Increased Gut Permeability Research Articles

Garcinol enriched fraction of Garcinia morella (Gaertn.) Desr. fruit rind improves gut health and reduces the risk of nonalcoholic fatty liver disease by regulating PCK1/ACC/SREBP1/FASn pathway in a mouse model

Nonalcoholic fatty liver disease (NAFLD), a fast-emerging global burden, is an umbrella term for several liver manifestations that result in excessive accumulation of fat in the liver. NAFLD leads to gut microbiome dysbiosis, loss in gut epithelia, increased gut permeability, etc. The limited availability of registered drugs for NAFLD highlights the urgent need to focus on understanding its pathogenesis and discovering new treatments, including the potential exploration of herbal therapies for managing the condition. In this study, we evaluated the bioactive potential of garcinol enriched fraction from Garcinia morella fruit rind in preventing NAFLD-associated increased gut permeability. Administration of garcinol-enriched fraction (GEF) significantly reduced body weight, serum lipids (triglyceride and total cholesterol) levels, and enzymes (alkaline phosphatase and aspartate aminotransferase) responsible for liver dysfunction in high-fat diet (HFD)-fed C57BL/6 mice. GEF treatment also regulated the alteration in signaling pathways of lipid metabolism in HFD-fed mice by inhibiting the overexpression of genes involved in de novo lipogenesis. Mice treated with GEF had increased gut microbial diversity, reduced pathogenic bacteria, and increased Lactococcus and Streptococcaceae genera. Additionally, GEF treatment could increase the expression of intestinal tight junction proteins, which were otherwise decreased in HFD-fed mice, stipulating its protective effect in maintaining gut barrier integrity. Our study demonstrated that GEF treatment reduces obesity in mice and improves gut health by keeping junctions tight and maintaining a healthy gut microbiome.

Concomitant gut dysbiosis and defective gut barrier serve as the bridges between hypercortisolism and chronic systemic inflammation in Cushing's disease.

The aim of this study was to investigate the gut microbial signatures and related pathophysiological implications in patients with Cushing's disease (CD). Twenty-seven patients with CD and 45 healthy controls were enrolled. Based on obtained metagenomics data, we performed correlation, network study, and genome interaction group (GIG) analysis. Fecal metabolomics and serum enzyme linked immunosorbent assay (ELISA) analysis were conducted in dichotomized CD patients. Caco-2 cells were incubated with gradient concentrations of cortisol for subsequent transepithelial electrical resistance (TEER) measurement, FITC-dextran transwell permeability assay, qPCR, and western blot analysis. Gut microbial composition in patients with CD was notably different from that in healthy controls. Network analysis revealed that Eubacterium siraeum might serve as the core specie in the gut microbial system of CD patients. Subsequent GIG analysis identified the positive correlations between GIG9 and UFC. Further serum ELISA and fecal metabolomics uncovered that CD patients with elevated UFC levels were characterized with increased lipopolysaccharide binding protein (LBP). Moreover, remarkable positive association was found between LBP level and relative abundance of E. siraeum. TEER and FITC-dextran transwell assays demonstrated that hypercortisolism induced increased gut permeability. Further qPCR and western blot analysis suggested that dysregulated AhR/Claudin 2 axis might be involved in the development of hypercortisolism-induced defective gut barrier function. Disease activity associated dysbiosis and defective gut barrier might jointly facilitate the development of systemic inflammation in patients with CD.

Gut-Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders.

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut-brain axis. The gut-brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation-a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders.

Maternal High-Fat Diet Exacerbates Epicutaneous Sensitization and Oral Challenge-Induced Food Allergy to Ovalbumin in Offspring Mice.

Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1β) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.

The Kynurenine Pathway in Gut Permeability and Inflammation.

The gut-brain axis (GBA) is a crucial communication network linking the gastrointestinal (GI) tract and the central nervous system (CNS). The gut microbiota significantly influences metabolic, immune, and neural functions by generating a diverse array of bioactive compounds that modulate brain function and maintain homeostasis. A pivotal mechanism in this communication is the kynurenine pathway, which metabolises tryptophan into various derivatives, including neuroactive and neurotoxic compounds. Alterations in gut microbiota composition can increase gut permeability, triggering inflammation and neuroinflammation, and contributing to neuropsychiatric disorders. This review elucidates the mechanisms by which changes in gut permeability may lead to systemic inflammation and neuroinflammation, with a focus on the kynurenine pathway. We explore how probiotics can modulate the kynurenine pathway and reduce neuroinflammation, highlighting their potential as therapeutic interventions for neuropsychiatric disorders. The review integrates experimental data, discusses the balance between neurotoxic and neuroprotective kynurenine metabolites, and examines the role of probiotics in regulating inflammation, cognitive development, and gut-brain axis functions. The insights provided aim to guide future research and therapeutic strategies for mitigating GI complaints and their neurological consequences.

Somatostatin peptides prevent increased human colonic epithelial permeability induced by hypoxia.

Mesenteric ischemia increases gut permeability and bacterial translocation. In human colon, chemical hypoxia induced by 2,4-dinitrophenol (DNP) activates basolateral intermediate conductance K+ (IK) channels (designated KCa3.1 or KCNN4) and increases paracellular shunt conductance/permeability (GS), but whether this leads to increased macromolecule permeability is unclear. Somatostatin (SOM) inhibits IK channels and prevents hypoxia-induced increases in GS. Thus, we examined whether octreotide (OCT), a synthetic SOM analog, prevents hypoxia-induced increases GS in human colon and hypoxia-induced increases in total epithelial conductance (GT) and permeability to FITC-dextran 4000 (FITC) in rat colon. The effects of serosal SOM and OCT on increases in GS induced by 100 µM DNP were compared in isolated human colon. The effects of OCT on DNP-induced increases in GT and transepithelial FITC movement were evaluated in isolated rat distal colon. GS in DNP-treated human colon was 52% greater than in controls (P = 0.003). GS was similar when 2 µM SOM was added after or before DNP treatment, in both cases being less (P < 0.05) than with DNP alone. OCT (0.2 µM) was equally effective preventing hypoxia-induced increases in GS, whether added after or before DNP treatment. In rat distal colon, DNP significantly increased GT by 18% (P = 0.016) and mucosa-to-serosa FITC movement by 43% (P = 0.01), and 0.2 µM OCT pretreatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate that it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.NEW & NOTEWORTHY Somatostatin (SOM, 2 µM) and octreotide (OCT, 0.2 µM, a long-acting synthetic analog of SOM) were equally effective in preventing chemical hypoxia-induced increases in paracellular shunt permeability/conductance in isolated human colon. In rat distal colon, chemical hypoxia significantly increased total epithelial conductance and transepithelial movement of FITC-dextran 4000, changes completely prevented by 0.2 µM OCT. OCT may prevent or limit gut ischemia during abdominal surgery, thereby decreasing the risk of bacterial/bacterial toxin translocation and sepsis.

The Spectrum of Postacute Sequelae of COVID-19 in Children: From MIS-C to Long COVID.

The effects of SARS-CoV-2 infection on children continue to evolve following the onset of the COVID-19 pandemic. Although life-threatening multisystem inflammatory syndrome in children (MIS-C) has become rare, long-standing symptoms stemming from persistent immune activation beyond the resolution of acute SARS-CoV-2 infection contribute to major health sequelae and continue to pose an economic burden. Shared pathophysiologic mechanisms place MIS-C and long COVID within a vast spectrum of postinfectious conditions characterized by intestinal dysbiosis, increased gut permeability, and varying degrees of immune dysregulation. Insights obtained from MIS-C will help shape our understanding of the more indolent and prevalent postacute sequelae of COVID and ultimately guide efforts to improve diagnosis and management of postinfectious complications of SARS-CoV-2 infection in children.

Exposure to the World Trade Center Particulate Matter Alters the Gut-Brain Axis in Early Onset Alzheimer's Disease Mice.

The September 11, 2001, catastrophe unleashed widespread destruction beyond the World Center (WTC), with fires and toxic gases leaving lasting impacts. First responders at Ground Zero faced prolonged exposure to hazardous particulate matter (PM), resulting in chronic health challenges. Among the multitude of health concerns, the potential association between the WTCPM and Alzheimer's disease (AD) has emerged as an area of intense inquiry, probing the intricate interplay between environmental factors and neurodegenerative diseases. We posit that a genetic predisposition to AD in mice results in dysregulation of the gut-brain axis following chronic exposure to WTCPM. This, in turn, may heighten the risk of AD-like symptoms in these individuals. 3xTg-AD and WT mice were intranasally administered with WTCPM collected at Ground Zero within 72 hours after the attacks. Working memory and learning and recognition memory were monitored for 4 months. Moreover, brain transcriptomic analysis and gut barrier permeability along with microbiome composition were examined. Our findings underscore the deleterious effects of WTCPM on cognitive function, as well as notable alterations in brain genes associated with synaptic plasticity, pro-survival, and inflammatory signaling pathways. Complementary, chronic exposure to the WTCPM led to increased gut permeability in AD mice and altered bacteria composition and expression of functional pathways in the gut. Our results hint at a complex interplay between gut and brain axis, suggesting potential mechanisms through which WTCPM exposure may exacerbate cognitive decline. Identifying these pathways offers opportunities for tailored interventions to alleviate neurological effects among first responders.

The Influence of Cecal Microbiota Transplantation on Chicken Injurious Behavior: Perspective in Human Neuropsychiatric Research.

Numerous studies have evidenced that neuropsychiatric disorders (mental illness and emotional disturbances) with aggression (or violence) pose a significant challenge to public health and contribute to a substantial economic burden worldwide. Especially, social disorganization (or social inequality) associated with childhood adversity has long-lasting effects on mental health, increasing the risk of developing neuropsychiatric disorders. Intestinal bacteria, functionally as an endocrine organ and a second brain, release various immunomodulators and bioactive compounds directly or indirectly regulating a host's physiological and behavioral homeostasis. Under various social challenges, stress-induced dysbiosis increases gut permeability causes serial reactions: releasing neurotoxic compounds, leading to neuroinflammation and neuronal injury, and eventually neuropsychiatric disorders associated with aggressive, violent, or impulsive behavior in humans and various animals via a complex bidirectional communication of the microbiota-gut-brain (MGB) axis. The dysregulation of the MGB axis has also been recognized as one of the reasons for the prevalence of social stress-induced injurious behaviors (feather pecking, aggression, and cannibalistic pecking) in chickens. However, existing knowledge of preventing and treating these disorders in both humans and chickens is not well understood. In previous studies, we developed a non-mammal model in an abnormal behavioral investigation by rationalizing the effects of gut microbiota on injurious behaviors in chickens. Based on our earlier success, the perspective article outlines the possibility of reducing stress-induced injurious behaviors in chickens through modifying gut microbiota via cecal microbiota transplantation, with the potential for providing a biotherapeutic rationale for preventing injurious behaviors among individuals with mental disorders via restoring gut microbiota diversity and function.

Dietary Milk Phospholipids Increase Body Fat and Modulate Gut Permeability, Systemic Inflammation, and Lipid Metabolism in Mice

The study aimed at how dietary milk polar lipids affect gut permeability, systemic inflammation, and lipid metabolism during diet-induced obesity (DIO). C57BL/6J mice (n = 6x3) were fed diets with 34% fat as energy for 15 weeks: (1) modified AIN-93G diet (CO); (2) CO with milk gangliosides (GG); (3) CO with milk phospholipids (MPL). Gut permeability was assessed by FITC-dextran and sugar absorption tests. Intestinal tight junction proteins were evaluated by Western blot. Plasma cytokines were measured by immunoassay. Body composition was assessed by magnetic resonance imaging. Tissue lipid profiles were obtained by thin layer chromatography. Hepatic expression of genes associated with lipid metabolism was assessed by RT-qPCR. MPL increased the efficiency of converting food into body fat and facilitated body fat accumulation compared with CO. MPL and GG did not affect fasting glucose or HOMA-IR during DIO. MPL increased while GG decreased plasma TG compared with CO. MPL decreased phospholipids subclasses in the muscle while increased those in the liver compared with CO. GG and MPL had little effect on hepatic expression of genes associated with lipid metabolism. Compared with CO, MPL decreased polar lipids content in colon mucosa. Small intestinal permeability decreased while colon permeability increased and then recovered during the feeding period. High-fat feeding increased plasma endotoxin after DIO but did not affect plasma cytokines. MPL and GG did not affect plasma endotoxin, adipokines and inflammatory cytokines. After the establishment of obesity, MPL increased gut permeability to large molecules but decreased intestinal absorption of small molecules while GG tended to have the opposite effects. MPL and GG decreased mannitol and sucralose excretions, which peaked at d 45 in the CO group. MPL decreased occludin in jejunum mucosa compared with CO. GG and MPL did not affect zonula occludens-1 in gut mucosa. In conclusion, during DIO, milk GG decreased gut permeability, and had little effect on systemic inflammation and lipid metabolism; MPL facilitated body fat accumulation, decreased gut permeability, did not affect systemic inflammation.

Toll-like receptor 4 mutation mitigates gut microbiota-mediated hypertensive kidney injury

Hypertension-associated dysbiosis is linked to several clinical complications, including inflammation and possible kidney dysfunction. Inflammation and TLR4 activation during hypertension result from gut dysbiosis-related impairment of intestinal integrity. However, the contribution of TLR4 in kidney dysfunction during hypertension-induced gut dysbiosis is unclear. We designed this study to address this knowledge gap by utilizing TLR4 normal (TLR4N) and TLR4 mutant (TLR4M) mice. These mice were infused with high doses of Angiotensin-II for four weeks to induce hypertension. Results suggest that Ang-II significantly increased renal arterial resistive index (RI), decreased renal vascularity, and renal function (GFR) in TLR4N mice compared to TLR4M. 16 S rRNA sequencing analysis of gut microbiome revealed that Ang-II-induced hypertension resulted in alteration of Firmicutes: Bacteroidetes ratio in the gut of both TLR4N and TLR4M mice; however, it was not comparably rather differentially. Additionally, Ang-II-hypertension decreased the expression of tight junction proteins and increased gut permeability, which were more prominent in TLR4N mice than in TLR4M mice. Concomitant with gut hyperpermeability, an increased bacterial component translocation to the kidney was observed in TLR4N mice treated with Ang-II compared to TLR4N plus saline. Interestingly, microbiota translocation was mitigated in Ang-II-hypertensive TLR4M mice. Furthermore, Ang-II altered the expression of inflammatory (IL-1β, IL-6) and anti-inflammatory IL-10) markers, and extracellular matrix proteins, including MMP-2, −9, −14, and TIMP-2 in the kidney of TLR4N mice, which were blunted in TLR4M mice. Our data demonstrate that ablation of TLR4 attenuates hypertension-induced gut dysbiosis resulting in preventing gut hyperpermeability, bacterial translocation, mitigation of renal inflammation and alleviation of kidney dysfunction.

Sexual dimorphism in neurobehavioural phenotype and gut microbial composition upon long-term exposure to structural analogues of bisphenol-A

Bisphenol S (BPS) and Bisphenol F (BPF), the analogues of the legacy endocrine disrupting chemical, Bisphenol A (BPA) are ubiquitous in the environment and present in various consumer goods, and potentially neurotoxic. Here, we studied sex-specific responses of bisphenols on behavioural phenotypes, including their association with pro-inflammatory biomarkers and altered neurotransmitters levels, and the key gut microbial abundances. Neurobehavioural changes, using standard test battery, biochemical and molecular estimations for inflammatory cytokines, neurotransmitters, and oxido-nitrosative stress markers, gene expression analysis using qRT-PCR, H&E based histological investigations, gut permeability assays and Oxford Nanopore-based 16S-rRNA metagenomics sequencing for the gut microbial abundance estimations were performed. Bisphenol(s) exposure induces anxiety and depression-like behaviours, particularly in the male mice, with heightened pro-inflammatory cytokines levels and systemic endotoxemia, altered monoamine neurotransmitters levels/turnovers and hippocampal neuronal degeneration and inflammatory responses in the brain. They also increased gut permeability and altered microbial diversity, particularly in males. Present study provides evidence for sex-specific discrepancies in neurobehavioural phenotypes and gut microbiota, which necessitate a nuanced understanding of sex-dependent responses to bisphenols. The study contributes to ongoing discussions on the multifaceted implications of bisphenols exposure and underscores the need for tailored regulatory measures to mitigate potential health risks associated with them.

Coactosin-like protein 1 regulates integrity and repair of model intestinal epithelial barriers via actin binding dependent and independent mechanisms.

The actin cytoskeleton regulates the integrity and repair of epithelial barriers by mediating the assembly of tight junctions (TJs), and adherens junctions (AJs), and driving epithelial wound healing. Actin filaments undergo a constant turnover guided by numerous actin-binding proteins, however, the roles of actin filament dynamics in regulating intestinal epithelial barrier integrity and repair remain poorly understood. Coactosin-like protein 1 (COTL1) is a member of the ADF/cofilin homology domain protein superfamily that binds and stabilizes actin filaments. COTL1 is essential for neuronal and cancer cell migration, however, its functions in epithelia remain unknown. The goal of this study is to investigate the roles of COTL1 in regulating the structure, permeability, and repair of the epithelial barrier in human intestinal epithelial cells (IEC). COTL1 was found to be enriched at apical junctions in polarized IEC monolayers in vitro. The knockdown of COTL1 in IEC significantly increased paracellular permeability, impaired the steady state TJ and AJ integrity, and attenuated junctional reassembly in a calcium-switch model. Consistently, downregulation of COTL1 expression in Drosophila melanogaster increased gut permeability. Loss of COTL1 attenuated collective IEC migration and decreased cell-matrix attachment. The observed junctional abnormalities in COTL1-depleted IEC were accompanied by the impaired assembly of the cortical actomyosin cytoskeleton. Overexpression of either wild-type COTL1 or its actin-binding deficient mutant tightened the paracellular barrier and activated junction-associated myosin II. Furthermore, the actin-uncoupled COTL1 mutant inhibited epithelial migration and matrix attachment. These findings highlight COTL1 as a novel regulator of the intestinal epithelial barrier integrity and repair.

PMN-MDSC: A Culprit Behind Immunosenescence and Increased Susceptibility to Clostridioides difficile Infection During Aging

Susceptibility to pathogens in the elderly is heightened with age, largely because of immunosenescence. As an immune regulatory organ, bone marrow creates immune cells that move to other organs and tissues through the blood. Despite the significance of this process of this organ, there is limited research on changes in immune cell generation in the bone marrow and their effects on immunosenescence. In this study, the compositions of immune cells in bone marrow from young (three months) and old (24+ months) mice were compared by means of mass cytometry, with further validation obtained through the reanalysis of single-cell RNA sequencing data and cell sorting via flow cytometry. The effects of differential immune cells on immunosenescence in old mice were evaluated using the Clostridioides difficile (C. difficile) infection model. Our results showed that aged mice presented with a reduction in bone trabeculae structure, which was accompanied by a notable increase in polymorphonuclear (PMN)-myeloid-derived suppressor cell (MDSC) abundance. Through bulk-seq and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis, we identified differential genes associated with the immune response—specifically, the Th17 cell differentiation pathway. Furthermore, the increase in exported PMN-MDSCs to the large intestine resulted in increased gut permeability and inflammatory damage to the colon following C. difficile infection. After clearing the PMN-MDSCs in old mice using the anti-Gr-1 antibody, the symptoms induced by C. difficile were significantly relieved, as evidenced by an inhibited IL-17 pathway in the colon and reduced gut permeability. In conclusion, aging increases the number of PMN-MDSCs in both the generated bone marrow and the outputted intestine, which contributes to susceptibility to C. difficile infection. This study provides a novel target for anti-aging therapy for immunosenescence, which is beneficial for improving immune function in elders.

Microbiome Dysbiosis in Depression: A Narrative Review

The comprehensive exploration of the microbial composition of the gut and its role in depression underscores a complex interplay involving alterations in gut microbiome, immune pathways, and inflammatory control. Studies reveal potential biomarkers and therapeutic targets linked to depression, with particular bacterial genera correlated with the severity of depressive symptoms. The dysregulation extends to disruptions in metabolic pathways and functions of bacterial proteins within the gut, contributing to intestinal barrier dysfunction and increased gut permeability. Notably, alterations in microbial composition are observed in various depressive conditions, including major depressive disorder (MDD), post-stroke depression (PSD), and depression during neoadjuvant cancer treatment. The influence of the gut microbiome on the central nervous system and the bidirectional relationship between depression and microbial changes are highlighted. Regulatory interventions, including antidepressants and probiotics, show promise in modulating the gut microbiome and alleviating depressive symptoms. The combination of probiotics with antidepressants emerges as a potential strategy for inducing a balanced microbiome. However, a lack of consensus exists regarding specific bacterial taxa associated with depression, emphasizing the need for further research to refine the therapeutic approaches for managing depression and related mood disorders. This review aims to explore the relationship between microbiome dysbiosis and depression, highlighting the role of dysbiosis as a potential contributing factor to depressive symptoms.

Exploring the Gut Microbiome - Autism Spectrum Disorder Connection: Implications for Therapeutic Interventions and Future Directions

The gut microbiome, a diverse community of microorganisms in the gastrointestinal tract, is vital for human health and has a symbiotic relationship with the host. Autism spectrum disorder (ASD), a complex condition affecting social interaction, speech, and behavior, manifests early in life and affects 1 in 36 children globally. Research shows a significant link between the gut microbiome and ASD symptoms, with dysbiosis observed in individuals with ASD compared to neurotypical populations. Pathogenic gut microbiota can produce toxins that increase gut permeability, impair the intestinal barrier, and activate the immune system. The vagal nerve, influencing central nervous system (CNS) activity, can release peripheral cytokines inducing depression-like behaviors. Thus, dietary changes and treatments targeting the gut microbiota, such as Microbiota Transfer Therapy (MTT), offer promising methods for treating ASD symptoms. Current research focuses on dietary therapies like gluten-free and casein-free diets, ketogenic diets, and probiotics/prebiotics supplementation to modify the gut microbiota and enhance ASD treatment outcomes. However, more research is needed to fully understand the gut microbiota-ASD connection and establish evidence-based interventions. Individualized approaches are crucial for the safety and effectiveness of therapeutic strategies for ASD. Exploring the gut microbiome's role in ASD offers promising avenues for novel treatments and improved understanding of the disorder.

From Gut Microbiota to Brain Waves: The Potential of the Microbiome and EEG as Biomarkers for Cognitive Impairment.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and a leading cause of dementia. Aging is a significant risk factor for AD, emphasizing the importance of early detection since symptoms cannot be reversed once the advanced stage is reached. Currently, there is no established method for early AD diagnosis. However, emerging evidence suggests that the microbiome has an impact on cognitive function. The gut microbiome and the brain communicate bidirectionally through the gut-brain axis, with systemic inflammation identified as a key connection that may contribute to AD. Gut dysbiosis is more prevalent in individuals with AD compared to their cognitively healthy counterparts, leading to increased gut permeability and subsequent systemic inflammation, potentially causing neuroinflammation. Detecting brain activity traditionally involves invasive and expensive methods, but electroencephalography (EEG) poses as a non-invasive alternative. EEG measures brain activity and multiple studies indicate distinct patterns in individuals with AD. Furthermore, EEG patterns in individuals with mild cognitive impairment differ from those in the advanced stage of AD, suggesting its potential as a method for early indication of AD. This review aims to consolidate existing knowledge on the microbiome and EEG as potential biomarkers for early-stage AD, highlighting the current state of research and suggesting avenues for further investigation.

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

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β 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. 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. 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. 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. 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.

Advanced age worsens respiratory function and pulmonary inflammation after burn injury and this correlates with changes in the fecal microbiome in mice.

Cutaneous burn injury in the elderly is associated with poor clinical outcomes and increased pulmonary-related complications. We and others have shown that burn injury triggers a cascade of inflammatory mediators which increase gut permeability and dysbiosis of the fecal microbiota and this is more dramatic in the aged. Since cross-talk between intestinal microbes and the lung, termed the "gut-lung axis," impacts immunity and homeostasis in the airway, we hypothesized that the increased intestinal dysbiosis in age and burn injury may contribute to excessive pulmonary inflammation and poor prognosis after injury. To explore this hypothesis, we used a clinically relevant murine model of burn injury in which young and aged mice are subjected to a 12% total body surface area dorsal scald burn or sham injury. 24 hours after injury, lung function was assessed and lungs and feces were collected for analysis of inflammatory mediators and fecal microbial species. The results show that, when compared to younger mice, burn injury in aged mice triggers a decline in respiratory function and exacerbates pulmonary inflammation. In addition to heightened levels of the neutrophil recruiting chemokine CXCL1, aged mice displayed a profound increase in the pro-inflammatory protein, calprotectin, in the lung after burn injury. Comparison of the fecal microbiome and inflammatory markers in the lung revealed unique, age-dependent, correlation patterns between individual taxa and pulmonary inflammation. Taken together, these findings suggest that the post-burn dysbiosis of the gut flora in aged mice may contribute to the changes in pulmonary inflammatory profiles.

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes.

Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.