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PubMed1997

Tissue factor pathway inhibitor (TFPI) antigen plasma level in patients with interstitial lung disease before and after heparin administration.

The extrinsic pathway is probably the predominant pathway in initiating blood coagulation in inflammatory lung diseases. Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor of factor VIIa/tissue factor in the presence of factor Xa. As it has been shown recently that TFPI plasma levels are increased under acute inflammatory conditions, we studied TFPI antigen plasma levels before and after injecting 20 IU/kg body weight of unfractionated heparin into 49 patients with different stages of sarcoidosis, into 9 with idiopathic pulmonary fibrosis, and into 15 normal controls. TFPI, before injecting heparin, was significantly increased in all sarcoidosis stages (stage I: 97.6 +/- 6.4 ng/mL; stage II: 116.2 +/- 11.9 ng/mL; stage III: 116.3 +/- 7.3 ng/mL) and in idiopathic pulmonary fibrosis (116.8 +/- 16.1 ng/mL), as compared to the control group (77.7 +/- 3.3 ng/mL). No correlation was found between the intensity of the activity of sarcoidosis, measured as BAL white cell count, and TFPI. Five minutes after heparin administration the rise in TFPI was lower, although not statistically significant, in all sarcoidosis stages than in controls. In contrast, idiopathic pulmonary fibrosis had a similar or even higher TFPI elevation than the control group. In sarcoidosis the elevated TFPI and the lower capacity by endothelial cells to release TFPI after heparin may represent a compensatory mechanism to prevent blood clotting and/or the endothelial cell dysfunction of the microvasculature in this condition. In contrast, the extensive mesenchymal cell proliferation present in idiopathic pulmonary fibrosis could explain our findings, as it has been shown that cultured human mesangial cells produce and release TFPI.

Adult↗
PubMed2004

Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases.

In the last decade, it has become recognized that reactive oxygen species (ROS) play important roles in the multiple biological processes involved in the pathophysiology of chronic inflammation such as cell proliferation, adhesion molecule expression, cytokine and chemoattractant production and matrix metalloproteinase generation. Intracellular redox homeostasis is maintained by balancing the production of ROS with their removal through cellular antioxidant defense systems. The antioxidant response element (ARE) is a cis-acting DNA regulatory element located in the regulatory regions of multiple genes including phase II detoxification enzymes as well as antioxidant proteins including glutathione-S-transferases, NAD(P)H:quinone oxidoreductase-1, gamma-glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is the primary transcription factor that binds to the ARE, and through heterodimerization with other leucine-zipper containing transcription factors, activates the expression of these genes. It is evident that activation of ARE-regulated genes contributes to the regulation of cellular antioxidant defense systems. More importantly, there is a growing body of evidence suggesting that modulation of these cytoprotective genes has profound effects on immune and inflammatory responses. Activation of cytoprotective Nrf2/ARE-regulated genes can suppress inflammatory responses, whereas decreased expression of these genes results in autoimmune disease and enhanced inflammatory responses to oxidant insults. Thus, coordinate induction of cytoprotective genes through Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of immune and inflammatory diseases.

Antioxidants↗
PubMed2006

[Inflammatory response and haematological disorders in cardiac surgery: toward a more physiological cardiopulmonary bypass].

The systemic inflammatory response in cardiac surgery is closely related to the haemostasis disturbances. It is responsible of a significant morbidity and mortality that was previously suspected to be caused by cardiopulmonary bypass alone. However, it is time now to clearly identify the factors that are material-dependent from that material-independent. From this point of view, off-pump surgery allowed for better comprehension of the multiple sources of the inflammatory response. Numerous pathways are activated, involving complement, platelets, neutrophiles and monocytes. The tissue pathway of the coagulation system, through tissue factor, is of major importance and has to be surgically considered in order to reduce the whole body inflammatory response postoperatively. The quality of the extracorporeal perfusion through its consequences on organ perfusion, particularly in the splanchnic area, also participates to this pathophysiological process. Beyond the progress of technology provided by the industry, particularly the minimally extracorporeal circulation derived from off-pump surgery evolution, the surgical approach is of major importance in the control of the systemic inflammatory response and must not be ignored yet.

Anesthetics↗
PubMed2026

Prenatal Alcohol Exposure Produces Selective Changes in Neuroimmune Gene Expression Across Brain Regions of Adult Mice.

BACKGROUND: An overwhelming body of evidence suggests neuroimmune dysfunction as a key underlying mechanism of fetal alcohol spectrum disorder (FASD)-associated adverse central nervous system (CNS) outcomes. While few studies have highlighted the lingering effects of prenatal alcohol exposure (PAE) on producing specific immune factors, others suggest a primed neuroimmune state in adulthood, in which a proinflammatory bias is unmasked following subsequent immune activation in later life. However, the PAE-induced neuroimmune landscape in adulthood remains poorly defined. We hypothesized that PAE induces long-term changes in gene expression linked to neuroimmune function that may be brain region-specific. METHODS: Using long-read next-generation RNA sequencing of brain tissues from a previously established model of a moderate PAE in mice, we compared across six regions: medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hypothalamus, hippocampus, midbrain, and medulla. A comprehensive bioinformatics analysis investigated PAE-induced changes, dysregulated gene pathways, and transcriptional regulators with a focus on neuroimmune function. RESULTS: Our data identified at least 60 differentially expressed genes per brain region, many of which were associated with neuroimmune function. Upregulation of multiple pro-inflammatory factors and pathways was observed, suggesting ongoing baseline neuroimmune activation, potentially involving PXR, TNF, TLR4, the complement pathway, and various cytokine and chemokine signaling. A comparative analysis identified multiple upstream transcriptional regulators across multiple brain regions, including MECP2, TCF7L2, and IL-4. Importantly, this unbiased analysis revealed heterogeneity across brain regions in the activation of canonical immune pathways and highlighted previously unprecedented roles of pathways such as PXR, matrix metalloproteases, and cytokine signaling (e.g., IL-15, IL-27, IL-17) in PAE. CONCLUSIONS: PAE creates a unique inflammatory signature in the adult brain, even in the absence of secondary injury, with novel patterns of region-specific changes in genes implicated in glial-immune function. These data identify potential immune targets to elucidate the mechanisms underlying behavioral dysfunction and provide a framework for future therapeutic interventions.

Animals↗
PubMed2006

Thiazolidinediones : beyond glycemic control.

Our knowledge and understanding of the role played by peroxisome proliferator-activated gamma receptors in physiology and pathophysiology has expanded dramatically over the past 5 years. Originally described as having important functions in adipogenesis and glucose homeostasis, their pharmacologic agonists, the thiazolidinediones, were introduced as antihyperglycemic, insulin-sensitizing agents for the management of type 2 diabetes mellitus. However, it was to some degree inevitable that the thiazolidinediones would be rapidly recognized as having vasculoprotective properties beyond glycemic control that might also be beneficial. First, diabetic complications are vascular in nature, the earliest feature of these is endothelial dysfunction. Second, it is being increasingly appreciated that these complications develop through inflammatory and procoagulant pathways in which increased oxidative stress is considered a major etiologic mechanism, and which are closely linked to the presence of insulin resistance, visceral obesity, and hyperglycemia. Early appreciation that the thiazolidinediones have antioxidant, anti-inflammatory, anti-procoagulant, and antiproliferative properties in addition to their insulin-sensitizing, anti-lipotoxic properties created a marriage of investigative pathways that has not only led to a very large body of literature on the pleiotropic effects of thiazolidinediones, but also to the development of new understandings of the connections between insulin resistance, obesity, and hyperglycemia and the onset of vascular disease. Understandably, most of the focus has been directed at the macrovascular complications of diabetes, since these are the major causes of morbidity and mortality in this population. However, there is evidence that these agents may have benefits for the microvascular complications as well, and their potential role for cardiovascular disease prevention in non-diabetic patients with the metabolic syndrome is a logical extension of the work performed in diabetes. The recently reported results of the effects of pioglitazone versus placebo on cardiovascular events in patients with type 2 diabetes support the contention that these agents have vasculoprotective effects.

Blood Glucose↗
PubMed2000

Lipopolysaccharide induces jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C zeta and phosphatidylcholine-dependent phospholipase C.

The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) zeta activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCzeta regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.

Androstadienes↗
PubMed1990

Pharmacologic modulation of acute uveitis with aminonicotinamide.

The hexose monophosphate shunt inhibitor 6-aminonicotinamide was observed to have an anti-inflammatory effect in the treatment of experimental uveitis. The electrons required for the reduction of molecular oxygen to superoxide radicals are generated by the pentose phosphate pathway in acute inflammatory cells. The inhibition of superoxide production is discussed as one of the potential antiphlogistic mechanisms.

6-Aminonicotinamide↗
PubMed2002

Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli.

The production of IL-12 is required for immunity to many intracellular pathogens. Recent studies have shown that c-Rel, a member of the NF-kappaB family of transcription factors, is essential for LPS-induced IL-12p40 production by macrophages. In this study, we demonstrate that c-Rel is also required for IL-12p40 production by macrophages in response to Corynebacterium parvum, CpG oligodeoxynucleotides, anti-CD40 and low molecular weight hyaluronic acid. However, c-Rel(-/-) mice infected with Toxoplasma gondii produce comparable amounts of IL-12p40 to infected wild-type mice and have an IL-12-dependent mechanism of resistance to this infection. Furthermore, c-Rel was not required for IL-12p40 production by macrophages or dendritic cells in response to soluble Toxoplasma Ag, and neutrophils from c-Rel(-/-) mice contain normal amounts of preformed IL-12p40. Together these studies reveal the presence of c-Rel-dependent pathways critical for IL-12p40 production in response to inflammatory stimuli and demonstrate a novel c-Rel-independent pathway of IL-12p40 production during toxoplasmosis.

Animals↗
PubMed2005

Advances in understanding adenosine as a plurisystem modulator in sepsis and the systemic inflammatory response syndrome (SIRS).

Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.

Adenosine↗
PubMed2005

Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1beta and IL-6 production.

We have found previously that phosphatidic acid (PA) can induce inflammatory mediators such as cytokines, which implies that PA plays a role in inflammatory response. In the present study, we provide evidence of the PA-mediated activation of the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which results in the production of interleukin (IL)-1beta and IL-6. PA elicited the rapid phosphorylations of JAK2 and STAT1/3, and the subsequent nuclear translocation. Macrophages that had been transiently transfected with a luciferase reporter construct containing eight consecutive gamma-interferon activating sequence (GAS) elements, a known STAT binding site, exhibited enhanced reporter gene activity in response to PA stimulation, which further supports the involvement of JAK-STAT activation in the PA-induced signaling pathway. Of the inflammatory cytokines, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha were detected in media from macrophages stimulated with PA. Moreover, the JAK2 inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490) abolished PA-induced IL-1beta and IL-6 release but not TNF-alpha production, which is consistent with the notion that IL-1beta and IL-6 but not TNF-alpha contain a STAT binding element in their promoter region. The knockdown of JAK2 in macrophages by small interfering RNA significantly attenuated PA-induced IL-1beta and IL-6 production. In addition, JAK2 inhibitor suppressed PA-induced Akt phosphorylation, and the Akt inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) blocked GAS activation (GAS contains a promoter that responds to PA), suggesting that PA-mediated JAK2 activation leads to phosphatidylinositol 3-kinase/Akt phosphorylation and STAT activation, and the subsequent translocation of STAT to the nucleus. Together, our data demonstrate that PA-activated macrophages produce IL-1beta and IL-6 and that these processes require the activation of the JAK2-STAT1/3 or JAK2-Akt-STAT signaling pathways.

Active Transport, Cell Nucleus↗
PubMed2001

Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway.

Caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. Here, we cloned the rat homolog of caspase-11, and investigated its inducibility by inflammatory stimuli and signal transduction pathways involved. Deduced amino acid sequence of rat caspase-11 showed 88.7% similarity to mouse caspase-11, and in vitro translation of rat caspase-11 cDNA yielded approximately a 43 kDa polypeptide, which was in agreement with predicted protein size generated from full-length rat caspase-11 cDNA. The expression of caspase-11 was strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumor necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes. LPS induced activation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) in C6 cells. However, SB203580 (specific inhibitor of p38 kinase), but not PD98059 (specific inhibitor of ERK kinase), inhibited LPS induction of caspase-11, indicating that induction of caspase-11 by LPS in astrocytes was mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites.

Amino Acid Sequence↗
PubMed2005

Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis.

OBJECTIVE: Clinical, pharmacologic, and epidemiologic evidence supports the hypothesis that common genetic pathways may underlie inflammatory diseases. In a previous study, a Crohn's disease gene, CARD15, was demonstrated to be associated with psoriatic arthritis (PsA). Recently, a functional haplotype of 2 single-nucleotide polymorphisms (SNPs) mapping to the organic cation transporter (OCTN) genes, SLC22A4 and SLC22A5, was identified as a second Crohn's disease susceptibility locus. The SLC22A4 gene has also been associated with rheumatoid arthritis. This study was undertaken to further elucidate associations of PsA with Crohn's disease susceptibility genes. METHODS: Association with CARD15 and OCTN was investigated in UK Caucasian patients with PsA (n = 472) and population controls (n = 594), using 5' allelic discrimination assays (TaqMan). Two SNPs in OCTN, forming a haplotype previously associated with Crohn's disease, were also tested in patients with psoriasis (n = 218) and patients with early undifferentiated inflammatory arthritis (n = 386). Allele and estimated haplotype frequencies were compared between patients and controls. RESULTS: No association of PsA with CARD15 was detected. In contrast, a functional SNP mapping to the promoter region of SLC22A5 (rs2631367) was associated with PsA (for CC versus GG, odds ratio 1.65, 95% confidence interval 1.13-2.41, uncorrected P = 0.005). In addition, the haplotype associated with Crohn's disease was also associated with PsA (P = 0.001). No association was detected in the cohort with psoriasis alone or in the cohort with undifferentiated inflammatory arthritis. CONCLUSION: The OCTN haplotype previously associated with Crohn's disease is also associated with PsA, suggesting that these 2 diseases may share some common genetic control in pathways of inflammation.

Adolescent↗
PubMed1998

Hypoxia stimulates the synthesis of cytochrome P450-derived inflammatory eicosanoids in rabbit corneal epithelium.

The corneal epithelium metabolizes arachidonic acid by a cytochrome P450-(CYP) mediated pathway to 12(R)hydroxy-5,8,10,14-eicosatrienoic acid [12(R)-HETE] and 12(R)hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE]. Both metabolites possess potent inflammatory properties with 12(R)-HETrE being a powerful angiogenic factor and assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea, in vivo. We developed an in vitro model of corneal organ culture to characterize the biochemical and molecular events involved in the increased synthesis of these metabolites. These cultured corneas exhibit epithelial cytochrome P450 CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis as indicated by chiral analysis and by the ability of CYP enzyme inhibitors to repress their synthesis. Hypoxia greatly and selectively stimulated the synthesis of 12(R)-HETE (7-fold over control normoxic conditions) and 12(R)-HETrE. The bacterial endotoxin, lipopolysaccharide, also increased the synthesis of these eicosanoids, substantiating the notion that this activity may function as an inflammatory pathway. These metabolites were detected in the culture medium by gas chromatography/mass spectroscopy (GC/MS) analysis and their levels significantly increased in hypoxia-treated corneas, further indicating their endogenous formation in response to injury. This in vitro model provides an excellent preparation for studying factors regulating the synthesis of these inflammatory eicosanoids and for isolating, identifying and characterizing the CYP protein responsible for their synthesis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2002

From extracellular to intracellular targets, inhibiting MAP kinases in treatment of Crohn's disease.

In recent years the emphasis in finding new therapeutic options for chronic inflammatory diseases has been on targeting extracellular mediators of inflammation. A range of tools has become available to interfere with signaling by cytokines and their receptors. As our understanding of the intracellular pathways that mediate inflammatory signals expands, new therapeutic targets within the inflammatory cells come into sight. In this review we will discuss possible intracellular targets for treatment in Crohn's disease, a chronic relapsing inflammatory disease of the gut. Despite the encouraging results with anti-TNF antibodies in patients with Crohn's disease, our current treatment options are still insufficient and warrant novel treatment strategies. The mitogen-activated protein kinase (MAPK) family of signal transduction proteins is an important intracellular mediator of inflammation, and recently a MAPK inhibitor was successfully used in patients with Crohn's disease. We will discuss our current understanding of the molecular pathophysiology of Crohn's disease and also novel therapies that specifically target members of the MAPK pathway.

Crohn Disease↗
PubMed2004

Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.

Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for alpha-smooth muscle actin, collagen I, and fibronectin EDA(+) (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased. cDNA microarray analysis was used to identify other changes in gene expression that might point to novel molecular mechanisms driving EMT. Of 1176 array genes, 61 demonstrated at least a twofold change at at least two consecutive time points, of the five time points examined (0.5, 4, 8, 16, and 48 h). Of these genes, 59% were upregulated and 41% were downregulated. The array indicated upregulation of expression of the oncostatin M (OSM)-specific receptor beta subunit from 4 to 48 h after exposure of kidney epithelial cells to activated PBMC conditioned medium, which contained high levels of OSM. In additional experiments, it was demonstrated that OSM induced EMT. OSM activated the Jak/Stat signaling pathway in epithelial cells, and a specific inhibitor of Jak2 blocked both its phosphorylation after exposure to OSM and the induction of alpha-actin and loss of cytokeratin 19 expression. Therefore, OSM is a novel inducer of EMT and is likely to be one of several cytokines produced by inflammatory infiltrates that contribute to this and subsequent tubulointerstitial fibrosis.

Cell Differentiation↗
PubMed2003

Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression.

INTRODUCTION: In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution. METHOD: Affymetrix microarrays, representing 8618 genes, were used to compare mammary tissue from 12 time points (one virgin, three gestation, three lactation and five involution stages). Six animals were used for each time point. Common patterns of gene expression across all time points were identified and related to biological function. RESULTS: The majority of significantly induced genes in involution were also differentially regulated at earlier stages in the pregnancy cycle. This included a marked increase in inflammatory mediators during involution and at parturition, which correlated with leukaemia inhibitory factor-Stat3 (signal transducer and activator of signalling-3) signalling. Before involution, expected increases in cell proliferation, biosynthesis and metabolism-related genes were observed. During involution, the first 24 hours after weaning was characterized by a transient increase in expression of components of the death receptor pathways of apoptosis, inflammatory cytokines and acute phase response genes. After 24 hours, regulators of intrinsic apoptosis were induced in conjunction with markers of phagocyte activity, matrix proteases, suppressors of neutrophils and soluble components of specific and innate immunity. CONCLUSION: We provide a resource of mouse mammary gene expression data for download or online analysis. Here we highlight the sequential induction of distinct apoptosis pathways in involution and the stimulation of immunomodulatory signals, which probably suppress the potentially damaging effects of a cellular inflammatory response while maintaining an appropriate antimicrobial and phagocytic environment.

Acute-Phase Reaction↗
PubMed2026

Gut microbiome composition and predicted functions relate to growth and behavior in a Japanese preschool cohort.

Early childhood is a period of rapid brain maturation and gut microbiome assembly, when emerging behavioral difficulties can shape later mental health and learning trajectories. Microbiota-gut-brain communication has been implicated in neurodevelopment through microbial metabolites and immune signaling. However, most pediatric evidence comes from high-risk or clinically referred cohorts, and gut microbiome-related correlates of typical behavioral variation in community-based preschool children remain poorly defined. In a cross-sectional sample of typically developing Japanese preschool children, we observed exploratory nominal associations between behavioral variation within normative ranges and gut microbiome composition and predicted functions. Internalizing domains showed candidate links with taxa and predicted pathways related to inflammatory potential and nucleotide biosynthesis, whereas somatic complaints and withdrawn behavior showed nominal associations with lower predicted respiratory and fermentative activity. Sleep-related difficulties showed multiple representative nominal pathway-level associations, including pathways related to methyl-donor and heme biosynthesis, while externalizing domains showed candidate links with predicted cell-envelope and carbohydrate-remodeling pathways. In contrast, age, height, and weight tracked expected maturation-related microbiome features, indicating that behavioral associations were not simple proxies of growth. Together, these findings provide an exploratory profile of microbiome-behavior correlations in a low-risk Japanese preschool cohort and highlight pathway-level candidates that may interface with neurodevelopment.

Humans↗