Brazil Nut (Bertholletia excelsa H.B.K.) Consumption in Energy-Restricted Intervention Decreases Proinflammatory Markers and Intestinal Permeability of Women with Overweight/Obesity: A Controlled Trial (Brazilian Nuts Study).

BACKGROUND: Obesity is associated with low-grade inflammation and increased intestinal permeability (IP). The Brazil nut (BN) (Bertholletia excelsa H.B.K.) appears to be a promising dietary intervention to control inflammation by enhancing antioxidant defenses. OBJECTIVES: We aimed to assess the effect of daily BN consumption on inflammatory biomarkers and IP in the context of an energy-restricted intervention. Furthermore, we evaluated the correlation between the changes in these inflammatory markers and the changes in serum selenium and IP. METHODS: In this 8-wk nonrandomized controlled trial, 56 women with overweight or obesity were allocated into 2 groups, both following an energy-restricted diet (-500 kcal/d). The control group (CO) consumed a nut-free diet, while the BN group consumed 8 g BN/d, providing 347.2 µg selenium (Se). Inflammatory cytokines were analyzed in plasma and Se in serum. IP was assessed using the lactulose/mannitol test (LM ratio). RESULTS: Forty-six women completed the intervention. Both groups achieved similar energy restriction (CO Δ= -253.7 ± 169.4 kcal/d; BN Δ= -265.8 ± 141.8 kcal/d) and weight loss (CO Δ= -2.5 ± 0.5 kg; BN Δ= -3.5 ± 0.5 kg). The BN group showed lower values of C-reactive protein, tumor necrosis factor, interleukin (IL)1-ß, IL-8, percentage lactulose excretion, and LM ratio than the CO group. Additionally, changes in serum Se concentration were predictive of changes in IL-8 concentration (ß: -0.054; adjusted R2: 0.100; 95% confidence interval [CI]: -0.100; -0.007; P = 0.025), and changes in IL-8 were predictive of changes in the LM ratio (ß: 0.006; adjusted R2: 0.101; 95% CI: 0.001, 0.011; P = 0.024). CONCLUSIONS: Regular intake of BNs can be a promising complementary dietary strategy for controlling low-grade inflammation and improving IP in women with overweight/obesity undergoing energy-restricted treatment. However, the effects of BNs seem to be Se status-dependent. This trial was registered at the Brazilian Registry of Clinical Trials (ReBEC: https://ensaiosclinicos.gov.br/rg/RBR-3ntxrm/.

Inflammation, oxidative stress and gut microbiome perturbation: A narrative review of mechanisms and treatment of the alcohol hangover.

Alcohol is the most widely abused substance in the world, the leading source of mortality in 15-49-year-olds, and a major risk factor for heart disease, liver disease, diabetes, and cancer. Despite this, alcohol is regularly misused in wider society. Consumers of excess alcohol often note a constellation of negative symptoms, known as the alcohol hangover. However, the alcohol hangover is not considered to have long-term clinical significance by clinicians or consumers. We undertook a critical review of the literature to demonstrate the pathophysiological mechanisms of the alcohol hangover. Hereafter, the alcohol hangover is re-defined as a manifestation of sickness behavior secondary to alcohol-induced inflammation, using the Bradford-Hill criteria to demonstrate causation above correlation. Alcohol causes inflammation through oxidative stress and endotoxemia. Alcohol metabolism is oxidative and increased intake causes relative tissue hypoxia and increased free radical generation. Tissue damage ensues through lipid peroxidation and the formation of DNA/protein adducts. Byproducts of alcohol metabolism such as acetaldehyde and congeners, sleep deprivation, and the activation of nonspecific inducible CYP2E1 in alcohol-exposed tissues exacerbate free radical generation. Tissue damage and cell death lead to inflammation, but in the intestine loss of epithelial cells leads to intestinal permeability, allowing the translocation of pathogenic bacteria to the systemic circulation (endotoxemia). This leads to a well-characterized cascade of systemic inflammation, additionally activating toll-like receptor 4 to induce sickness behavior. Considering the evidence, it is suggested that hangover frequency and severity may be predictors of the development of later alcohol-related diseases, meriting formal confirmation in prospective studies. In light of the mechanisms of alcohol-mediated inflammation, research into gut permeability and the gut microbiome may be an exciting future therapeutic avenue to prevent alcohol hangover and other alcohol-related diseases.

Intestinal Permeability, Irritable Bowel Syndrome with Constipation, and the Role of Sodium-Hydrogen Exchanger Isoform 3 (NHE3).

Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut-brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of "leaky gut syndrome" upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients' misconceptions about "leaky gut syndrome".

Investigation of the relationship between inflammation and microbiota in the intestinal tissue of female and male rats fed with fructose: Modulatory role of metformin.

BACKGROUND: It has been reported that High-Fructose (HF) consumption, considered one of the etiological factors of Metabolic Syndrome (MetS), causes changes in the gut microbiota and metabolic disorders. There is limited knowledge on the effects of metformin in HF-induced intestinal irregularities in male and female rats with MetS. OBJECTIVES: In this study, we investigated the sex-dependent effects of metformin treatment on the gut microbiota, intestinal Tight Junction (TJ) proteins, and inflammation parameters in HF-induced MetS. METHODS: Fructose was given to the male and female rats as a 20% solution in drinking water for 15 weeks. Metformin (200 mg/kg) was administered by gastric tube once a day during the final seven weeks. Biochemical, histopathological, immunohistochemical, and bioinformatics analyses were performed. Differences were considered statistically significant at p < 0.05. RESULTS: The metformin treatment in fructose-fed rats promoted glucose, insulin, Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR), and Triglyceride (TG) values in both sexes. The inflammation score was significantly decreased with metformin treatment in fructose-fed male and female rats (p < 0.05). Moreover, metformin treatment significantly decreased Interleukin-1 Beta (IL-1ß) and Tumor Necrosis Factor-Alpha (TNF-α) in ileum tissue from fructose-fed males (p < 0.05). Intestinal immunoreactivity of Occludin and Claudin-1 was increased with metformin treatment in fructose-fed female rats. HF and metformin treatment changed the gut microbial composition. Firmicutes/Bacteroidetes (F/B) ratio increased with HF in females. In the disease group, Bifidobacterium pseudolongum; in the treatment group, Lactobacillus helveticus and Lactobacillus reuteri are the prominent species in both sexes. When the male and female groups were compared, Akkermansia muciniphila was prominent in the male treatment group. CONCLUSION: In conclusion, metformin treatment promoted biochemical parameters in both sexes of fructose-fed rats. Metformin showed a sex-dependent effect on inflammation parameters, permeability factors, and gut microbiota. Metformin has partly modulatory effects on fructose-induced intestinal changes.

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D.

Introduction: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing ß cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear. Objectives: This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset. Methods: The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development. Results: B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9 fl/fl Cd19-Cre+ mice showed delayed diabetes onset, indicating microbiota's impact. Conclusion: B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.

The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review.

Studies consistently showed that sodium-glucose cotransporter inhibitors (SGLTi) have cardiovascular and renal benefits, independent of their glucose lowering effects. Recent studies showed that SGLTi might influence gut microbiota. We performed a narrative review of publications focusing on use of SGLTi and changes in gut microbiota. Most studies showed that use of SGLTi re-shapes gut microbiota. These studies are heterogeneous regarding in study designs, doses and types of drugs used (SGLT1i vs. SGLT2i, or SGLT1/2i in combination) and the methods used to determine gut microbiota. However, existing data showed that SGLTi might alter food fermentation and gut permeability, which might translate into clinical outcomes. Thus the objective of this review is to summarize and discuss the updated data regarding SGLTi and changes in gut microbiota for the first time and suggest further study points that needs to be discovered.

Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype.

Introduction: The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. Methods: In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. Results: LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). Discussion: These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.

Dietary milk polar lipids modulate gut barrier integrity and lipid metabolism in C57BL/6J mice during systemic inflammation induced by Escherichia coli lipopolysaccharide.

The focus of this work is the role milk polar lipids play in affecting gut permeability, systemic inflammation, and lipid metabolism during acute and chronic inflammation induced by a single subcutaneous injection of lipopolysaccharide. Three groups of C57BL/6J mice were fed: modified AIN-93G diet with moderate level of fat (CO); CO with milk gangliosides (GG); CO with milk phospholipids (MPL). The MPL did not prevent a gut permeability increase upon LPS stress but increased the expression of tight junction proteins zonula occludens-1 and occludin in colon mucosa. The GG prevented the gut permeability increase upon LPS stress. The MPL decreased absolute and relative liver mass and decreased hepatic gene expression of acetyl-CoA carboxylase 2 and 3-hydroxy-3-methylglutaryl-CoA reductase. The GG increased hepatic gene expression of acetyl-CoA acyltransferase 2. In conclusion, milk GG protected the intestinal barrier integrity but had little effect on systemic inflammation and lipid metabolism; milk MPL, conversely, had complex effects on gut permeability, did not affect systemic inflammation, and had beneficial effect on hepatic lipid metabolism.

Gut microbiota associations with chronic kidney disease: insights into nutritional and inflammatory parameters.

Introduction: The gut barrier, comprising gut microbiota, plays a pivotal role in chronic kidney disease (CKD) progression and nutritional status. This study aimed to explore gut barrier alterations in hemodialyzed (HD) patients, non-HD (NHD) CKD patients, and healthy volunteers. Methods: Our cross-sectional study enrolled 22 HD patients, 11 NHD patients, and 11 healthy volunteers. We evaluated fecal microbiota composition (assessed via bacterial 16S rRNA gene sequencing), fecal IgA levels, surrogate markers of gut permeability, serum cytokines, appetite mediators, nutritional status, physical activity, and quality of life. Results: HD patients exhibited significant alterations in fecal microbiota composition compared to healthy volunteers, with observed shifts in taxa known to be associated with dietary patterns or producing metabolites acting on human host. In comparison to healthy volunteers, individuals with HD patients exhibited elevated levels of inflammatory markers (CRP, IL-6 and TNF-α), glucagon-like peptide-2, and potential anorexigenic markers (including leptin and peptide YY). NHD patients had increased levels of CRP and peptide YY. Overall fecal microbiota composition was associated with height, soft lean mass, resting energy expenditure, handgrip strength, bone mineral content and plasma albumin and TNF-α. Discussion: Compared to healthy volunteers, HD patients have an altered fecal microbiota composition, a higher systemic inflammation, and a modification in plasma levels of appetite mediators. While some differences align with previous findings, heterogeneity exists likely due to various factors including lifestyle and comorbidities. Despite limitations such as sample size, our study underscores the multifaceted interplay between gut microbiota, physiological markers, and kidney function, warranting further investigation in larger cohorts.

HO-1-induced autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to reduce gut permeability in cholestatic liver disease.

OBJECTIVES: The gut-liver axis disruption is a unified pathogenetic principle of cholestatic liver disease (CSLD). Increased gut permeability is the leading cause of gut-liver axis disruption. HO-1 is capable of protecting against gut-liver axis injury. However, it has rarely been reported whether autophagy is involved in HO-1 protecting gut-liver barrier integrity and the underlying mechanism. MATERIALS AND METHODS: Mice underwent bile duct ligation (BDL) was established as CSLD model in vivo. Caco-2 cells with LPS treatment was established as in vitro cell model. Immunofluorescence, western blot and transepithelial electrical resistance (TER) assay were used to observe epithelial tight junction (TJ) and autophagy. Liver injury and fibrosis were evaluated as well through H&E staining, masson staining, sirius red staining and ELISA. RESULTS AND CONCLUSIONS: Our study demonstrated that the epithelial TJ and TER were notably reduced both in BDL mice and in LPS treated intestinal epithelial cells. Increased HO-1 expression could significantly induce intestinal epithelial cell autophagy. Additionally, this increased autophagy level reversed the reduction effects of BDL or LPS on epithelial TJ and TER in vivo and in vitro, therefore decreased transaminase level in serum and relieved liver fibrosis in BDL mice. Besides, increased autophagy level in turn upregulated the expression of HO-1 by p62 degradation of Keap1 and subsequent activation of Nrf2 pathway. Collectively, these results indicate that HO-1 reduces gut permeability by enhancing autophagy level in CSLD, the increased autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to further improve gut-liver axis disruption. Therefore, our study confirms the critical role of autophagy in HO-1 ameliorating gut-liver axis injury during CSLD, highlighting HO-1 as a promising therapeutic target.

Biochemical, Hematological, Inflammatory, and Gut Permeability Biomarkers in Patients with Alcohol Withdrawal Syndrome with and without Delirium Tremens.

Background: Delirium Tremens (DT) is known to be a serious complication of alcohol withdrawal syndrome (AWS). Neurotransmitter abnormalities, inflammation, and increased permeability are associated with the pathogenesis of AWS and DT. However, the biomarkers of these conditions are still poorly understood. Methods: In this work, biochemical, hematologic, inflammatory, and gut permeability biomarkers were investigated in the following three groups: healthy controls (n = 75), severe AWS patients with DT (n = 28), and mild/moderate AWS without DT (n = 97). Blood sampling was performed after resolution of the acute condition (on 5 ± 1 day after admission) to collect clinical information from patients and to investigate associations with clinical scales. Biomarker analysis was performed using automated analyzers and ELISA. Inflammatory biomarkers included the erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), and platelet-to-lymphocyte ratio (PLR). Results: Among the biochemical biomarkers, only glucose, total cholesterol, and alanine aminotransferase (ALT) changed significantly in the analyzed groups. A multiple regression analysis showed that age and ALT were independent predictors of the CIWA-Ar score. Hematologic biomarker analysis showed an increased white blood cell count, and the elevated size and greater size variability of red blood cells and platelets (MCV, RDWc, and PDWc) in two groups of patients. Gut permeability biomarkers (FABP2, LBP, and zonulin) did not change, but were associated with comorbid pathologies (alcohol liver disease and pancreatitis). The increase in inflammatory biomarkers (ESR and PLR) was more evident in AWS patients with DT. Cluster analysis confirmed the existence of a subgroup of patients with evidence of high inflammation, and such a subgroup was more frequent in DT patients. Conclusions: These findings contribute to the understanding of biomarker variability in AWS patients with and without DT and support the heterogeneity of patients by the level of inflammation.

Bacillus siamensis Improves the Immune Status and Intestinal Health of Weaned Piglets by Improving Their Intestinal Microbiota.

Previous studies on the early interference of gut microbiota by Bacillus siamensis (B. siamensis) in weaned piglets are rarely reported, and the present trial is a preliminary study. This experiment was conducted to investigate the effects of B. siamensis supplementation on the growth performance, serum biochemistry, immune response, fecal short-chain fatty acids and microbiota of weaned piglets. Sixty weaned piglets were randomly divided into a control group (CON) and a B. siamensis group (BS), which were fed a basal diet and the basal diet supplemented with 5 × 1010 CFU B. siamensis per kg, respectively. Each group had 3 replicates and 10 piglets per replicate. The trial lasted for 28 days. The results showed that B. siamensis significantly increased the serum growth hormone (GH) and insulin-like growth factor (IGF) in piglets. Compared with the CON group, the levels of serum immunoglobulin and inflammatory factors in the BS group were significantly improved. In addition, the serum concentrations of zonulin and endotoxin (ET) in the BS group were lower. The dietary addition of B. siamensis significantly increased fecal short-chain fatty acid (SCFA) levels in piglets. Notably, B. siamensis improved the microbial composition by increasing beneficial genera, including Weissella, Lachnospiraceae_NK4A136_group and Bifidobacterium, and decreasing pathogenic genera, including Pantoea, Fusobacterium and Gemella, in piglet feces. Correlation analysis showed that the benefits of dietary B. siamensis supplementation were closely related to its improved microbial composition. In summary, the addition of B. siamensis can improve the immunity function, inflammatory response, gut permeability and SCFA levels of weaned piglets, which may be achieved through the improvement of their microbiota.

Deciphering the complex interplay of obesity, epithelial barrier dysfunction, and tight junction remodeling: Unraveling potential therapeutic avenues.

Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions.

The neonatal gut microbiome and global health.

The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

The transplantation of the gut microbiome of fat-1 mice protects against colonic mucus layer disruption and endoplasmic reticulum stress induced by high fat diet.

High-fat diets alter gut barrier integrity, leading to endotoxemia by impacting epithelial functions and inducing endoplasmic reticulum (ER) stress in intestinal secretory goblet cells. Indeed, ER stress, which is an important contributor to many chronic diseases such as obesity and obesity-related disorders, leads to altered synthesis and secretion of mucins that form the protective mucus barrier. In the present study, we investigated the relative contribution of omega-3 polyunsaturated fatty acid (PUFAs)-modified microbiota to alleviating alterations in intestinal mucus layer thickness and preserving gut barrier integrity. Male fat-1 transgenic mice (exhibiting endogenous omega-3 PUFAs tissue enrichment) and wild-type (WT) littermates were fed either an obesogenic high-fat diet (HFD) or a control diet. Unlike WT mice, HFD-fed fat-1 mice were protected against mucus layer alterations as well as an ER stress-mediated decrease in mucin expression. Moreover, cecal microbiota transferred from fat-1 to WT mice prevented changes in the colonic mucus layer mainly through colonic ER stress downregulation. These findings highlight a novel feature of the preventive effects of omega-3 fatty acids against intestinal permeability in obesity-related conditions.

The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut.

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon.

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.

BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.

Randomized clinical trial evaluating the efficacy of synbiotic supplementation on serum endotoxin and trimethylamine N-oxide levels in patients with dyslipidaemia.

Introduction: Elevated serum endotoxin and trimethylamine N-oxide (TMAO) are associated with metabolic disorders including dyslipidaemia and insulin resistance. This study aimed to evaluate the impact of a 12-week treatment with a synbiotic supplement on serum endotoxin and TMAO levels in patients diagnosed with dyslipidaemia. Material and methods: A total of 56 patients who met the study inclusion criteria were recruited in this randomized, double-blind clinical trial. Participants were randomly assigned into intervention and control groups and received either synbiotic or placebo sachets twice a day for 12 weeks. The sociodemographic data, food intake, physical activity, and anthropometric indices of participants were assessed before and after intervention. Serum endotoxin, TMAO, and fasting blood glucose (FBG) levels were measured at the baseline and end of the study. Results: No significant difference in the baseline characteristics of participants in the 2 groups was observed. After the 12 weeks of intervention, the mean of serum endotoxin (p < 0.0001), TMAO (p < 0.0001), and FBG (p < 0.0001) was decreased in patients who received synbiotic supplements while no significant change was observed in the control group. Moreover, a significant positive correlation between changes in endotoxin (r = 0.41, p = 0.041) and TMAO (r = 0.40, p = 0.047) with FBG changes was observed. Conclusions: A significant reduction in serum endotoxin and TMAO levels, as well as improvements in FBG, following 12 weeks of supplementation with synbiotics, may offer a potential approach for improving metabolic status in patients with dyslipidaemia.

Curcumin protects mice with myasthenia gravis by regulating the gut microbiota, short-chain fatty acids, and the Th17/Treg balance.

Curcumin is widely used as a traditional drug in Asia. Interestingly, curcumin and its metabolites have been demonstrated to influence the microbiota. However, the effect of curcumin on the gut microbiota in patients with myasthenia gravis (MG) remains unclear. This study aimed to investigate the effects of curcumin on the gut microbiota community, short-chain fatty acids (SCFAs) levels, intestinal permeability, and Th17/Treg balance in a Torpedo acetylcholine receptor (T-AChR)-induced MG mouse model. The results showed that curcumin significantly alleviated the clinical symptoms of MG mice induced by T-AChR. Curcumin modified the gut microbiota composition, increased microbial diversity, and, in particular, reduced endotoxin-producing Proteobacteria and Desulfovibrio levels in T-AChR-induced gut dysbiosis. Moreover, we found that curcumin significantly increased fecal butyrate levels in mice with T-AChR-induced gut dysbiosis. Butyrate levels increased in conjunction with the increase in butyrate-producing species such as Oscillospira, Akkermansia, and Allobaculum in the curcumin-treated group. In addition, curcumin repressed the increased levels of lipopolysaccharide (LPS), zonulin, and FD4 in plasma. It enhanced Occludin expression in the colons of MG mice induced with T-AChR, indicating dramatically alleviated gut permeability. Furthermore, curcumin treatment corrected T-AChR-induced imbalances in Th17/Treg cells. In summary, curcumin may protect mice against myasthenia gravis by modulating both the gut microbiota and SCFAs, improving gut permeability, and regulating the Th17/Treg balance. This study provides novel insights into curcumin's clinical value in MG therapy.

Stool titanium dioxide is positively associated with stool alpha-1 antitrypsin and calprotectin in young healthy adults.

Titanium dioxide (TiO2/E171) is used widely in foods, primarily as a food additive. Animal models have shown that chronic TiO2 exposure may disturb homeostasis of the gastrointestinal tract by increasing gut permeability, inducing gut inflammation, and increasing the likelihood of microbial infection. Adults have a wide range of ingested TiO2,which span two to three orders of magnitude, with a small portion of individuals consuming near gram quantities of TiO2/day. However, research on the health effects of chronic ingestion of TiO2/E171 in humans is limited. We hypothesized that regularly ingested TiO2/E171 is associated with increased gut inflammation and gut permeability in healthy adults. We tested this hypothesis in a cross-sectional design by measuring clinically established stool markers of gut inflammation (calprotectin, lactoferrin) and gut permeability (alpha-1 antitrypsin; A1AT) in 35 healthy adults, and comparing these markers between relatively high and low TiO2 exposure groups. Participants were stratified by TiO2 stool content (high dry stool TiO2 content: 0.95-9.92 µg/mg, n = 20; low content: 0.01-0.04 µg/mg; n = 15). Differences in gut health markers were tested between high and low exposure groups by independent samples t-test or Mann-Whitney U test. Multivariable linear regression was used to assess the association between TiO2 in dry stool and measured stool alpha-1 antitrypsin (A1AT). Participants in the high stool TiO2 group had greater stool A1AT (42.7 ± 21.6 mg/dL; median: 38.3; range: 1.0-49.2 mg/dL), compared to the low TiO2 group (22.8 ± 13.6 mg/dL; median: 20.9; range: 8.7-93.0 mg/dL), P = 0.003. There was also greater stool calprotectin in the high TiO2 group (51.4 ± 48.6 µg/g; median 29.2 µg/g; range: 15.3-199.0 µg/g) than in the low group (47.5 ± 63.3 µg/g; median 18.8 µg/g; range: 1.6-198.1 µg/g), P = 0.04. No clear difference was observed for lactoferrin (high TiO2 group 1.6 ± 2.1 µg/g; median: 0.68 µg/g; range: 0.01-7.7 µg/g, low TiO2 group: 1.3 ± 2.6 µg/g; median: 0.2; range: 0.01-7.6 µg/g) (P = 0.15). A1AT concentration was positively associated with stool TiO2, after adjusting for confounders (ß ± SE: 19.6 ± 7.2; P = 0.01) R2 = 0.38). Community dwelling, healthy adults with the highest TiO2 stool content had higher stool A1AT and calprotectin, compared to those with the lowest TiO2 stool content. Ongoing research is needed to validate these observations in larger groups, and to determine the long-term effects of ingested TiO2 on human gut health, using these and additional health endpoints.