Brain, Behavior, and Immunity最新文献

{"title":"Constitutive DAMPs in CNS injury: From preclinical insights to clinical perspectives","authors":"","doi":"10.1016/j.bbi.2024.07.047","DOIUrl":"10.1016/j.bbi.2024.07.047","url":null,"abstract":"<div><p>Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124005750/pdfft?md5=8a4c9751a130a31e2609d7a58f6ff315&pid=1-s2.0-S0889159124005750-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate","authors":"","doi":"10.1016/j.bbi.2024.08.057","DOIUrl":"10.1016/j.bbi.2024.08.057","url":null,"abstract":"<div><p>Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [¹⁸F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124005889/pdfft?md5=653e620c777dfb371d810dea863a1e0c&pid=1-s2.0-S0889159124005889-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of cytokines in acute and chronic postsurgical pain after major musculoskeletal surgeries in a quaternary pediatric center","authors":"","doi":"10.1016/j.bbi.2024.08.056","DOIUrl":"10.1016/j.bbi.2024.08.056","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Study Objective&lt;/h3&gt;&lt;p&gt;To determine if baseline cytokines/chemokines and their changes over postoperative days 0–2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Design&lt;/h3&gt;&lt;p&gt;Prospective, observational, longitudinal nested study.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Setting&lt;/h3&gt;&lt;p&gt;University-affiliated quaternary children’s hospital.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Patients&lt;/h3&gt;&lt;p&gt;Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Measurements&lt;/h3&gt;&lt;p&gt;Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score &gt; 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Main Results&lt;/h3&gt;&lt;p&gt;Analyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5–17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (β = 0.95, SE 0.31; &lt;em&gt;p&lt;/em&gt; = 0.003), IL-1β (β = 0.84, SE 0.36; &lt;em&gt;p&lt;/em&gt; = 0.02), IL-2 (β = 0.78, SE 0.34; &lt;em&gt;p&lt;/em&gt; = 0.03), and IL-12 p70 (β = 0.88, SE 0.40; &lt;em&gt;p&lt;/em&gt; = 0.03) and longitudinal postoperative elevations in GM-CSF (β = 1.38, SE 0.57; &lt;em&gt;p&lt;/em&gt; = 0.03), IFNγ (β = 1.36, SE 0.6; &lt;em&gt;p&lt;/em&gt; = 0.03), IL-1β (β = 1.25, SE 0.59; &lt;em&gt;p&lt;/em&gt; = 0.03), IL-7 (β = 1.65, SE 0.7; &lt;em&gt;p&lt;/em&gt; = 0.02), and IL-12 p70 (β = 1.17, SE 0.58; &lt;em&gt;p&lt;/em&gt; = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (β = -0.39, SE 0.17; &lt;em&gt;p&lt;/em&gt; = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (β = -0.57, SE 0.26; &lt;em&gt;p&lt;/em&gt; = 0.03), IL-8 (β = -0.68, SE 0.24; &lt;em&gt;p&lt;/em&gt; = 0.006), and IL-13 (β = -0.48, SE 0.22; &lt;em&gt;p&lt;/em&gt; = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;We identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accentuate the positive: Cultivating positive affect during treatment for stimulant use disorder can regulate the immune system","authors":"","doi":"10.1016/j.bbi.2024.08.058","DOIUrl":"10.1016/j.bbi.2024.08.058","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Herpes simplex virus type 1, dorsal root ganglia and fibromyalgia","authors":"","doi":"10.1016/j.bbi.2024.08.052","DOIUrl":"10.1016/j.bbi.2024.08.052","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia depletion and repopulation do not alter the effects of cranial irradiation on hippocampal neurogenesis","authors":"","doi":"10.1016/j.bbi.2024.08.055","DOIUrl":"10.1016/j.bbi.2024.08.055","url":null,"abstract":"<div><p>Cranial radiotherapy can cause lifelong cognitive complications in childhood brain tumor survivors, and reduced hippocampal neurogenesis is hypothesized to contribute to this. Following irradiation (IR), microglia clear dead neural progenitors and give rise to a neuroinflammatory microenvironment, which promotes a switch in surviving progenitors from neuronal to glial differentiation. Recently, depletion and repopulation of microglia were shown to promote neurogenesis and ameliorate cognitive deficits in various brain injury models. In this study, we utilized the <em>Cx3cr1^{CreERt2-YFP/+}Rosa26^DTA</em>^/+ transgenic mouse model to deplete microglia in the juvenile mouse brain before subjecting them to whole-brain IR and investigated the short- and long-term effects on hippocampal neurogenesis. Within the initial 24 h after IR, the absence of microglia led to an accumulation of dead cells in the subgranular zone, and 50-fold higher levels of the chemokine C-C motif ligand 2 (CCL2) in sham brains and 7-fold higher levels after IR. The absence of microglia, and the subsequent repopulation within 10 days, did neither affect the loss of proliferating or doublecortin-positive cells, nor the reduced growth of the granule cell layer. Our results argue against a role for a pro-inflammatory microenvironment in the dysregulation of hippocampal neurogenesis and suggest that the observed reduction of neurogenesis was solely due to IR.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124005762/pdfft?md5=93be78c394653e79229af753b68f8f36&pid=1-s2.0-S0889159124005762-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can you outrun a headache?","authors":"","doi":"10.1016/j.bbi.2024.08.037","DOIUrl":"10.1016/j.bbi.2024.08.037","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping prenatal predictors and neurobehavioral outcomes of an epigenetic marker of neonatal inflammation – A longitudinal population-based study","authors":"","doi":"10.1016/j.bbi.2024.08.053","DOIUrl":"10.1016/j.bbi.2024.08.053","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for − or offspring outcomes of − elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;MPS-CRP at birth was validated with serum CRP in cord blood (cut-off &gt; 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., &lt; 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the ","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124005798/pdfft?md5=863bb4f20812a15630ccc2a067631737&pid=1-s2.0-S0889159124005798-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis","authors":"","doi":"10.1016/j.bbi.2024.08.044","DOIUrl":"10.1016/j.bbi.2024.08.044","url":null,"abstract":"<div><h3>Background</h3><p>Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation.</p></div><div><h3>Study design and settings</h3><p>A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated.</p></div><div><h3>Results</h3><p>Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: &gt;4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline.</p></div><div><h3>Conclusions and relevance</h3><p>In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival.</p></div><div><h3>Trial registration</h3><p>Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> number NCT03456882.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome-derived indole-3-lactic acid reduces amyloidopathy through aryl-hydrocarbon receptor activation","authors":"","doi":"10.1016/j.bbi.2024.08.051","DOIUrl":"10.1016/j.bbi.2024.08.051","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) pathogenesis has been associated with the gut microbiome and its metabolites, though the specific mechanisms have remained unclear. In our study, we used a multi-omics approach to identify specific microbial strains and metabolites that could potentially mitigate amyloidopathy in 5xFAD mice, a widely used model for AD research. Among the microbial strains tested, three showed promising results in reducing soluble amyloid-beta (Aβ) levels. Plasma metabolomics analysis revealed an enrichment of tryptophan (Trp) and indole-3-lactic acid (ILA) in mice with reduced soluble Aβ levels, suggesting a potential preventative role. The administration of a combined treatment of Trp and ILA prevented both Aβ accumulation and cognitive impairment in the 5xFAD mice. Our investigation into the mechanism revealed that ILA’s effect on reducing Aβ levels was mediated through the activation of microglia and astrocytes, facilitated by the aryl hydrocarbon receptor (AhR) signaling pathway. These mechanisms were verified through experiments in 5xFAD mice that included an additional group with the administration of ILA alone, as well as in vitro experiments using an AhR inhibitor. Clinical data analysis revealed a greater abundance of <em>Lactobacillus reuteri</em> in the gut of healthy individuals compared to those at early stages of Aβ accumulation or with mild cognitive impairment. Additionally, human post-mortem brain analyses showed an increased expression of genes associated with the AhR signaling pathway in individuals without AD, suggesting a protective effect against AD progression. Our results indicate that ILA from gut microbes could inhibit the progression of amyloidopathy in 5xFAD mice through activation of AhR signaling in the brain.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}