Alzheimer's disease (AD) -a progressive neurodegenerative disorder that is characterized by insidious cognitive decline and distinct neuropathological features- significantly impacts daily life functioning and behavior and is disproportionally prevalent in women compared to men. The reasons and risk factors for sex-based disparities in AD prevalence are still largely unclear, however early life exposures (e.g., education and stress) may be important contributing factors. Therefore, it is increasingly important to disentangle the complex interactions between known early environmental protective and risk factors and genetic susceptibility and uncover how these factors might impact and shape neurobiological processes. Moreover, it is critical to assess how these processes, in turn, influence later cognitive and brain health outcomes that may confer sex-specific pathways of risk for developing AD. In this paper we describe the rationale and study protocol for The Reducing Inequities through Social and Educational Change Follow-Up in Early Adulthood Extension (RISE-Up EA+; R01AG089426) study, a follow-up study of 300 participants aged 24-26 years old that leverages a natural quasi-experimental cohort to investigate how health outcomes tied to socioeconomic mobility opportunity may contribute to sex-specific vulnerability for developing AD later in life. To examine how sex-specific vulnerabilities related to early educational experiences may set the stage for later AD risk, we will assess self-report, cognitive, biological (e.g., inflammation and microbiome), and brain health measures. Results from this work provide the opportunity to better understand how adolescent mobility opportunities might contribute to later life health outcomes and influence sex-specific developmental pathways important for later AD risk.

Evidence suggests significant interindividual differences in stress reactivity (SR), but mechanisms and therapeutic implications of these differences are poorly understood. The aim of this study was to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of unprovoked tonic increased sympathetic nervous system (SNS) activation and neuroimaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). A cross-sectional study design, transcriptomics profiling, multimodal neuroimaging, and psychosocial assessments were obtained in 291 IBS participants and HCs. Unsupervised clustering was applied to derive high and low SR subgroups across all participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression. The high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Neuroplastic brain changes were observed in the high SR group consistent with an upregulation of ascending arousal systems, sensory processing and integration regions, and functional connectivity changes in the central autonomic network. In IBS, SR moderated sex differences in extraintestinal symptoms. The findings support a model of tonically increased, unprovoked SNS activity as a plausible risk factor for increased reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater likelihood in IBS. These findings may have important implications for personalized treatment interventions in IBS.

Cognitive impairment is increasing with global aging, yet mechanisms linking diet, the gut microbiome, and metabolism to cognitive function remain unclear. To investigate a diet-microbiome-metabolome axis associated with cognition, we integrated fecal metagenomics, diet, and multi-platform plasma metabolomics in 505 older adults from four ADRCs. Several microbes broadly associated with circulating metabolites were also linked to multiple measures of cognitive performance. These taxa exhibited coordinated metabolic signatures, with cognition-positive microbes associated with antioxidant, lipid, and microbial-host co-metabolites, and microbes negatively associated with cognition were linked to inflammatory and aromatic amino acid-derived metabolites. Dietary patterns, particularly the Healthy Eating Index Greens and Beans component, were associated with microbial composition and metabolomic structure. Mediation analyses supported a diet-microbe-metabolite-cognition pathway, while metabolites remained associated with cognition after accounting for microbial features. These findings highlight the metabolome as a central integrator of diet, microbial activity, and cognitive function.

Background Although the efficacy of mindfulness-based interventions for improvements in IBS symptoms has been demonstrated, the specific neural mechanisms contributing to these changes remain unclear.Methods A single arm interventional design was employed to explore functional brain network changes underpinning IBS symptom improvement in response to an 8-week mindfulness-based stress reduction (MBSR) intervention. Differences in brain resting state functional connectivity (RSFC) changes between 32 MBSR Responders and 16 Nonresponders with IBS after MBSR were computed using general linear models. An elastic-net regression model determined which RSFC changes were most impactful in determining MBSR responder status. Integrative association analyses elucidated the relationships between RSFC and symptom changes post MBSR.Key Results Following MBSR, Responders compared to Nonresponders showed large effect size decreases in IBS symptom severity and increased mindfulness. Responder status was associated with widespread changes in RSFC. In particular, decreases in the intrinsic connectivity of the default mode network along with decreased cognitive control-somatomotor network connectivity after MBSR contributed 56% variance explained in IBS symptom severity improvement. Decreases in these two connections were associated with extensive increases in connectivity between salience, default mode, somatomotor, control, and dorsal attention networks that were further linked to reductions in comorbid psychological symptoms.Conclusions and Inferences Overall, Responders compared to Nonresponders showed widespread RSFC changes suggesting a shift from a predominantly inward, ruminative focus to one characterized by more externally focused attention to the body and the environment. The results suggest that MBSR may improve IBS symptom severity via impact on the brain's RSFC.

PURPOSE: The brain-gut-microbiome (BGM) system encompasses a bidirectional communication network between the gut microbiome and the brain and plays a critical role in maintaining gut function and modulating behavior. Here, we specifically focus on the interactions between sensory over-responsivity (SOR), a common phenotype in Autism Spectrum Disorder (ASD), and the BGM system and discuss potential mechanisms underlying these interactions. METHODS: We examine key constructs and frameworks related to sensory processing, autism, and the BGM system, synthesize literature to identify knowledge gaps, and propose a model linking the BGM system and SOR in autism. RESULTS: Grounded in prior literature, we propose a conceptual model involving the brain, the gut microbiome, and SOR in autism. In this model sensory features of foods commonly associated with SOR contribute to atypical eating behaviors, resulting in differences in dietary intake, which in turn affect the gut and oral microbiomes. The gut microbiome can impact neural activity and brain structure via the connection between the gut and the brain, further contributing to SOR. CONCLUSION: The interdisciplinary nature of this topic is emphasized, bridging research from neuroscience, microbiology, pediatrics, nutrition, psychology, and occupational therapy/occupational science. Reflecting on the intersection of autism characteristics and microbiome health, this analysis offers critical insights for research and clinical practice.

The exposome factors, such as diet, lifestyle, microbiome, chemical exposures and social exposome, shapes human health beyond genetic influences, but the mechanisms remain only partially understood. Leveraging the Area Deprivation Index (ADI) of Neighborhood Atlas, a validated measure of the US social exposome, we derive molecular insights on how adverse social exposome (ASE) may impact cardiometabolic and brain health. Using complementary metabolomics platforms, we measured blood metabolome as readouts on net influences of exposome factors. Participants from six Alzheimer's disease research centers (n=449) were studied with generalizability confirmed in the UK Biobank using its harmonizable metric for ASE (n=380,943). Our results suggest that participants living in ASE have metabolic features often shown to predispose individuals to higher risks for cardiovascular diseases and cognitive decline, with impaired mitochondrial energetics, amino acid and lipid metabolism. Diet, microbiome and chemical exposures may contribute to these metabolic features. Molecular insights from metabolic signatures for ASE allows us to map potential modifiable risk factors that can impact and sustain health including brain health.

BACKGROUND:Brain age deviation is a promising neuroimaging biomarker of brain health, but its relevance in young and mid-life adults and its biological underpinnings remain insufficiently characterised. We aimed to test whether a functional-connectivity-derived brain ageing index (BAI) captures reproducible variability in early brain ageing and whether it is associated with cognitive-affective function and gut-derived biological signatures. METHODS:We analysed resting-state fMRI from a discovery cohort (n = 674) with validation in a replication cohort (n = 444) and an independent cohort (n = 344). Whole-brain functional connectivity was computed using a 100-region Schaefer parcellation, and Bayesian ridge regression was used to predict chronological age; BAI was defined as the age-bias-corrected residual (predicted brain age minus chronological age). We tested associations between BAI and cognitive and affective measures across cohorts. In the independent cohort, we applied multi-view sparse partial least squares to integrate stool metagenomic and metabolomic profiles with BAI, and performed KEGG pathway enrichment analyses on features with non-zero weights. FINDINGS:Predicted brain age correlated with chronological age across cohorts (r = 0.50-0.59). Higher BAI was consistently associated with connectivity patterns involving posterior cingulate/praecuneus and medial frontal regions, poorer cognitive performance, particularly working memory and executive function, and greater depressive symptoms. Multi-omics integration identified microbial taxa and stool metabolites, including ceramides, 24-hydroxycholesterol, dicarboxylic acids, and inverse associations with estetrol, linked to BAI. Enrichment analyses suggested involvement of neuroimmune, vascular, synaptic, and mitochondrial pathways. INTERPRETATION:A connectivity-derived BAI captures reproducible variability in early brain ageing and links large-scale brain network organisation to gut-derived biological signatures. These findings suggest that BAI captures individual variability associated with brain health-related phenotypes and support the potential association of peripheral brain-gut biological pathways in early brain ageing. FUNDING:National Institutes of Health, National Institute on Ageing.

While it has been suggested that alterations in the composition of gut microbial metabolites may play a causative role in the pathophysiology of autism spectrum disorder (ASD), it is not known how gut microbial metabolites are associated with ASD-specific brain alterations. In this cross-sectional, case-control observational study, (i) fecal metabolomics, (ii) task-based functional magnetic resonance imaging (fMRI), and (iii) behavioral assessments were obtained from 43 ASD and 41 neurotypical (NT) children, aged 8-17. The fMRI tasks used socio-emotional and sensory paradigms that commonly reveal strong evoked brain differences in ASD participants. Our results show that fecal levels of specific tryptophan-related metabolites, including kynurenate, were significantly lower in ASD compared to NT, and were associated with: 1) alterations in insular and cingulate cortical activity previously implicated in ASD; and 2) ASD severity and symptoms (e.g., ADOS scores, disgust propensity, and sensory sensitivities). Moreover, activity in the mid-insula and mid-cingulate significantly mediated relationships between the microbial tryptophan metabolites (indolelactate and tryptophan betaine) and ASD severity and disgust sensitivity. Thus, we identify associations between gut microbial tryptophan metabolites, ASD symptoms, and brain activity in humans, particularly in brain regions associated with interoceptive processing.

OBJECTIVE:This study examined the impact of high levels of ongoing stress on responses to acute stress and cognitive challenge. We used a multimeasure approach to define the stress groups and to test multiple facets of the acute stress response, including mood, emotional arousal, autonomic responses, cognitive flexibility, and plasma metabolites. METHODS:Fifty healthy women designated as high stress (HS) based on the above threshold scores on a measure of perceived stress and current anxiety were compared with 50 women with low stress (LS) on both measures. Psychological, autonomic nervous system, and plasma metabolite assessments were obtained before, during, and after exposure to multiple tasks, including viewing affective pictures, performing stressful mental arithmetic, and figure-ground discrimination. RESULTS:The HS group showed a greater increase in negative affect when challenged with a laboratory stressor [b(SE) = 1.78, p < .001] and in response to neutral affective pictures (d = 0.41, p = .040); this same group showed overall less sympathetic arousal than the LS group during a mental arithmetic challenge [b(SE) = 0.28, p = .034]. The HS group had a higher plasma metabolite tryptophan/kynurenine ratio than the LS group at baseline, but this did not change with stress. CONCLUSIONS:Increased negative psychological responses to both a psychological challenge and neutral affective pictures suggest that high-stress individuals process everyday challenging stimuli more negatively. Combined with the blunted ANS responses and potentially altered microbiome, this pattern suggests this high-stress responsive group, while currently healthy, may be at risk for biological stress-related morbidity in the immune, cardiovascular, or pain modulation systems.

BackgroundAlterations in the gastrointestinal (GI) microbiome (i.e., dysbiosis) are a feature of systemic sclerosis (SSc). Diet is a known modifier of the GI microbiome, and ultra-processed food (UPF) consumption has been associated with adverse changes in GI microbial composition. This study aimed to determine whether UPF consumption affects the GI microbiota and GI symptoms in patients with SSc.MethodsAdult SSc patients provided stool samples and completed both the Diet History Questionnaire II (DHQ-2) and the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (GIT 2.0). Shotgun metagenomics were performed using the Illumina NovaSeq 6000 with a target depth of 10 million 150x2 sequences per sample. UPF items (N=54) on the DHQ-2 were identified using the NOVA scale of food classification, and UPF intake was calculated as gram-per-week consumption according to patient reported frequency. General linear models were created to identify differentially abundant species based on UPF consumption and to evaluate the relationship between UPF consumption and GI symptoms as measured by the GIT 2.0. These models adjusted for body mass index (BMI), current proton pump inhibitor (PPI) use, current probiotic use, current or prior immunomodulatory therapy, and presence of small intestinal bacterial overgrowth (SIBO).ResultsOf the 65 total SSc patients included, 84.6% were female. The mean age was 53.83 ± 13.19 years, and the mean BMI was 25.25 ± 4.75. The median UPF consumption was 2395.82 g/week. Increased UPF consumption was significantly associated with increased GI symptoms in our multivariate model (β=0.34; p<0.01). Among 257 species analyzed, 5 bacterial species were significantly associated with UPF consumption in the multivariate models, including Limosilactobacillus fermentum (β=0.32; p<0.01) and Faecalicatena fissicatena (β= -0.36; p-value<0.01), while the abundance of 6 bacterial species was significantly associated with GI symptom severity after adjusting for the aforementioned covariates.ConclusionsSSc patients reporting a higher UPF consumption demonstrated alterations in GI microbial composition as well as increased GI symptoms, even after adjusting for factors known to affect the microbiota of patients with SSc. Future studies are needed to determine whether interventions aimed at lowering UPF consumption may improve GI outcomes for patients with SSc.

Bile acids (BA) are steroids regulating nutrient absorption, energy metabolism, and mitochondrial function, and serve as important signaling molecules with a role in the gut-brain axis. The composition of BAs in humans changes with diet type and health status, which is well documented with a few known bile acids. In this study, we leveraged a new BA-specific spectral library curated in the Dorrestein lab at UCSD to expand the pool of detected BAs in Alzheimer-related LC-MS/MS datasets and provide links to dietary profiles and AD markers. Fecal untargeted metabolomics (LC-MS/MS) data from the ADRC cohort was analyzed using GNPS-based molecular networking. Spectral matching and annotation were performed using the BA-specific spectral library which consists of 21,549 BA spectra, with many previously undiscovered candidates. We obtained spectral matches to 113 BAs with 108 matches to new candidate BAs from our library. Further, using the score for delayed recall of Benson figure (UDSBENTD), peak areas of the BAs were plotted with the amyloid status. For diet readout, spectral match to a food database (“global foodomics”) was performed, and correlation with BAs was obtained by joint-RPCA analysis. The joint-RPCA analysis yielded many di-, tri-, and tetrahydroxylated BAs among the top 20 features guiding the separation in the ADRC samples (Figure 1a). From diet, meat, fish, and fruits were among the top features, with meat and fish vectors pointing in the opposite direction as grapes, onions, and lettuce. Peak area-based levels of a candidate tetrahydroxylated BA, which was among the top 20 features, changed with the amyloid status measured with the UDSBENTD (Figure 1b). The spectral count of vegetables and dairy also increased in amyloid-positive samples. However, the spectral counts related to meat and poultry products did not change significantly with amyloid status, implying a potential vegetable-based diet impacting the change in some BA levels. Previously unknown BAs are correlated to diet and AD markers in the ADRC cohort. This study highlights the importance of expanding our metabolite annotations, in this case with BAs, and performing integrative analysis with diet to aid our understanding of AD progression.