Impaired Gut Barrier Function Research Articles

The gut microbiota in thrombosis.

The gut microbiota has emerged as an environmental risk factor that affects thrombotic phenotypes in several cardiovascular diseases. Evidence includes the identification of marker species by sequencing studies of the gut microbiomes of patients with thrombotic disease, the influence of antithrombotic therapies on gut microbial diversity, and preclinical studies in mouse models of thrombosis that have demonstrated the functional effects of the gut microbiota on vascular inflammatory phenotypes and thrombus formation. In addition to impaired gut barrier function promoting low-grade inflammation, gut microbiota-derived metabolites have been shown to act on vascular cell types and promote thrombus formation. Therefore, these meta-organismal pathways that link the metabolic capacities of gut microorganisms with host immune functions have emerged as potential diagnostic markers and novel drug targets. In this Review, we discuss the link between the gut microbiota, its metabolites and thromboembolic diseases.

Gut Mucosal Immunity in HIV-Exposed Infants: A Review

Gut mucosal immunity in infants exposed to Human Immunodeficiency Virus (HIV) presents a complex interplay of developmental processes, viral dynamics, and therapeutic interventions that significantly impact clinical outcomes. This review synthesizes current knowledge on the mechanisms, clinical implications, and therapeutic strategies concerning gut mucosal immunity in HIV-exposed infants. The gut mucosa serves as a critical site for immune maturation and defense against pathogens, but HIV infection disrupts this delicate balance, leading to compromised immune function and increased susceptibility to infections. Infants born to HIV-positive mothers experience unique challenges in gut mucosal immunity due to vertical transmission of the virus and exposure to antiretroviral therapy (ART). HIV infection disrupts gut-associated lymphoid tissue (GALT), resulting in early depletion of CD4+ T cells and compromised mucosal barrier function. These alterations contribute to microbial translocation, chronic inflammation, and immune dysregulation, impacting overall immune competence and increasing susceptibility to opportunistic infections. Despite advances in ART, persistent immune activation and residual gut mucosal damage pose ongoing challenges in achieving optimal immune reconstitution and preventing long-term complications in HIV-exposed infants. Clinical implications of compromised gut mucosal immunity in HIV-exposed infants extend beyond gastrointestinal health to encompass systemic immune dysfunction and increased risks of non-AIDS comorbidities. Impaired gut barrier function exacerbates microbial translocation, leading to systemic inflammation that may contribute to neurodevelopmental abnormalities and metabolic disorders. Keywords: Gut, Immunity, HIV, Infants

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

BackgroundThe gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function.ResultsWe identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae.ConclusionsOur findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

Understanding How Pre- and Probiotics Affect the Gut Microbiome and Metabolic Health.

The gut microbiome, a complex assembly of microorganisms, significantly impacts human health by influencing nutrient absorption, the immune system, and disease response. These microorganisms form a dynamic ecosystem that is critical to maintaining overall well-being. Prebiotics and probiotics are pivotal in regulating gut microbiotacomposition. Prebiotics nourish beneficial bacteria, and promote their growth, while probiotics help maintain balance within the microbiome. This intricate balance extends to several aspects of health, including maintaining the integrity of the gut barrier, regulating immune responses, and producing metabolites crucial for metabolic health. Dysbiosis, or an imbalance in the gut microbiota, has been linked to metabolic disorders such as type 2 diabetes, obesity, and cardiovascular disease. Impaired gut barrier function, endotoxemia, and low-grade inflammation are associated with toll-like receptors influencing pro-inflammatory pathways. Short-chain fatty acids derived from microbial fermentation modulate anti-inflammatory and immune system pathways. Prebiotics positively influence gut microbiota, while probiotics, especially Lactobacillus and Bifidobacterium strains, may improve metabolic outcomes, such as glycemic control in diabetes. It is important to consider strain-specific effects and study variability when interpreting these findings, highlighting the need for further research to optimize their therapeutic potential. The aim of this report is therefore to review the role of the gut microbiota in metabolic health and disease and the effects of prebiotics and probiotics on the gut microbiome and their therapeutic role, integrating a broad understanding of physiological mechanisms with a clinical perspective.

Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery

ObjectivesTo investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis.MethodsIEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different...

Korean red ginseng extract prevents bone loss in an oral model of glucocorticoid induced osteoporosis in mice.

The gut microbiota and barrier function play important roles in bone health. We previously demonstrated that chronic glucocorticoid (GC)-induced bone loss in mice is associated with significant shifts in gut microbiota composition and impaired gut barrier function. Korean Red Ginseng (KRG, Panax Ginseng Meyer, Araliaceae) extract has been shown to prevent glucocorticoid-induced osteoporosis (GIO) in a subcutaneous pellet model in mice, but its effect on gut microbiota and barrier function in this context is not known. The overall goal of this study was to test the effect of KRG extract in a clinically relevant, oral model of GIO and further investigate its role in modulating the gut-bone axis. Growing male mice (CD-1, 8weeks) were treated with 75μg/mL corticosterone (∼9mg/kg/day) or 0.4% ethanol vehicle in the drinking water for 4weeks. During this 4-week period, mice were treated daily with 500mg/kg/day KRG extract dissolved in sterile water or an equal amount of sterile water via oral gastric gavage. After 4weeks of treatment, we assessed bone volume, microbiota composition, gut barrier integrity, and immune cells in the bone marrow (BM) and mesenteric lymph nodes (MLNs). 4weeks of oral GC treatment caused significant distal femur trabecular bone loss, and this was associated with changes in gut microbiota composition, impaired gut barrier function and altered immune cell composition. Importantly, KRG extract prevented distal femur trabecular bone loss and caused significant alterations in gut microbiota composition but had only modest effects on gut barrier function and immune cell populations. Taken together, these results demonstrate that KRG extract significantly modulates the gut microbiota-bone axis and prevents glucocorticoid-induced bone loss in mice.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

Alterations of Gut Microbiota Related with Status of Iron-Overload in Thalassemia Patients: A Cross-Sectional Pilot Study

Background: Gut dysbiosis can cause an impaired gut-barrier function and may contribute to the pathogenesis of various diseases. Iron overload is a common complication in thalassemia patients and can result in numerous complications, including those affecting the cardiovascular, endocrine, and immune systems. However, it is unclear how iron overload affects the gut microbiota of patients with thalassemia. Objective: To characterize the profiles of the gut microbiome in thalassemia patients compared with healthy participants, as well as to determine the association of these profiles with iron status. Method: Transfusion-dependent thalassemia (TDT) patients and healthy controls aged ≥ 18 years old were enrolled in the study. Stool samples were collected prior to receiving regular blood transfusions in the thalassemia group. Paired-end sequencing of 16s rRNA bacterial DNA extracted from each stool sample was performed. Serum ferritin levels were assessed in each participant to reflect iron status. Results: A total of 14 adult TDT patients and 14 healthy controls were enrolled, with a similar proportion of age and sex. The TDT patients had a significantly higher iron overload status than the controls (median serum ferritin level = 1424 in the TDT group and 197 in the control group; p < 0.001). The Shannon diversity index demonstrated a significant increase in gut microbial diversity in TDT patients as compared to healthy controls (7.06 vs. 6.48; p = 0.001). The TDT group showed a higher abundance of several gram-negative bacterial phyla, such as Bacteroidota, but a reduction in the abundance of Actinobacteriota as compared to the control group. Serum ferritin levels showed a positive correlation with higher gut diversity index. Conclusions: Our study suggests that TDT patients develop gut dysbiotic characteristics compared to the healthy population, with gut diversity associated with serum ferritin levels. This association suggests that iron overload induces gut dysbiosis.

Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19.

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.

Gut microbiota alterations induced by intensive chemotherapy in acute myeloid leukaemia patients are associated with gut barrier dysfunction and body weight loss

Acute myeloid leukaemia (AML) chemotherapy has been reported to impact gut microbiota composition. In this study, we investigated using a multi -omics strategy the changes in the gut microbiome induced by AML intense therapy and their association with gut barrier function and cachectic hallmarks. 10 AML patients, allocated to standard induction chemotherapy (SIC), were recruited. Samples and data were collected before any therapeutic intervention (T0), at the end of the SIC (T1) and at discharge (T4). Gut microbiota composition and function, markers of inflammation, metabolism, gut barrier function and cachexia, as well as faecal, blood and urine metabolomes were assessed. AML patients demonstrated decreased appetite, weight loss and muscle wasting during hospitalization, with an incidence of cachexia of 50%. AML intensive treatment transiently impaired the gut barrier function and led to a long-lasting change of gut microbiota composition characterized by an important loss of diversity. Lactobacillaceae and Campylobacter concisus were increased at T1 while Enterococcus faecium and Staphylococcus were increased at T4. Metabolomics analyses revealed a reduction in urinary hippurate and faecal bacterial amino acid metabolites (bAAm) (2-methylbutyrate, isovalerate, phenylacetate). Integration using DIABLO revealed a deep interconnection between all the datasets. Importantly, we identified bacteria which disappearance was associated with impaired gut barrier function (Odoribacter splanchnicus) and body weight loss (Gemmiger formicilis), suggesting these bacteria as actionable targets. AML intensive therapy transiently impairs the gut barrier function while inducing enduring alterations in the composition and metabolic activity of the gut microbiota that associate with body weight loss. NCT03881826, https://clinicaltrials.gov/ct2/show/NCT03881826.

MiR-10b-5p rescues leaky gut linked with gastrointestinal dysmotility and diabetes.

Diabetes has substantive co-occurrence with disorders of gut-brain interactions (DGBIs). The pathophysiological and molecular mechanisms linking diabetes and DGBIs are unclear. MicroRNAs (miRNAs) are key regulators of diabetes and gut dysmotility. We investigated whether impaired gut barrier function is regulated by a key miRNA, miR-10b-5p,linking diabetesand gut dysmotility. We created a new mouse line using the Mb3Cas12a/Mb3Cpf1 endonuclease todeletemir-10b globally. Loss of function studies in the mir-10b knockout (KO) mice were conducted to characterize diabetes, gut dysmotility, and gut barrier dysfunction phenotypes in these mice. Gain of function studieswere conducted by injecting these mir-10b KO mice with a miR-10b-5p mimic. Further, we performed miRNA-sequencing analysis from colonic mucosa from mir-10bKO, wild type,and miR-10b-5p mimic injected mice to confirm (1) deficiency of miR-10b-5p in KO mice, and (2) restoration of miR-10b-5p after the mimic injection. Congenital loss of mir-10b in mice led to the development of hyperglycemia, gut dysmotility, and gut barrier dysfunction. Gut permeability was increased, but expression of the tight junction protein Zonula occludens-1 was reducedin the colon of mir-10b KO mice. Patients with diabetes or constipation- predominant irritable bowel syndrome, a known DGBI that is linked to leaky gut, had significantly reduced miR-10b-5p expression. Injection of a miR-10b-5p mimic in mir-10b KO mice rescued these molecular alterations and phenotypes. Our study uncovered a potential pathophysiologic mechanism of gut barrier dysfunction that links both the diabetes and gut dysmotility phenotypes in mice lacking miR-10b-5p. Treatment with a miR-10b-5p mimic reversed the leaky gut, diabetic, and gut dysmotility phenotypes, highlighting the translational potential of the miR-10b-5p mimic.

Colon-Targeted Release of Turmeric Nonextractable Polyphenols and Their Anticolitis Potential via Gut Microbiota-Dependent Alleviation on Intestinal Barrier Dysfunction in Mice.

Solid evidence has emerged supporting the role of nonextractable polyphenols (NEPs) and dietary fibers (DFs) as gut microbiota modulators. This study aims to elucidate gut microbiota-dependent release of turmeric NEPs and examine the possible anti-inflammatory mechanism in the dextran sulfate sodium-induced ulcerative colitis (UC) model. 1.5% DSS drinking water-induced C57BL/6J mice were fed a standard rodent chow supplemented with or without 8% extractable polyphenols (EPs), NEPs, or DFs for 37 days. The bound curcumin, demethoxycurcumin, and bisdemethoxycurcumin in NEPs were released up to 181.5 ± 10.6, 65.2 ± 6.0, and 69.5 ± 7.6 μg/mL by in vitro gut microbiota-simulated fermentation and released into the colon of NEP-supplemented mice by 5.7-, 11.0-, and 7.8-fold higher than pseudo germ-free mice, respectively (p < 0.05). NEPs also enhanced the colonic microbiota-dependent production of short-chain fatty acids in vitro and in vivo (p < 0.05). Interestingly, NEP feeding significantly improved the DSS-caused gut microbiota disorder, epithelial barrier damage, and inflammation of UC mice better than EPs or DFs (p < 0.05). Meanwhile, the pseudo germ-free mice supplemented with NEPs failed to ameliorate UC symptoms. These findings manifest that turmeric NEPs as macromolecular carriers exert the target delivery of polyphenols into the colon for regulating gut microbiota to restore the impaired gut barrier function for alleviation of inflammation.

Male-Biased Gut Microbiome and Metabolites Aggravate Colorectal Cancer Development.

Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex-biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/ + mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo-germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo-germ mice receiving fecal sample from male mice. Sex-biased gut metabolites in pseudo-germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex-biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex-biased gut microbiota and metabolites could be a potential sex-targeting therapeutic strategy of CRC.

Size-specific effects of microplastics and lead on zebrafish

Microplastics (MPs) can adsorb heavy metals and induce combined toxicity to aquatic organisms. However, the combined effects on the gut-liver and gut-brain axes are yet to be fully comprehended. This study investigated the combined effects of polystyrene microplastics (PS-MPs) with two concentrations (20 and 200 μg/L) and three sizes (0.1, 10, and 250 μm) and Pb (50 μg/L) on zebrafish through gut-liver and gut-brain axes. The results showed that the combined exposure of 0.1 μm PS-MPs and Pb resulted in the most significant changes to the community diversity of gut microbiota. The combined exposures of PS-MPs (0.1 μm and 250 μm PS-MPs) and Pb significantly down-regulated expression of zo-1 and occludin but increased the lipopolysaccharide content in zebrafish liver compared to the PS-MPs or Pb alone exposure groups, indicating impaired gut barrier function. Subsequent studies showed that combined exposure of PS-MPs (0.1 μm and 250 μm) and Pb induced liver inflammation through the TLR4/NF-κB pathway. Moreover, all exposure groups had an impact on the expression of genes related to bile acid metabolism (cyp7a1, fgf19, abcb11b, and slc10a2) and neurotransmitters (tph1a, tph2, pink, and trh). The findings of this study provide new evidence on the combined effects of MPs and heavy metals, which are significant for their hazard identification and risk assessment.

An overview of traditional Chinese medicine affecting gut microbiota in obesity.

Obesity, a chronic metabolic disease with a complex pathophysiology, is caused by several variables. High-fat diets lead to the disruption of the gut microbiota and impaired gut barrier function in obese people. The dysbiosis and its metabolites through the intestinal barrier lead to an imbalance in energy metabolism and inflammatory response, which eventually contributes to the development of chronic diseases such as diabetes, hypertension, and cardiovascular disease. Current medicines are therapeutic to obesity in the short term; however, they may bring significant physical and emotional problems to patients as major side effects. Therefore, it is urgent to explore new therapeutic methods that have definite efficacy, can be taken for a long time, and have mild adverse effects. Numerous studies have demonstrated that traditional Chinese medicine (TCM) can control the gut microbiota in a multi-targeted and comprehensive manner, thereby restoring flora homeostasis, repairing damaged intestinal mucosal barriers, and eventually curbing the development of obesity. The active ingredients and compounds of TCM can restore the normal physiological function of the intestinal mucosal barrier by regulating gut microbiota to regulate energy metabolism, inhibit fat accumulation, affect food appetite, and reduce intestinal mucosal inflammatory response, thereby effectively promoting weight loss and providing new strategies for obesity prevention and treatment. Although there are some studies on the regulation of gut microbiota by TCM to prevent and treat obesity, all of them have the disadvantage of being systematic and comprehensive. Therefore, this work comprehensively describes the molecular mechanism of obesity mediated by gut microbiota based on the research state of obesity, gut microbiota, and TCM. A comprehensive and systematic summary of TCM targeting the regulation of gut microbiota for the treatment of obesity should be conducted in order to provide new strategies and ideas for the treatment of obesity.

Chronic exposure to zearalenone induces intestinal inflammation and oxidative injury in adult Drosophila melanogaster midgut

In the past decade, mycotoxin zearalenone (ZEN)-induced gastrointestinal adverse effects have been increasingly attracting worldwide attention. This study aimed to determine the gastrointestinal adverse effects of ZEN in Drosophila melanogaster (D. melanogaster) and reveal possible mechanisms of action of ZEN in insects. Here, chronic exposure of D. melanogaster to ZEN killed flies in a dose-dependent manner (2–20 µM). ZEN (20 µM) decreased the survival rates and climbing ability of flies, and activated immune deficiency-mediated intestinal immunity in midgut, leading to the production of antimicrobial peptides. Meanwhile, ZEN exposure induced morphological alteration of adult midgut. Further study suggested that high levels of oxidative stress was observed in ZEN-treated midgut due to the imbalance between the production of reactive oxygen species and the expression and activities of cellular antioxidant enzyme, including superoxide dismutase and catalase. ZEN-induced oxidative stress then caused cell death, impaired gut barrier function and increased gut permeability, leading to oxidative injury in midgut. Subsequently, ZEN-induce midgut injury further disrupted intestinal stem cell (ISC) homeostasis, stimulating ISC proliferation and tissue regeneration, but did not alter cell fate specification of ISC. Additionally, activation of Jun N-terminal kinase pathway was involved in ZEN-induced oxidative injury and tissue regeneration in midgut. Antioxidant vitamin E alleviated ZEN-induced oxidative injury to midgut epithelium. Collectively, this study provided additional evidences for ZEN-induced gastrointestinal adverse effects from an invertebrate model, extended our understanding of the mechanisms mediating mycotoxin toxicity in organisms.

Impact of selected novel plant bioactives on improvement of impaired gut barrier function using human primary cell intestinal epithelium

Gut barrier function is compromised in the obese state. The N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), two naturally occurring bioactive compounds in hemp hulls, identified using in silico approaches, have the potential to improve gut barrier function and their effects were studied here in vitro. Proliferative human transverse colon epithelial cells were plated and co-cultured with tumor necrosis factor (TNF) along with NCT, NFT or NCT/NFT (2.2 ratio) post-differentiation, over a 48-hour period to induce inflammation and to observe the effects of NCT and NFT. A decrease in transepithelial electrical resistance (TEER) and increase in the intestinal permeability were observed with increased addition of TNF. Co-administration of NCT and NFT demonstrated a dose-dependent and statistically significant reversal of impaired TEER and intestinal permeability. NCT and NFT demonstrated a physiologically relevant reversal of impaired gut barrier function in the setting of inflammation via significant improvement in TEER and percent permeability.

Autoclaved Diet with Inactivated Spores of Bacillus spp. Decreased Reproductive Performance of Muc2-/- and Muc2+/- Mice.

Simple SummaryWithin barrier facilities for the housing of laboratory animals, the sterilization of feed, bedding, and cages is used to reduce contact with bacteria. However, in nature, animals come into contact with a lot of bacteria. We investigated the effect of an autoclaved diet on the reproductive performance of Muc2−/− mice. Muc2−/− mice develop intestinal barrier defects and are sensitive to changes of the gut microbiota. We have shown that the autoclaved diet negatively affects the reproductive performance of Muc2−/− females and their healthy Muc2+/− siblings. Thus, the autoclaved diet led to earlier rectal prolapse of Muc2−/− females combined with intestinal inflammation, compared to mice fed with the non-autoclaved diet. We hypothesize that this effect is due to the reduction of the diet nutritional value and inactivation of Bacillus spp. spores in the autoclaved diet. Within barrier facilities, autoclaved diet and bedding are used for husbandry of laboratory rodents. Bacillus spp. are ubiquitous in nature and some of them are known as probiotics. Inactivation of the Bacillus spores and reduction of the diet nutritional value due to autoclavation could be especially critical for immunodeficient mice. We studied the effect of the autoclaved and non-autoclaved diets on the reproductive performance and the age of prolapse manifestation in Muc2−/− mice with impaired gut barrier function and, therefore, sensitive to change of microbiota. We found that the non-autoclaved diet led to enhancement of the fertility index of Muc2−/− and Muc2+/− female mice. The non-autoclaved diet affected the prolapse of Muc2−/− mice that occurred later in comparison with females eating the autoclaved diet. We showed that Bacillus spp. was present in the non-autoclaved diet and feces of mice on the non-autoclaved diet. Bacterial strains of the non-autoclaved diet and feces belonged to B. amyloliquefaciens, B. thuringiensis, B. subtilis, Lysinibacillus macrolides, B. cereus, and other representatives of Bacillus spp. Moreover, autoclavation of the diet affected on the percent of the blood and spleen immune cells, the bacterial composition of the intestine, and increased the level of methionine in the thigh muscle of mice. Enhanced reproductive performance and delayed prolapse manifestation in Muc2−/− mice could be due to improved digestion, as Bacillus spp. from diet and feces had enzymatic activity.

Interactive Effect of Combined Intermittent and Sustained Hypoxia and High-Fat Diet on the Colonic Mucosal Microbiome and Host Gene Expression in Mice.

PurposeGut dysbiosis can cause cardiometabolic disease. Gut dysbiosis can be independently caused by high-fat diet (HFD) and intermittent hypoxia (IH; characterizing obstructive sleep apnea), but the interactive effect of combined intermittent and sustained hypoxia (IH+SH) (characterizing obesity hypoventilation syndrome) and HFD on gut dysbiosis is unclear. We aimed to investigate the interactive effect of a combination of IH and SH and HFD on proximal colonic microbiota and colonic gene expression pattern.MethodsMale mice (n=16) were randomly received four different combinations of diet (normal versus HFD) and oxygen conditions (normoxia versus IH+SH) for 4 weeks. Bacterial DNA and mucosal epithelial cell RNA from proximal colon were collected for analysis of adherent microbiome and host’s gene expression analysis.ResultsHFD during IH+SH (22.6 ± 5.73; SD) led to greater Firmicutes: Bacteroidetes ratio than HFD during normoxia (5.89 ± 1.19; p=0.029). HFD significantly decreased microbial diversity as compared to normal diet, but the addition of IH+SH to HFD mildly reversed such effects. When compared to HFD during normoxia, HFD with combination of IH+SH resulted in changes to host mucosal gene expression for apical junctional complexes and adhesion molecules. Specifically, when compared to HFD during normoxia, HFD during IH+SH led to upregulation of Claudin 2 and Syk (tight junction dysfunction and increased mucosal permeability), while the barrier promoting claudin 4 was downregulated.ConclusionHFD during combined IH and SH causes greater gut dysbiosis and potentially adverse changes in colonic epithelial transcriptome than HFD during normoxia. The latter changes are suggestive of impaired gut barrier function.