbiome in overweight and obesity.

The gut microbiome may be related to the prevalence of overweight and obesity, but high interindividual variability of the human microbiome complicates our understanding. Obesity often occurs concomitantly with micronutrient deficiencies that impair energy metabolism. Microbiota composition is affected by diet. Host-microbiota interactions are bidirectional. We propose three pathways whereby these interactions may modulate the gut microbiome and obesity: (1) ingested compounds or derivatives affecting small intestinal transit, endogenous secretions, digestion, absorption, microbiome balance, and gut barrier function directly affect host metabolism; (2) substrate availability affecting colonic microbial composition and contact with the gut barrier; and (3) microbial end products affecting host metabolism. The quantity/concentration, duration, and/or frequency (circadian rhythm) of changes in these pathways can alter the gut microbiome, disrupt the gut barrier, alter host immunity, and increase the risk of and progression to overweight and obesity. Host-specific characteristics (e.g., genetic variations) may further affect individual sensitivity and/or resilience to diet- and microbiome-associated perturbations in the colonic environment. In this narrative review, the effects of selected interventions, including fecal microbiota transplantation, dietary calorie restriction, dietary fibers and prebiotics, probiotics and synbiotics, vitamins, minerals, and fatty acids, on the gut microbiome, body weight, and/or adiposity are summarized to help identify mechanisms of action and research opportunities.

Dietary Fermented Blueberry Pomace Supplementation Improves Small Intestinal Barrier Function and Modulates Cecal Microbiota in Aged Laying Hens.

This study aimed to investigate the effects of fermented blueberry pomace (FBP) on the intestinal barrier function and cecal microbiome of aged laying hens. A total of 320 Yukou Jingfen No. 8 laying hens (345-day-old) were randomly divided into a control group, 0.25% FBP group, 0.5% FBP group, or 1.0% FBP group. The results showed that the villus height (VH) in the jejunum of the 0.25-0.5% FBP groups and villus surface area in the jejunum of the 0.25% FBP group were higher (p < 0.05), while 0.25% FBP supplementation displayed a higher (p = 0.070) VH in the ileum compared to the control group. Mucin-2 expression was upregulated (p < 0.05) in the jejunum of the 0.5% FBP group and the ileum of the 0.25-0.5% FBP groups. Compared to the control group, interleukin (IL)-4 and IL-13 expressions were upregulated (p < 0.05) in the 1.0% FBP group. Microbiota analysis revealed that Prevotella abundance in the cecum of the 0.5-1.0% FBP groups was higher (p < 0.05) than in the 0.25% FBP group. In addition, microbial function prediction analysis showed that cecal microbiota in the 0.25% FBP group were mainly enriched by alanine/aspartate/glutamate metabolism and methane metabolism. Moreover, Spearman's correlation analysis revealed the potential correlations between the abundance of the cecal microbiota and intestinal-barrier-function-related gene expressions, as well as the short-chain fatty acid content, of laying hens. In summary, dietary FBP supplementation enhanced intestinal barrier function by improving intestinal morphology, upregulating gene expressions related to barrier function, and altering the cecal microbiota of aged laying hens.

Soybean Bioactive Peptide Supplementation Affects the Intestinal Immune Antioxidant Function, Microbial Diversity, and Reproductive Organ Development in Roosters.

Soybean is an important source of high-quality vegetable protein with various health-improving properties, and its main bioactive substances are small peptides produced by in vitro enzymatic hydrolytic processes. In traditional layer breeding, the nutritional health of roosters is frequently neglected, ultimately affecting the quality and quantity of offspring. This study investigated the effects of various quantities (0%, 0.15%, 0.30%, 0.45%, and 0.60%) of soybean bioactive peptide (SBP) feed additives on immunological and antioxidant functions, gut health, and reproductive performance of roosters. SBP supplementation significantly improved male growth and reproductive performance, including growth rate, feed conversion ratio, reproductive organ development, and semen quality. SBP also increased immune and antioxidant levels, boosted the integrity of the small intestinal physiological structure and barrier function, and diversity of cecal microbes, and decreased the apoptotic ratio of small intestinal epithelial cells. The effects of SBP on various functions of males showed a quadratic trend, with the optimal concentration determined to be 0.45%.

Clostridium butyricum upregulates GPR109A/AMPK/PGC-1α and ameliorates acute pancreatitis-associated intestinal barrier injury in mice.

Acute pancreatitis frequently causes intestinal barrier damage, which aggravates pancreatitis. Although Clostridium butyricum exerts anti-inflammatory and protective effects on the intestinal barrier during acute pancreatitis, the underlying mechanism is unclear. The G protein-coupled receptors 109A (GPR109A) and adenosine monophosphate-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) signaling pathways can potentially influence the integrity of the intestinal barrier. Our study generated acute pancreatitis mouse models via intraperitoneal injection of cerulein and lipopolysaccharides. After intervention with Clostridium butyricum, the model mice showed reduced small intestinal and colonic intestinal barrier damage, dysbiosis amelioration, and increased GPR109A/AMPK/PGC-1α expression. In conclusion, Clostridium butyricum could improve pancreatic and intestinal inflammation and pancreatic injury, and relieve acute pancreatitis-induced intestinal barrier damage in the small intestine and colon, which may be associated with GPR109A/AMPK/PGC-1α.

Tributyrin Supplementation Rescues Chronic-Binge Ethanol-Induced Oxidative Stress in the Gut-Lung Axis in Mice.

Excessive alcohol consumption increases the severity and worsens outcomes of pulmonary infections, often due to oxidative stress and tissue damage. While the mechanism behind this relationship is multifaceted, recent evidence suggests ethanol-induced changes to the gut microbiome impact the gut-lung axis. To assess this, a chronic-binge ethanol feeding mouse model was used to determine how ethanol altered the gut microbiome, small intestinal epithelial barrier, and immune responses, as well as neutrophil abundance and oxidative stress in the lungs, and how supporting gut health with tributyrin supplementation during chronic-binge ethanol exposure affected these responses. We found that ethanol consumption altered gut bacterial taxa and metabolic processes, distorted small intestinal immune responses, and induced both bacteria and endotoxin translocation into the lymphatic and circulatory systems. These changes were associated with increased neutrophil (Ly6G) presence and markers of oxidative stress, lipocalin-2 and myeloperoxidase, in the lungs. Importantly, tributyrin supplementation during ethanol exposure rescued gut bacterial function (p < 0.05), small intestinal barrier integrity, and immune responses, as well as reducing both Ly6G mRNA (p < 0.05) and lipocalin-2 mRNA (p < 0.01) in the lungs. These data suggest ethanol-associated disruption of gut homeostasis influenced the health of the lungs, and that therapeutics supporting gut health may also support lung health.

N-3 enriched Fish oil diet enhanced intestinal barrier integrity in broilers after Eimeria infection

Coccidiosis caused by Eimeria spp. results in substantial economic losses in the poultry industry. The objective of this study was to investigate the effects of dietary supplementation with n-3 polyunsaturated fatty acids-enriched fish oil on growth performance, intestinal barrier integrity, and intestinal immune response of broilers challenged with Eimeria spp. A total of 576 14-day-old broilers were randomly assigned in a completely randomized design with a 3×2 factorial arrangement, comprising two diets supplemented with either 5% fish oil or 5% soybean oil, and three Eimeria spp. infection levels: a non-challenge control, a low dose of Eimeria challenge, and a high challenge dose. The results of the study revealed significant interactions between diet and Eimeria challenge to parameters of gut barrier integrity and feed intake. A significant interaction was observed in feed intake between 5-8 days post-infection (DPI), where the fish oil groups exhibited a higher amount of feed intake compared to the soybean oil diet groups after coccidiosis infection. The effects of the fish oil diet resulted in enhanced gut barrier integrity, as evidenced by a trend of decreased gastrointestinal leakage and a lower mean of small intestine lesion scores after Eimeria challenge. Additionally, significant interactions were noted between Eimeria spp. challenge and diet regarding jejunal crypt depth. The positive impact of the fish oil diet was particularly noticeable with the high Eimeria challenge dose. Overall, these findings underscore the relationship between the fish oil diet and Eimeria challenge on broiler chicken intestinal health. Dietary supplementation of fish oil has the potential to maintain small intestine barrier integrity with severe Eimeria infection conditions.

Procyanidin B1 and p-coumaric acid from whole highland barley ameliorated HFD-induced impaired glucose tolerance via small intestinal barrier and hepatic glucose metabolism.

Highland barley is a natural source for the development of phenolic compounds that exhibit potential in preventing type 2 diabetes, which is important for the agricultural and industrial utilization of highland barley. However, very few studies have focused on their effect on small intestinal absorption and barrier dysfunction, as well as the direct target for the modulation of hepatic glucose metabolism. In this study, procyanidin B1 (PB) and p-coumaric acid (CA) isolated from highland barley supplementation in impaired glucose tolerance (IGT) mice significantly increased lactase-phlorizin hydrolase (LPH), sulfotransferase 1A1 (SULT1A1), UDP glucuronosyltransferase 1A (UGT1A) families and sodium-dependent glucose transporter 1 (SGLT1) expression in the small intestine of IGT mice, indicating beneficial effects on polyphenol deglycosylation and transportation. Supplementation with PB and CA also exhibited attenuation of small intestinal barrier dysfunction by improving the mucus layer and tight junctions, which was closely related to the transportation of phenolic compounds. In addition, PB and CA supplementation were explored directly to bind to the insulin receptor and activate the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, thereby modulating hepatic glucose metabolism and ameliorating hyperglycemic in IGT mice. These results offer crucial insights into the potential development of PB and CA as non-food nutraceuticals, as well as the extensive utilization of highland barley as an industrial crop.

The relationship between AGR2 levels and intestinal barrier function in high-fat diet animal models.

This study aimed to observe the effect of anterior gradient protein 2 (AGR2) levels on intestinal barrier function in HFD animal models. For this purpose, thirty healthy male clean-grade C57BL/6 mice were randomly separated into a normal control group and a high-fat group. The normal control group was fed a normal diet, while the high-fat group was fed an HFD for a total of 8 weeks. It collected body weight changes before and after modeling of two groups of rats and serum samples and detected fasting blood glucose, total cholesterol, triglycerides, AGR2, and diamine oxidase (DAO) concentrations. It collected the expression levels of AGR2 in the colon of rats after modeling, evaluated the permeability of the colon and small intestine barrier by Ussing chamber and Evan's blue (EB) methods, and analyzed the correlation between AGR2 levels and intestinal barrier function using Pearson correlation. Results showed that when the two groups of mice were fed for 8 weeks, their body weight, fasting blood glucose, total cholesterol, and triglycerides all met the characteristics of an HFD mouse model, and the model was successfully established. When the two groups of mice were fed for 8 weeks, the serum AGR2 concentration, relative expression of AGR2 in colon tissue, Gt, and EB content of the high-fat group mice were higher than those of the normal control group, and the difference was significant (P<0.05); Meanwhile, the serum DAO concentration and Isc of the high-fat group mice were lower than those of the normal control group, with statistically significant differences (P<0.05); The relative expression levels of serum AFR2 and colon AGR2 were negatively correlated with Isc (r=-0.503, -0.623, P<0.05), and positively correlated with Gt (r=0.461, 0.560, P<0.05). There was a homogeneous distribution characteristic between the relative expression levels of serum AFR2 and serum DAO, colon AGR2, and Isc variables. It was concluded that HFD could upregulate the expression of AGR2 in mice, downregulate the level of DAO, and damage the intestinal barrier function of mice. Both serum AGR2 concentration and colonic AGR2 relative expression can participate in the regulation of colonic intestinal barrier function and can serve as potential indicators for evaluating intestinal barrier damage.

Utility of human induced pluripotent stem cell-derived small intestinal epithelial cells for pharmacokinetic, toxicological, and immunological studies

The small intestine, which plays a crucial role in the absorption and metabolism of drugs and foods, serves as a target organ for drug-induced toxicity and immune interactions with functional foods and intestinal bacteria. Current alternative models of the human small intestine, such as Caco-2 cells and experimental animals, have limitations due to variations in the expression levels of metabolic enzymes, transporters, and receptors. This study presents investigations into the utility of human induced pluripotent stem cell-derived small intestinal epithelial cells (hiSIECs) for pharmacokinetic, toxicological, and immunological studies, respectively. While hiSIECs displayed small intestinal epithelial cell characteristics and barrier function, they demonstrated pharmacokinetic properties such as cytochrome P450 3A4/5 activity equivalent to human primary enterocytes and stable P-glycoprotein activity. These cells also demonstrated potential for assessing two forms of intestinal toxicity caused by anticancer drugs and gamma-secretase inhibitors, displaying immune responses mediated by toll-like and fatty acid receptors while serving as an inflammatory gut model through the addition of tumor necrosis factor alpha and interferon gamma. Overall, hiSIECs hold promise as an in vitro model for assessing pharmacokinetics, toxicity, and effects on the intestinal immunity of pharmaceuticals, functional foods, supplements, and intestinal bacteria.

Maternal Selenium-Enriched Yeast Supplementation in Sows Enhances Offspring Growth and Antioxidant Status through the Nrf2/Keap1 Pathway.

This study evaluated the effects of maternal selenium-enriched yeast (SeY) supplementation during late gestation and lactation on sow performance, transfer of selenium (Se) and redox status, and gut microbiota community, as well as on the gut health of offspring. Seventy pregnant sows on day 85 of gestation were randomly allocated to the following two treatments: (1) sows who were fed a basal diet (basal diet contained 0.3 mg/kg Se as Na2SeO3, n = 35); (2) and sows who were fed a SeY-supplemented diet (basal diet with 0.2 mg/kg Se as SeY, n = 35). The offspring piglets were only cross-fostered within the group on day 3 of lactation (L3) according to the pig farm epidemic prevention policy. The plasma, milk, and feces samples from 10 sows, as well as plasma and intestinal samples per treatment, were collected on L1 and L21, respectively. Our results showed that maternal SeY supplementation increased the first week average weight and ADG of piglets (p < 0.05). Compared with the CON group, the SeY supplementation increased the Se content in the plasma and milk of sows and the plasma of piglets on L1 and L21 (p < 0.05). In addition, in sows, the levels of fat in the milk on L21, the level of IgA, T-AOC, and GSH-Px in the plasma on L21, and the level of T-AOC and GSH-Px in the colostrum were increased, while the MDA content was decreased in the plasma on L1 and in the colostrum and milk on L14 (p < 0.05). In the piglet plasma, the levels of IgA on L1 and L21, GSH-Px on L1, and GSH on L21 were increased, while the MDA content was decreased on L1 (p < 0.05). Maternal SeY supplementation up-regulated the small intestinal protein abundances of MUC1, E-cadherin, ZO-1, occludin, and claudin and activated the Nrf2/Keap1 signaling pathway in weaned offspring piglets. The 16S rRNA sequencing results showed that fecal microbiota had distinct separations during lactation, and the relative abundances of unclassified_f_Lachnospiraceae, Prevotaceae_UCG-001, and Lachnospiraceae_NK4A136_group were increased on L1. Collectively, the current findings suggest that maternal SeY supplementation during late gestation and lactation could improve the piglet's growth performance, Se status, antioxidant capacity and immunoglobulins transfer at the first week of lactation, as well as alter the fecal microbiota composition by increasing antioxidative-related and SCFA-producing microbiota in sows. These changes contributed to enhancing the small intestinal barrier function and activating the Nrf2/Keap1 pathway in offspring.

21 Intentionally Induced Barrier Dysfunction Causes Inflammation, Decreases Growth, and Alters Carcass Characteristics of Feedlot Cattle

Abstract There are a variety of acute and chronic psychological and physical stressors associated with management practices used in beef production systems. Primary challenges in feedlot cattle include heat stress, acute and subacute acidosis, weaning, transportation, feed deprivation/restriction, and social mixing/crowding. These stressors disturb the homeostatic state of the host and microbiome and cause acute or chronic inflammation resulting in damage to the gastrointestinal tract (GIT) epithelial barrier that leaves the animal vulnerable to enteric pathogens and toxins. A breach of the small intestinal barrier (leaky gut) allows unwanted pathogens and toxins to infiltrate into blood, causing infection, depressed feed intake, and diverts nutritional resources away from anabolic processes. We have demonstrated that intentionally inducing GIT inflammation in feedlot cattle with aspirin, which is known to cause mucosal injury and increase GIT barrier dysfunction, provides a model system to better understand the metabolic cost of leaky gut in grain-fed feedlot cattle. Indeed, aspirin increased leakage of chromium-EDTA into urine, raised serum concentrations of lipopolysaccharide binding protein (LBP), decreased growth by 4.5 to 8.5%, and re-partitioned carcass components from lean tissue (rib-eye area) into fat. Thus, the chronic inflammatory effects of leaky gut have the potential to create a significant economic loss. Our work also shows that in-feed administration of monensin and tylosin have offered a solution to the non-specific immune response observed in grain-fed cattle by increasing jejunal villus height to crypt depth ratio, diminishing leaky gut, and decreasing serum LBP. Finally, we have observed that molasses based liquid supplements increase ruminal butyrate concentration, resulting in improved gut barrier function, decreased serum inflammatory markers, and greater DMI and ADG in newly received feedlot cattle fed a 30% roughage diet.

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

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

Development of small intestinal barrier function and underlying mechanism in Chinese indigenous and Duroc piglets during suckling and weaning periods

This study explored the developmental changes in small intestinal barrier function and the potential regulatory roles of intestinal microbiota and metabolites in different breeds of piglets during suckling and weaning periods. Taoyuan black (TB), Xiangcun black (XB), and Duroc (DR) piglets (10 litters per breed; half male and half female) were selected for sampling to evaluate the intestinal barrier-related indexes and intestinal microbiota and metabolites at 1, 10, 21 (weaned), and 24 (3 d after weaning) d old. The results showed that weaning led to severe shedding of small intestinal microvilli and sparse microvilli arrangement. D-lactate level in the ileum of TB and XB piglets during suckling and weaning periods was lower (P < 0.01) than that of DR piglets, as well as the ileal diamine oxidase level at 1 d old. The expression level of mucin 1 was higher (P < 0.05) in the ileum of TB and XB piglets than that of DR piglets, and it was the highest in the ileum of TB piglets at 21 d old. The expression levels of mucin 2 and mucin 13 were higher (P < 0.10) in TB and XB piglets than those of DR piglets at 21 d old, whereas mucin 2 and mucin 13 in the ileum of TB and XB piglets were higher (P < 0.05) than those of DR piglets at 24 d old. TB and XB piglets had a lower relative abundance of Escherichia_Shigella at 21 and 24 d old, but they had higher Streptococcus at 1 and 24 d old than DR piglets (P < 0.01). Differential metabolites between the three breeds of piglets were mainly related to oxidative phosphorylation, steroid biosynthesis, and bile acid synthesis. Collectively, these findings suggest that different pig breeds present differences in the development of the small intestinal barrier function. Compared with DR piglets, TB and XB piglets had higher intestinal permeability during the suckling period and a stronger intestinal mechanical barrier after weaning. Moreover, intestinal microbiota and metabolites are the key factors for developing small intestinal barrier functions in different breeds of piglets.

Arsenic exposure induces small intestinal toxicity in mice by barrier damage and inflammation response via activating RhoA/ROCK and TLR4/Myd88/NF-κB signaling pathways

Numerous studies have shown that arsenic (As) is an important hazardous metalloid that is commonly considered to have systemic toxicity. The main pathway of arsenic exposure is oral; however, many of the events that occur during its passage through the gastrointestinal tract are unclear, and there are few reports on the effect of arsenic on small intestinal mucosal barrier. This study aimed to investigate arsenic-induced mucosal barrier damage in the small intestine of mice induced by oral exposure and its potential mechanisms. In the present study, histomorphometric and immunohistochemical analyses showed that arsenic-treated mice exhibited signs of irregularly arranged and atrophied small intestinal villi, reduced villus lengths, inflammatory cells infiltration, along with up-regulated expression of inflammatory factors TNF-α, IL-6 and IL-1β in the small intestine of mice. The myeloperoxidase (MPO) activity was also increased in As-exposed mice. Transmission electron microscopy (TEM) analysis demonstrated that intestinal epithelial tight junctions (TJs) were impaired in the small intestines of mice in As group. In addition, arsenic down-regulated mRNA levels of TJ-related genes (ZO-1, ZO-2, occludin, claudin-1, and claudin-7) and protein levels of ZO-1, occludin and claudin-1 were significantly reduced in arsenic-treated groups, while arsenic also increased levels of TLR4, Myd88, NF-κB, RhoA, and ROCK mRNA and protein expression. In summary, these results indicate that the small intestine toxicity in mice evoked by arsenic was correlated with the activation of TLR4/Myd88/NF-κB and RhoA/ROCK pathways.

Review: A systematic review of the effects of functional amino acids on small intestine barrier function and immunity in piglets.

The need to reduce the use of antibiotics and zinc oxide at the pharmacological level, while preserving the performance of postweaning piglets, involves finding adequate nutritional strategies which, coupled with other preventive strategies, act to improve the sustainability of the piglet-rearing system. Amino acids (AAs) are the building blocks of proteins; however, they also have many other functions within the body. AA supplementation, above the suggested nutritional requirement for piglets, has been investigated in the diets of postweaning piglets to limit the detrimental consequences occurring during this stressful period. A systematic review was carried out to summarise the effects of AAs on gut barrier function and immunity, two of the parameters contributing to gut health. An initial manual literature search was completed using an organised search strategy on PubMed, utilising the search term "<amino acid> AND <parameter related to intestinal health>". These searches yielded 302 articles (published before October 2021); 59 were selected. Based on the method for extracting data (synthesis of evidence), this review showed that L-Arginine, L-Glutamine and L-Glutamate are important functional AAs playing major roles in gut morphology and immune functions. Additional benefits of AA supplementation, refereed to a supplementation above the suggested nutritional requirement for piglets, could also be observed; however, data are needed to provide consistent evidence. Taken together, this review showed that supplementation with AAs during the weaning phase supported a plethora of the physiological functions of piglets. In addition, the data reported confirmed that each amino acid targets different parameters related to gut health, suggesting the existence of potential synergies among them.

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease.

Voxelotor is an allosteric haemoglobin (Hb) modulator that binds covalently and reversibly to Hb alpha chain to facilitate improved Hb-O2 affinity and arterial oxygen. It, therefore, reduces the susceptibility of erythrocytes carrying Haemoglobin S to sickle. In this study, we have used GBT1118, an analog of voxelotor, to treat male Townes sickle cell disease (SCD) mice to investigate whether the Hb modulator could attenuate the intestinal pathophysiologic changes associated with SCD. Compared with mice fed with control chow, GBT1118-treated mice showed improvement in the intestinal pathophysiology. These mice exhibited improved small intestinal barrier functions, reduced intestinal microbial density, reduced enterocyte injury, lower serum lipopolysaccharides and smaller spleens. These improvements were observed after only 3 weeks of GBT1118 treatment. Benefits were also observed after experimentally-induced vaso-occlusive crisis (VOC). Recovery from the VOC-induced changes was faster in mice that were treated with GBT1118. The improved small intestinal barrier function was associated with higher expression of genes encoding enterocyte E-cadherin, JAM-A, ZO-1, MUC-2 and occludin while the lower intestinal microbial density associated with higher expression of genes encoding the antimicrobial peptides defensin-α 1 and defensin-α 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology.

Sustained oral intake of nano-iron oxide perturbs the gut-liver axis

Nanomaterial have shown excellent properties in the food industry. Although iron oxides are often considered safe and widely used as food additives, the toxicity of nano‑iron oxide remains unclear. Here we established a subchronic exposure mouse model by gavage, tested the biodistribution of nano‑iron oxide, and explored the mechanism of liver injury caused by it through disturbance of the gut-liver axis. Oral intake of nano‑iron oxide will likely disrupt the small intestinal epithelial barrier, induce hepatic lipid metabolism disorders through the gut–liver axis, and cause hepatic damage accompanied with hepatic iron deposition. Nano‑iron oxide mainly caused hepatic lipid metabolism disorder by perturbing glycerophospholipid metabolism and the sphingolipid metabolism pathways, with the total abundance of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) tending to decrease while that of triglyceride tended to increase, in a time- and dose-dependent manner. The imbalanced lipid homeostasis could cause damage via membrane disruption, lipid accumulation, and lipotoxicity. This data provides information about the subchronic toxicity of nano‑iron oxide, highlights the importance of gut-liver axis in the hepatotoxicity.