Expression Of Intestinal Tight Junction Proteins Research Articles

An integrated network pharmacology approach reveals that Ampelopsis grossedentata improves alcoholic liver disease via TLR4/NF-κB/MLKL pathway.

BackgroundAlcohol-related liver damage is the most prevalent chronic liver disease, which creates a heavy public health burden worldwide. The leaves of Ampelopsis grossedentata have been considered a popular tea and traditional herbal medicine in China for more than one thousand years, and possess anti-inflammatory, antioxidative, hepatoprotective, and antiviral activities. PurposeWe explored the protective effects of Ampelopsis grossedentata extract (AGE) against chronic alcohol-induced hepatic injury (alcoholic liver disease, ALD), aiming to elucidate its underlying mechanisms. MethodsFirstly, UPLC-Q/TOF-MS analysis and network pharmacology were used to identify the constituents and elucidate the potential mechanisms of AGE against ALD. Secondly, C57BL/6 mice were pair-fed the Lieber-DeCarli diet containing either isocaloric maltodextrin or ethanol, AGE (150 and 300 mg/kg/d) and silymarin (200 mg/kg) were administered to chronic ethanol-fed mice for 7 weeks to evaluate the hepatoprotective effects. Serum biochemical parameters were determined, hepatic and ileum sections were used for histologic examination, and levels of inflammatory cytokines and oxidative stress in the liver were examined. The potential molecular mechanisms of AGE in improving ALD were demonstrated by RNA-seq, Western blotting analysis, and immunofluorescence staining. ResultsTen main constituents of AGE were identified using UPLC-Q/TOF-MS and 274 potential ALD-related targets were identified. The enriched KEGG pathways included Toll-like receptor signaling pathway, NF-κB signaling pathway, and necroptosis. Moreover, in vivo experimental studies demonstrated that AGE significantly reduced serum aminotransferase levels and improved pathological abnormalities after chronic ethanol intake. Meanwhile, AGE improved ALD in mice by down-regulating oxidative stress and inflammatory cytokines. Furthermore, AGE notably repaired damaged intestinal epithelial barrier and suppressed the production of gut-derived lipopolysaccharide by elevating intestinal tight junction protein expression. Subsequent RNA-seq and experimental validation indicated that AGE inhibited NF-κB nuclear translocation, suppressed IκB-α, RIPK3 and MLKL phosphorylation and alleviated hepatic necroptosis in mice. ConclusionIn this study, we have demonstrated for the first time that AGE protects against alcoholic liver disease by regulating the gut-liver axis and inhibiting the TLR4/NF-κB/MLKL-mediated necroptosis pathway. Therefore, our present work provides important experimental evidence for AGE as a promising candidate for protection against ALD.

Shen-yan-yi-hao oral solution ameliorates IgA nephropathy via intestinal IL-17/NF-κB pathway

Ethnopharmacological relevanceImmunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, it is one of the most common causes of kidney disease and can lead to end-stage kidney disease, however, its pathogenesis is still complicated. The Shen-yan-yi-hao oral solution (SOLI) is an effective prescription for the clinical treatment of IgAN while its specific mechanism remains to be further elucidated. Aim of the studyThis study investigates SOLI’s effects on IgAN in rats, particularly on the intestinal mucosal barrier, and identifies potential therapeutic targets through network pharmacology and molecular docking, validated experimentally. Materials and methodsTarget genes for SOLI in IgAN were identified and analyzed through molecular docking and KEGG pathway enrichment. An IgAN rat model examined SOLI’s effect on renal biomarkers and cytokines involved in specific pathways, ileum mucosal lesions, and the intestinal immune system. The IL-17 pathway’s role was studied in IEC-6 cells with SOLI in vitro. ResultRats developed increased proteinuria and kidney damage marked by IgA deposition and inflammation. SOLI treatment significantly ameliorated these symptoms, reduced galactose-deficient Ig A1 (Gd-IgA1), and decreased cytokines like IL-17, TNF-α, IL-6 and IL-1β etc. SOLI also normalized intestinal tight junction protein expression, ameliorated intestinal damage, and regulated intestinal immune response (focused on IL-17/NF-κB signal pathway). SOLI moderated the abnormally activated IL-17 pathway, which damages intestinal epithelial cells, suggesting IgAN treatment potential. ConclusionSOLI reduces proteinuria and enhances intestinal mucosal function in IgAN rats, kidney protection in the IgAN rat model may initiate from modulating the intestinal IL-17/NF-κB pathway and subsequent Gd-IgA1 accumulation.

Xylitol attenuates diabetes induced intestinal permeability changes and inflammatory injury by improving intestinal tight junction protein expression and mucus secretion in rats

ABSTRACT The purpose of this study was to investigate the protective effect of xylitol on gut mucosal barrier injury in a type 2 diabetes rat model. Treatment with xylitol not only ameliorated diabetic-induced changes to small intestinal mucosa morphology and decreased diamine oxidase concentration in the serum of diabetic rats, but also modified the inflammatory infiltrates and improved the secretory IgA levels of the small intestinal epithelium. Increased expression of zo-1, occludin, mucin-2 and intestinal trefoil factor also was detected in small intestinal tissue. Intragastric administration of xylitol suppressed diabetes-induced increases of myeloperoxidase, eosinophil peroxidase, IL-6 and TNF-α. These results suggest that xylitol reduces mucosal inflammatory lesions and improves the intestinal barrier in diabetic rats by maintaining the structural integrity of the mucous layer, inhibiting the expression of inflammatory mediators and enhancing the expression of tight junction proteins associated with intestinal permeability.

Aged oolong tea alleviates dextran sulfate sodium-induced colitis in mice by modulating the gut microbiota and its metabolites

In this study, the mechanism of aged oolong tea (AOT) to alleviate colitis was investigated in terms of microbiome, metabolome, and fecal microbiota transplantation (FMT). AOT storage period could alleviate colitis in mice and there were some differences in AOT between storage periods, especially AOT-10. AOT improves UC by modulating oxidative stress and inflammatory factors and upregulating intestinal tight junction protein expression (Occludin, Claudin-1, ZO-1 and MUC2), which is associated with the recovery of gut microbiota. FMT and targeted metabolomics further demonstrate that the anti-inflammatory effects of AOT can reshape the gut microbiota through faecal bacterial transfer. Anti-inflammatory effects are exerted through the stimulation of metabolic pathways associated with amino acid, fatty acid and bile acid metabolites. Importantly, the study identified key bacteria (e.g., Sutterella, Clostridiaceae_Clostridium, Mucispirillum, Oscillospira and Ruminococcus) for the development and remission of inflammation. Conclusively, AOT may have great potential in the future adjuvant treatment of colitis.

Amelioration of Acute Alcoholic Liver Injury via Attenuating Oxidative Damage and Modulating Inflammation by Means of Ursodeoxycholic Acid-Zein Nanoparticles.

Ursodeoxycholic acid (UDCA) has been broadly adopted for the clinical treatment of hepatic and biliary diseases; however, its poor water-solubility becomes an obstacle in wide applications. To overcome these challenges, herein, a two-tier UDCA-embedded system of zein nanoparticles (NPs) along with a polyelectrolyte complex was designed under facile conditions. Both the UDCA-zein NPs and their inclusion microcapsules showed a spherical shape with a uniform size. A typical wall plus capsule/core structure was formed in which UDCA-zein NPs distributed evenly in the interior. The UDCA inclusion microcapsules had an encapsulation rate of 67% and were released in a non-Fickian or anomalous transport manner. The bioavailability and efficacy of UDCA-zein NPs were assessed in vivo through the alcoholic liver disease (ALD) mouse model via intragastric administration. UDCA-zein NPs ameliorated the symptoms of ALD mice remarkably, which were mainly exerted through attenuation of antioxidant stress levels. Meanwhile, it notably upregulated the intestinal tight junction protein expression and improved and maintained the integrity of the mucosal barrier effectively. Collectively, with the improvement of bioavailability, the UDCA-zein NPs prominently alleviated the oxidative damage induced by alcohol, modulating the inflammation so as to restore ALD. It is anticipated that UDCA-zein NPs have great therapeutic potential as sustained-nanovesicles in ALD treatment.

Sterile soil mitigates the intergenerational loss of gut microbial diversity and anxiety-like behavior induced by antibiotics in mice

The decline in gut microbial diversity in modern humans is closely associated with the rising prevalence of various diseases. It is imperative to investigate the underlying causes of gut microbial loss and restoring methods. Although the impact of non-perinatal antibiotic use on gut microbiota has been recognized, its intergenerational effects remain unexplored. Our previous research has highlighted soil in the farm environment as a key factor for gut microbiome health by restoring gut microbial diversity and balance. In this study, we investigated the intergenerational consequences of antibiotic exposure and the therapeutic potential of sterile soil. We treated C57BL/6 mice with vancomycin and streptomycin for 2 weeks continuously, followed by a 4–8 week withdrawal period before breeding. The process was repeated across 3 generations. Half of the mice in each generation received an oral sterile soil intervention. We assessed gut microbial diversity, anxiety behavior, microglial reactivity, and gut barrier integrity across generations. Antibiotic exposure led to a decrease in gut microbial diversity over generations, along with aggravated anxiety behavior, microgliosis, and altered intestinal tight junction protein expression. Oral sterile soil intervention restored gut microbial diversity in adult mice across generations, concomitantly rescuing abnormalities in behavior, microgliosis, and intestinal barrier integrity. In conclusion, this study simulated an important process of the progressive loss of gut microbiota diversity in modern humans and demonstrated the potential of sterile soil to reverse this process. This study provides a theoretical and experimental basis for research and interventions targeting multiple modern chronic diseases related to intestinal microorganisms.

Effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury: role of peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway

ObjectiveEnteral nutrition is the key therapy in septic patients. Different formulas of enteral nutrition have various effects on gastrointestinal sepsis. Therefore, we investigated the effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury and explored the potential mechanism. MethodsFirst, to investigate the effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury, rats were randomly divided into four groups: sham, lipopolysaccharide, lipopolysaccharide + enteral nutrition, and lipopolysaccharide + enteral nutrition + octanoic acid. Then, to explore whether enteral nutrition supplemented with octanoic acid can prevent lipopolysaccharide-induced intestinal injury via the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway, rats were randomly divided into five groups: sham, lipopolysaccharide, lipopolysaccharide + enteral nutrition + octanoic acid, lipopolysaccharide + enteral nutrition + octanoic acid + SR202, and lipopolysaccharide + pioglitazone. All rats received nutritional support for 3 d. We examined the serum levels of inflammatory factors, pathologic changes, goblet cell density, intestinal tight junction protein expression, and the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway in the ileum and colon. The effect of octanoic acid on intestinal epithelium injury was also explored in vitro. ResultsEnteral nutrition supplemented with octanoic acid significantly decreased the serum levels of inflammatory factors and prevented intestinal barrier dysfunction compared with enteral nutrition alone (P < 0.05). Inhibiting the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway exacerbated effects of enteral nutrition supplemented with octanoic acid on intestinal injury (P < 0.05). Activation of the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway prevented intestinal injury (P < 0.05). Octanoic acid also exerted a similar effect on intestinal epithelium injury in vitro. ConclusionsEnteral nutrition supplemented with octanoic acid prevents lipopolysaccharide-induced intestinal injury via the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway.

Protective effect of carbon dots derived from scrambled Coptidis Rhizoma against ulcerative colitis in mice.

Introduction: Ulcerative colitis (UC) is a chronic and progressive inflammatory disease of the intestines. The primary symptoms, such as bloody diarrhea, can result in weight loss and significantly diminish the patient's quality of life. Despite considerable research endeavors, this disease remains incurable. The scrambled Coptidis Rhizoma (SCR) has a rich historical background in traditional Chinese medicine as a remedy for UC. Drawing from a wealth of substantial clinical practices, this study is focused on investigating the protective effects and underlying mechanisms of the active component of SCR, namely SCR-based carbon dots (SCR-CDs), in the treatment of UC. Methods: SCR-CDs were extracted and isolated from the decoction of SCR, followed by a comprehensive characterization of their morphological structure and functional groups. Subsequently, we investigated the effects of SCR-CDs on parameters such as colonic length, disease activity index, and histopathological architecture using the dextran sulfate sodium (DSS)-induced colitis mice model. Furthermore, we delved into the assessment of key aspects, including the expression of intestinal tight junction (TJ) proteins, inflammatory cytokines, oxidative stress markers, and gut microbial composition, to unravel the intricate mechanisms underpinning their therapeutic effects. Results: SCR-CDs displayed a consistent spherical morphology, featuring uniform dispersion and diameters ranging from 1.2 to 2.8nm. These SCR-CDs also exhibited a diverse array of surface chemical functional groups. Importantly, the administration of SCR-CDs, particularly at higher dosage levels, exerted a noteworthy preventive influence on colonic shortening, elevation of the disease activity index and colonic tissue impairment caused by DSS. These observed effects may be closely associated with the hygroscopic capability and hemostatic bioactivity inherent to SCR-CDs. Concurrently, the application of SCR-CDs manifested an augmenting impact on the expression of intestinal TJ proteins, concomitantly leading to a significant reduction in inflammatory cell infiltration and amelioration of oxidative stress. Additionally, SCR-CDs treatment facilitated the restoration of perturbed gut microbial composition, potentially serving as a fundamental mechanism underlying their observed protective effects. Conclusion: This study demonstrates the significant therapeutic potential of SCR-CDs in UC and provides elucidation on some of their mechanisms. Furthermore, these findings hold paramount importance in guiding innovative drug discovery for anti-UC agents.

Cordyceps militaris polysaccharide alleviates diabetic symptoms by regulating gut microbiota against TLR4/NF-κB pathway

The relationship between gut microbiota and type 2 diabetes mellitus (T2DM) has attracted increasing attention. In our work, one purified fraction a (AEPSa) was obtained from Cordyceps militaris polysaccharides, and its hypoglycemic activity and underlying mechanisms were investigated in high-fat diet (HFD)- and streptozotocin (STZ)-induced T2DM mice. The results revealed that AEPSa reshaped gut microbiota by increasing Allobaculum, Alistipes, Lachnospiraceae_NK4A136_group and norank_f_Muribaculaceae and decreasing Enterococcus and Ruminococcus_torques_group to inhibit the colonic toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and upregulate intestinal tight junction protein expression, thereby improving glucose and serum lipid metabolism, hormone secretion and complications. Fecal microbiota transplantation (FMT) also confirmed these findings. These results indicated that symptomatic relief of T2DM might be related to AEPSa regulating the gut microbiota against the TLR4/NF-κB pathway to protect the intestinal barrier. Therefore, AEPSa might be developed as a prebiotic agent against T2DM by regulating gut microbiota.

Apple Polyphenols Improve Intestinal Antioxidant Capacity and Barrier Function by Activating the Nrf2/Keap1 Signaling Pathway in a Pig Model.

In recent years, the function of plant polyphenols to improve the intestinal barrier has been fully demonstrated. However, the exact mechanisms linking plant polyphenols with the intestinal barrier function have not yet been established. Apple polyphenols (APs) are safe and healthy nutrients, which are extracted from apples and their byproducts. Using pig and IPEC-J2 cell models, this study investigated the effects of dietary AP supplementation on intestinal antioxidant capacity and barrier function. Then, we further explored the role of the Nrf2/Keap1 signaling pathway in maintaining intestinal antioxidant capacity and barrier function. Our study found that dietary AP supplementation improved the intestinal mechanical barrier by promoting the intestinal morphology and intestinal tight junction protein expression, improved the intestinal immune barrier by increasing intestinal secretory immunoglobulin A production, and improved the intestinal biological barrier by increasing probiotics and decreasing the Escherichia coli population. Further research found that dietary AP supplementation increased the intestinal antioxidant capacity and activated the Nrf2/Keap1 signaling pathway. Finally, after treatment with Nrf2-specific inhibitor ML-385, the upregulation effect of APs on antioxidant capacity and tight junction protein expression was reduced in IPEC-J2 cells. Our results suggested that APs promoted intestinal antioxidant capacity and barrier function via the Nrf2/Keap1 signaling pathway.

The Panda-Derived Lactobacillus plantarum G201683 Alleviates the Inflammatory Response in DSS-Induced Panda Microbiota-Associated Mice.

Intestinal diseases are one of the main causes of captive giant panda death. Their special dietary habits and gastrointestinal tract structure often lead to intestinal epithelium damage and secondary intestinal infection. The captive giant panda is predisposed to suffer from microbiota dysbiosis due to long-term artificial feeding and antibiotic misuse. However, there are few reported probiotics to treat giant panda enteritis and the associated dysbiosis. This study aims to elucidate the mechanism by which Lactobacillus plantarum G201683 (L. plantarum G83), a promising panda-derived probiotic, exerts a protective effect on intestinal inflammation in the dextran sulfate sodium- (DSS) induced panda microbiota-associated (DPMA) mouse model. The DPMA mouse was generated by antibiotic treatment and 5% DSS drinking water administration to assess the effect of L. plantarum G83 on intestinal inflammation and microbiota in vivo. Our results demonstrated the successful generation of a DPMA mouse model with Enterobacteriaceae enrichment, consistent with the giant panda intestinal microbiota. L. plantarum G83 decreased clinical and histological severity of intestinal inflammation, enhanced intestinal tight junction protein expression (ZO-1, Occludin) and alleviated inflammatory cytokine production (TNF-) in the colon of DPMA mice. The administration of L. plantarum G83 altered the microbiota composition by decreasing pathogen associated taxa such as E. coli and increasing abundance of beneficial bacteria including Bifidobacterium spp. These changes in microbiota composition were associated with an increased concentration of short chain fatty acids (SCFA), reduced NF-κB signaling, and an altered balance of T helper cell subsets. Our findings support L. plantarum G83 as a promising probiotic to treat intestinal inflammation in the giant panda.

Prophylactic Treatment of Probiotic and Metformin Mitigates Ethanol-Induced Intestinal Barrier Injury: In Vitro, In Vivo, and In Silico Approaches.

Ethanol depletes intestinal integrity and promotes gut dysbiosis. Studies have suggested the individual role of probiotics and metformin Met in protecting intestinal barrier function from injuries induced by ethanol. The objective of the current study is to investigate the potential mechanism by which coadministration of probiotic Visbiome® (V) and Met blocks the ethanol-induced intestinal barrier dysfunction/gut leakiness utilizing Caco-2 monolayers, a rat model with chronic ethanol injury, and in silico docking interaction models. In Caco-2 monolayers, exposure to ethanol significantly disrupted tight junction (TJ) localization, elevated monolayer permeability, and oxidative stress compared with controls. However, cotreatment with probiotic V and Met largely ameliorated the ethanol-induced mucosal barrier dysfunction, TJ disruption, and gut oxidative stress compared with ethanol-exposed monolayers and individual treatment of either agent. Rats fed with ethanol-containing Lieber-DeCarli liquid diet showed decreased expression of TJ proteins, and increased intestinal barrier injury resulting in pro-inflammatory response and oxidative stress in the colon. We found that co-administration of probiotic V and Met improved the expression of intestinal TJ proteins (ZO-1 and occludin) and upregulated the anti-inflammatory response, leading to reduced ER stress. Moreover, co-administration of probiotic V and Met inhibited the CYP2E1 and NOX gene expression, and increase the translocation of Nrf-2 as well as anti-oxidative genes (SOD, catalase, Gpx, and HO-1), leading to reduced colonic ROS content and malondialdehyde levels. The combined treatment of probiotic V and Met also improved their binding affinities towards HO-1, Nrf-2, SLC5A8, and GPR109A, which could be attributed to their synergistic effect. Our findings based on in-vitro, in-vivo, and in-silico analyses suggest that the combination of probiotic V and Met potentially acts in synergism, attributable to their property of inhibition of inflammation and oxidative stress against ethanol-induced intestinal barrier injury.

Neonatal hyperoxia induces gut dysbiosis and behavioral changes in adolescent mice.

Supplemental oxygen is often required to treat preterm infants with respiratory disorders. Experimental studies have demonstrated that hyperoxia results in the disruption of intestinal and neuronal plasticity and myelination of the brain. The association between the neonatal hyperoxia and changes of phenotypes in gut microbiota and in behaviors is not clear to date. We designed an animal experiment that C57BL/6 mice pups were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. From postnatal days 8 to 42, the mice were reared in RA. Intestinal microbiota was sampled from the lower gastrointestinal tract on postnatal days 7 and 42, and behavioral tests were performed and brain tissues were collected on postnatal day 42. Neonatal hyperoxia decreased intestinal tight junction protein expression and altered intestinal bacterial composition and diversity on postnatal day 7. Among the concrete discriminative features, Proteobacteria and Epsilonbacteraeota were significantly elevated in hyperoxia-reared mice on postnatal days 7 and 42, respectively. Hyperoxia-reared mice exhibited significantly reduced sociability and interest in social novelty and impaired motor coordination compared with RA-reared mice on postnatal day 42. Hyperoxia-reared mice also exhibited significantly reduced myelination and a significantly higher number of apoptotic cells in the brain compared with RA-reared mice on postnatal day 42. Neonatal hyperoxia during the first week of life altered gut microbiota and reduced brain myelination that might associate with the deficits of social interaction and motor coordination in adolescent mice.

Epigallocatechin gallate but not catechin prevents nonalcoholic steatohepatitis in mice similar to green tea extract while differentially affecting the gut microbiota

Catechin-rich green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by alleviating gut-derived endotoxin translocation and hepatic Toll-like receptor-4 (TLR4)–nuclear factor κB (NFκB) inflammation. We hypothesized that intact GTE would attenuate NASH-associated responses along the gut–liver axis to a greater extent than purified (−)-epigallocatechin gallate (EGCG) or (+)-catechin (CAT). Male C57BL/6J mice were fed a low-fat diet, a high-fat (HF) diet, or the HF diet with 2% GTE, 0.3% EGCG or 0.3% CAT for 8 weeks prior to assessing NASH relative to endotoxemia, hepatic and intestinal inflammation, intestinal tight junction proteins (TJPs) and gut microbial ecology. GTE prevented HF-induced obesity to a greater extent than EGCG and CAT, whereas GTE and EGCG more favorably attenuated insulin resistance. GTE, EGCG and CAT similarly attenuated serum alanine aminotransferase and serum endotoxin, but only GTE and EGCG fully alleviated HF-induced NASH. However, hepatic TLR4/NFκB inflammatory responses that were otherwise increased in HF mice were similarly attenuated by GTE, EGCG and CAT. Each treatment also similarly prevented the HF-induced loss in expression of intestinal TJPs and hypoxia inducible factor-1α and the otherwise increased levels of ileal and colonic TNFα mRNA and fecal calprotectin protein concentrations. Gut microbial diversity that was otherwise lowered in HF mice was maintained by GTE and CAT only. Further, microbial metabolic functions were more similar between GTE and CAT. Collectively, GTE catechins similarly protect against endotoxin–TLR4–NFκB inflammation in NASH, but EGCG and CAT exert differential prebiotic and antimicrobial activities suggesting that catechin-mediated shifts in microbiota composition are not entirely responsible for their benefits along the gut–liver axis.

Contribution of uremic dysbiosis to insulin resistance and sarcopenia.

Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.

Intestinal environmental disorders associate with the tissue damages induced by perfluorooctane sulfonate exposure.

Perfluorooctane sulfonate (PFOS) is a recently identified and persistent organic pollutant that becomes enriched in living organisms via bioaccumulation and the food chain. PFOS can induce various disorders, including liver toxicity, neurotoxicity and metabolic dysregulation. Most recent studies have shown a close association of the gut microbiota with the occurrence of diseases. However, few studies have explored the effects of PFOS on the gut environment, including the intestinal flora and barrier. In this study, we evaluated the effects of PFOS in C57BL/6J male mice and explored the relationship between tissue damage and the gut environment. Mice were orally exposed to PFOS for 16 days. Liver damage was assessed by examining the inflammatory reaction in the liver and serum liver enzyme concentrations. Metabolic function was assessed by the hepatic cholesterol level and the serum concentrations of glucose, high-density lipoprotein cholesterol, total cholesterol and triglycerides. Intestinal environmental disorders were assessed by evaluating the gut microbiota, SCFAs production, inflammatory reactions and intestinal tight junction protein expression. Our results indicated that PFOS affected inflammatory reactions in the liver and colon and promoted the development of metabolic disorders (especially of cholesterol and glucose metabolism). Moreover, PFOS dysregulated various populations in the gut microbiota (e.g., Firmicutes, Bacteroides, Proteobacteria, Gammaproteobacteria, Clostridiales, Enterobacteriales, Lactobacillales, Erysipelotrichaceae, Rikenellaceae, Ruminococcaceae and Blautia) and induced a loss of gut barrier integrity by reducing short-chain fatty acids (SCFAs) production and intestinal tight junction protein expression. A Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis mainly identified metabolic pathways (e.g., the adipocytokine signalling pathway), endocrine system pathways (e.g., steroid hormone biosynthesis, flavonoid biosynthesis), the latter of which is widely considered to be associated with metabolism. Overall, our results suggest that PFOS damages various aspects of the gut environment, including the microbiota, SCFAs and barrier function, and thereby exacerbates the toxicity associated with liver, gut and metabolic disorders.

The gut microbiota from lupus-prone B6. Sle1.Sle2.Sle3 (TC) induces inflammation via a mechanism other than bacterial translocation

Abstract The lupus-prone microbiota from TC mice induces autoimmunity when transferred to germ-free B6 mice and broad-spectrum antibiotic treatment attenuates autoimmunity in TC mice, demonstrating a microbiota involvement in inflammation. Aged TC mice show colon inflammation relative to B6 controls Fecal blood was detected in approximately 30% of aged TC mice tested, whereas B6 mice were negative. Based on these findings, we sought to understand if compromised barrier integrity could account for the proinflammatory nature of the TC microbiota. Serum endotoxin and intestinal tight junction protein expression were similar between TC and B6 controls, and serum FITC levels were lower in TC mice following FITC-dextran gavage. Colony growth was found in about 30% of aged TC liver and mesenteric lymph node homogenates, but not in the tissues of pre-autoimmune TC mice. The TC bacterial colonies were identified as Staphylococcus xylosus, a non-pathogenic commensal. These findings suggest that TC mice do not have a compromised intestinal barrier, and that the bacterial translocation that occurs in a minority of TC mice only after the onset of autoimmunity is a consequence, rather than a cause of autoimmunity. Therefore, the inflammatory nature of the TC microbiota is likely related to immune activation starting in the gut itself through the production of specific metabolites.

Tryptophan increases intestinal permeability and decreases intestinal tight junction protein expression in weanling piglets1

Tryptophan increases intestinal permeability and decreases intestinal tight junction protein expression in weanling piglets1

Probiotic Bacteria Induce Maturation of Intestinal Claudin 3 Expression and Barrier Function

An immature intestinal epithelial barrier may predispose infants and children to many intestinal inflammatory diseases, such as infectious enteritis, inflammatory bowel disease, and necrotizing enterocolitis. Understanding the factors that regulate gut barrier maturation may yield insight into strategies to prevent these intestinal diseases. The claudin family of tight junction proteins plays an important role in regulating epithelial paracellular permeability. Previous reports demonstrate that rodent intestinal barrier function matures during the first 3 weeks of life. We show that murine paracellular permeability markedly decreases during postnatal maturation, with the most significant change occurring between 2 and 3 weeks. Here we report for the first time that commensal bacterial colonization induces intestinal barrier function maturation by promoting claudin 3 expression. Neonatal mice raised on antibiotics or lacking the toll-like receptor adaptor protein MyD88 exhibit impaired barrier function and decreased claudin 3 expression. Furthermore, enteral administration of either live or heat-killed preparations of the probiotic Lactobacillus rhamnosus GG accelerates intestinal barrier maturation and induces claudin 3 expression. However, live Lactobacillus rhamnosus GG increases mortality. Taken together, these results support a vital role for intestinal flora in the maturation of intestinal barrier function. Probiotics may prevent intestinal inflammatory diseases by regulating intestinal tight junction protein expression and barrier function. The use of heat-killed probiotics may provide therapeutic benefit while minimizing adverse effects.