Gut Microbiome Compositional and Functional Features Associate with Alzheimer's Disease Pathology.

BACKGROUND: The gut microbiome is a potentially modifiable factor in Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited. METHODS: Shallow-shotgun metagenomic data was used to analyze fecal microbiome from participants enrolled in the Wisconsin Microbiome in Alzheimer's Risk Study, leveraging clinical data and cerebrospinal fluid (CSF) biomarkers. Differential abundance and ordinary least squares regression analyses were performed to find differentially abundant gut microbiome features and their associations with CSF biomarkers of AD and related pathologies. RESULTS: Gut microbiome composition and function differed between people with AD and cognitively unimpaired individuals. The compositional difference was replicated in an independent cohort. Differentially abundant gut microbiome features were associated with CSF biomarkers of AD and related pathologies. DISCUSSION: These findings enhance our understanding of alterations in gut microbial composition and function in AD, and suggest that gut microbes and their pathways are linked to AD pathology.

Differential brainstem connectivity according to sex and menopausal status in healthy men and women.

Background Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus (DRN), right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants. Methods Resting-state fMRI was performed in 50 healthy men (age, 31.2 ± 8.0 years), 53 healthy premenopausal women (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal women (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 men and 17 women (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis. Results Left LCC-executive control network (ECN) connectivity showed an overall sex difference (p = 0.02), with higher connectivity in women than in men; however, this was mainly due to differences between men and pre-menopausal women (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal women than in men (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal women than in men (p = 0.03) and postmenopausal women (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal women (p < 0.01). Conclusions Healthy women show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than men, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal women. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.

IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional brain changes.

Background & Aims: Clinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood. We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). Methods: A cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across 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. Results: 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. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms. Conclusions: The findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.

Early life adversity impacts alterations in brain structure and food addiction in individuals with high BMI.

Obesity and food addiction are associated with distinct brain signatures related to reward processing, and early life adversity (ELA) also increases alterations in these same reward regions. However, the neural mechanisms underlying the effect of early life adversity on food addiction are unknown. Therefore, the aim of this study was to examine the interactions between ELA, food addiction, and brain morphometry in individuals with obesity. 114 participants with high body mass index (BMI) underwent structural MRIs, and completed several questionnaires (e.g., Yale Food Addiction Scale (YFAS), Brief Resilience Scale (BRS), Early Traumatic Inventory (ETI)). Freesurfer 6 was applied to generate the morphometry of brain regions. A multivariate pattern analysis was used to derive brain morphometry patterns associated with food addiction. General linear modeling and mediation analyses were conducted to examine the effects of ELA and resilience on food addiction in individuals with obesity. Statistical significance was determined at a level of p < 0.05. High levels of ELA showed a strong association between reward control brain signatures and food addiction (p = 0.03). Resilience positively mediated the effect of ELA on food addiction (B = 0.02, p = 0.038). Our findings suggest that food addiction is associated with brain signatures in motivation and reward processing regions indicative of dopaminergic dysregulation and inhibition of cognitive control regions. These mechanistic variabilities along with early life adversity suggest increased vulnerability to develop food addiction and obesity in adulthood, which can buffer by the neuroprotective effects of resilience, highlighting the value of incorporating cognitive appraisal into obesity therapeutic regimens.

Social Isolation, Brain Food Cue Processing, Eating Behaviors, and Mental Health Symptoms.

Importance: Perceived social isolation is associated with negative health outcomes, including increased risk for altered eating behaviors, obesity, and psychological symptoms. However, the underlying neural mechanisms of these pathways are unknown. Objective: To investigate the association of perceived social isolation with brain reactivity to food cues, altered eating behaviors, obesity, and mental health symptoms. Design, Setting, and Participants: This cross-sectional, single-center study recruited healthy, premenopausal female participants from the Los Angeles, California, community from September 7, 2021, through February 27, 2023. Exposure: Participants underwent functional magnetic resonance imaging while performing a food cue viewing task. Main Outcomes and Measures: The main outcomes included brain reactivity to food cues, body composition, self-reported eating behaviors (food cravings, reward-based eating, food addiction, and maladaptive eating behaviors), and mental health symptoms (anxiety, depression, positive and negative affect, and psychological resilience). Results: The study included 93 participants (mean [SD] age, 25.38 [7.07] years). Participants with higher perceived social isolation reported higher fat mass percentage, lower diet quality, increased maladaptive eating behaviors (cravings, reward-based eating, uncontrolled eating, and food addiction), and poor mental health (anxiety, depression, and psychological resilience). In whole-brain comparisons, the higher social isolation group showed altered brain reactivity to food cues in regions of the default mode, executive control, and visual attention networks. Isolation-related neural changes in response to sweet foods correlated with various altered eating behaviors and psychological symptoms. These altered brain responses mediated the connection between social isolation and maladaptive eating behaviors (ß for indirect effect, 0.111; 95% CI, 0.013-0.210; P = .03), increased body fat composition (ß, -0.141; 95% CI, -0.260 to -0.021; P = .02), and diminished positive affect (ß, -0.089; 95% CI, -0.188 to 0.011; P = .09). Conclusions and Relevance: These findings suggest that social isolation is associated with altered neural reactivity to food cues within specific brain regions responsible for processing internal appetite-related states and compromised executive control and attentional bias and motivation toward external food cues. These neural responses toward specific foods were associated with an increased risk for higher body fat composition, worsened maladaptive eating behaviors, and compromised mental health. These findings underscore the need for holistic mind-body-directed interventions that may mitigate the adverse health consequences of social isolation.

Microbial and Metabolite Signatures of Stress Reactivity in Ulcerative Colitis Patients in Clinical Remission Predict Clinical Flare Risk.

BACKGROUND: Stress reactivity (SR) is associated with increased risk of flares in ulcerative colitis (UC) patients. Because both preclinical and clinical data support that stress can influence gut microbiome composition and function, we investigated whether microbiome profiles of SR exist in UC. METHODS: Ninety-one UC subjects in clinical and biochemical remission were classified into high and low SR groups by questionnaires. Baseline and longitudinal characterization of the intestinal microbiome was performed by 16S rRNA gene sequencing and fecal and plasma global untargeted metabolomics. Microbe, fecal metabolite, and plasma metabolite abundances were analyzed separately to create random forest classifiers for high SR and biomarker-derived SR scores. RESULTS: High SR reactivity was characterized by altered abundance of fecal microbes, primarily in the Ruminococcaceae and Lachnospiraceae families; fecal metabolites including reduced levels of monoacylglycerols (endocannabinoid-related) and bile acids; and plasma metabolites including increased 4-ethyl phenyl sulfate, 1-arachidonoylglycerol (endocannabinoid), and sphingomyelin. Classifiers generated from baseline microbe, fecal metabolite, and plasma metabolite abundance distinguished high vs low SR with area under the receiver operating characteristic curve of 0.81, 0.83, and 0.91, respectively. Stress reactivity scores derived from these classifiers were significantly associated with flare risk during 6 to 24 months of follow-up, with odds ratios of 3.8, 4.1, and 4.9. Clinical flare and intestinal inflammation did not alter fecal microbial abundances but attenuated fecal and plasma metabolite differences between high and low SR. CONCLUSIONS: High SR in UC is characterized by microbial signatures that predict clinical flare risk, suggesting that the microbiome may contribute to stress-induced UC flares.

Neural correlates of perceived and relative resilience in male and female patients with irritable bowel syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) show lower resilience than healthy controls (HCs), associated with greater symptom severity and worse quality of life. However, little is known about affected markers of resilience or the influence of sex. Furthermore, as resilience is complex, a comprehensive assessment, with multiple resilience measures, is needed. Therefore, we aimed to evaluate perceived and relative resilience and their neural correlates in men and women with IBS. METHODS: In 402 individuals (232 IBS [73.3% women] and 170 HCs [61.2% women]), perceived resilience was assessed by the Connor-Davidson Resilience Scale (CDRISC) and Brief Resilience Scale (BRS); relative resilience was assessed by the standardized residual of the Short Form-12 mental component summary score predicted by the Adverse Childhood Experiences score. Non-rotated partial least squares analysis of region-to-region resting-state connectivity data was used to define resilience-related signatures in HCs. Disease and sex-related differences within these signatures were investigated. KEY RESULTS: Scores on all resilience measures were lower in IBS than in HCs (p's < 0.05). In all three resilience-related signatures, patients with IBS showed reduced connectivity largely involving the central autonomic network (p's < 0.001). Men with IBS showed lower CDRISC scores than women with IBS, and greater reductions in CDRISC-related connectivity, associated with worse symptom severity (p < 0.05). CONCLUSIONS AND INFERENCES: Individuals with IBS show reduced perceived and relative resilience, with reduced connectivity suggesting impaired homeostasis maintenance. Men with IBS may show additional impairment in specific aspects of resilience. Treatments aimed at improving resilience may benefit patients with IBS, especially men with IBS.

The Association Between a Mediterranean Diet and Symptoms of Irritable Bowel Syndrome.

BACKGROUND & AIMS: Low adherence to Mediterranean diet (MD) has been shown to be associated with a higher prevalence of irritable bowel syndrome (IBS), but its association with IBS symptoms is not established. We aim to assess the association between MD and IBS symptoms, identify components of MD associated with IBS symptoms, and determine if a symptom-modified MD is associated with changes in the gut microbiome. METHODS: One hundred and six Rome +IBS and 108 health control participants completed diet history and gastrointestinal symptom questionnaires. Adherence to MD was measured using Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener. Sparse partial least squares analysis identified MD food items associated with IBS symptoms. Stool samples were collected for 16S ribosomal RNA gene sequencing and microbial composition analysis in IBS subjects. RESULTS: Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener scores were similar between IBS and health control subjects and did not correlate with Irritable Bowel Syndrome Severity Scoring System, abdominal pain, or bloating. Among IBS participants, a higher consumption of fruits, vegetables, sugar, and butter was associated with a greater severity of IBS symptoms. Multivariate analysis identified several MD foods to be associated with increased IBS symptoms. A higher adherence to symptom-modified MD was associated with a lower abundance of potentially harmful Faecalitalea, Streptococcus, and Intestinibacter, and higher abundance of potentially beneficial Holdemanella from the Firmicutes phylum. CONCLUSIONS: A standard MD was not associated with IBS symptom severity, although certain MD foods were associated with increased IBS symptoms. Our study suggests that standard MD may not be suitable for all patients with IBS and likely needs to be personalized in those with increased symptoms.

Discrimination exposure impacts unhealthy processing of food cues: crosstalk between the brain and gut.

Experiences of discrimination are associated with adverse health outcomes, including obesity. However, the mechanisms by which discrimination leads to obesity remain unclear. Utilizing multi-omics analyses of neuroimaging and fecal metabolites, we investigated the impact of discrimination exposure on brain reactivity to food images and associated dysregulations in the brain-gut-microbiome system. We show that discrimination is associated with increased food-cue reactivity in frontal-striatal regions involved in reward, motivation and executive control; altered glutamate-pathway metabolites involved in oxidative stress and inflammation as well as preference for unhealthy foods. Associations between discrimination-related brain and gut signatures were skewed towards unhealthy sweet foods after adjusting for age, diet, body mass index, race and socioeconomic status. Discrimination, as a stressor, may contribute to enhanced food-cue reactivity and brain-gut-microbiome disruptions that can promote unhealthy eating behaviors, leading to increased risk for obesity. Treatments that normalize these alterations may benefit individuals who experience discrimination-related stress.

Mediation of the association between disadvantaged neighborhoods and cortical microstructure by body mass index.

BACKGROUND: Living in a disadvantaged neighborhood is associated with worse health outcomes, including brain health, yet the underlying biological mechanisms are incompletely understood. We investigated the relationship between neighborhood disadvantage and cortical microstructure, assessed as the T1-weighted/T2-weighted ratio (T1w/T2w) on magnetic resonance imaging, and the potential mediating roles of body mass index (BMI) and stress, as well as the relationship between trans-fatty acid intake and cortical microstructure. METHODS: Participants comprised 92 adults (27 men; 65 women) who underwent neuroimaging and provided residential address information. Neighborhood disadvantage was assessed as the 2020 California State area deprivation index (ADI). The T1w/T2w ratio was calculated at four cortical ribbon levels (deep, lower-middle, upper-middle, and superficial). Perceived stress and BMI were assessed as potential mediating factors. Dietary data was collected in 81 participants. RESULTS: Here, we show that worse ADI is positively correlated with BMI (r = 0.27, p = .01) and perceived stress (r = 0.22, p = .04); decreased T1w/T2w ratio in middle/deep cortex in supramarginal, temporal, and primary motor regions (p < .001); and increased T1w/T2w ratio in superficial cortex in medial prefrontal and cingulate regions (p < .001). Increased BMI partially mediates the relationship between worse ADI and observed T1w/T2w ratio increases (p = .02). Further, trans-fatty acid intake (high in fried fast foods and obesogenic) is correlated with these T1w/T2w ratio increases (p = .03). CONCLUSIONS: Obesogenic aspects of neighborhood disadvantage, including poor dietary quality, may disrupt information processing flexibility in regions involved in reward, emotion regulation, and cognition. These data further suggest ramifications of living in a disadvantaged neighborhood on brain health.

Neighborhood disadvantage (a combination of low average income, more people leaving education earlier, crowding, lack of complete plumbing, etc.) is known to impact the health of people's brains. We evaluated whether neighborhood disadvantage was associated with differences in the structure of people's brains, and whether any differences were related to an unhealthily high weight and a high intake of trans-fatty acids, a component of fried fast food, on the structure of people's brains. Based on our results, regions of the brain that are involved in reward, emotion and gaining knowledge and understanding might be affected by aspects of neighborhood disadvantage that contribute to obesity, such as poor dietary quality. This suggests that it might be important to make healthier food more readily available in disadvantaged neighborhoods to improve the health of people's brains.

How Discrimination Gets Under the Skin: Biological Determinants of Discrimination Associated With Dysregulation of the Brain-Gut Microbiome System and Psychological Symptoms.

BACKGROUND: Discrimination is associated with negative health outcomes as mediated in part by chronic stress, but a full understanding of the biological pathways is lacking. Here we investigate the effects of discrimination involved in dysregulating the brain-gut microbiome (BGM) system. METHODS: A total of 154 participants underwent brain magnetic resonance imaging to measure functional connectivity. Fecal samples were obtained for 16S ribosomal RNA profiling and fecal metabolites and serum for inflammatory markers, along with questionnaires. The Everyday Discrimination Scale was administered to measure chronic and routine experiences of unfair treatment. A sparse partial least squares-discriminant analysis was conducted to predict BGM alterations as a function of discrimination, controlling for sex, age, body mass index, and diet. Associations between discrimination-related BGM alterations and psychological variables were assessed using a tripartite analysis. RESULTS: Discrimination was associated with anxiety, depression, and visceral sensitivity. Discrimination was associated with alterations of brain networks related to emotion, cognition and self-perception, and structural and functional changes in the gut microbiome. BGM discrimination-related associations varied by race/ethnicity. Among Black and Hispanic individuals, discrimination led to brain network changes consistent with psychological coping and increased systemic inflammation. For White individuals, discrimination was related to anxiety but not inflammation, while for Asian individuals, the patterns suggest possible somatization and behavioral (e.g., dietary) responses to discrimination. CONCLUSIONS: Discrimination is attributed to changes in the BGM system more skewed toward inflammation, threat response, emotional arousal, and psychological symptoms. By integrating diverse lines of research, our results demonstrate evidence that may explain how discrimination contributes to health inequalities.

Multi-omics profiles of the intestinal microbiome in irritable bowel syndrome and its bowel habit subtypes.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is thought to involve alterations in the gut microbiome, but robust microbial signatures have been challenging to identify. As prior studies have primarily focused on composition, we hypothesized that multi-omics assessment of microbial function incorporating both metatranscriptomics and metabolomics would further delineate microbial profiles of IBS and its subtypes. METHODS: Fecal samples were collected from a racially/ethnically diverse cohort of 495 subjects, including 318 IBS patients and 177 healthy controls, for analysis by 16S rRNA gene sequencing (n = 486), metatranscriptomics (n = 327), and untargeted metabolomics (n = 368). Differentially abundant microbes, predicted genes, transcripts, and metabolites in IBS were identified by multivariate models incorporating age, sex, race/ethnicity, BMI, diet, and HAD-Anxiety. Inter-omic functional relationships were assessed by transcript/gene ratios and microbial metabolic modeling. Differential features were used to construct random forests classifiers. RESULTS: IBS was associated with global alterations in microbiome composition by 16S rRNA sequencing and metatranscriptomics, and in microbiome function by predicted metagenomics, metatranscriptomics, and metabolomics. After adjusting for age, sex, race/ethnicity, BMI, diet, and anxiety, IBS was associated with differential abundance of bacterial taxa such as Bacteroides dorei; metabolites including increased tyramine and decreased gentisate and hydrocinnamate; and transcripts related to fructooligosaccharide and polyol utilization. IBS further showed transcriptional upregulation of enzymes involved in fructose and glucan metabolism as well as the succinate pathway of carbohydrate fermentation. A multi-omics classifier for IBS had significantly higher accuracy (AUC 0.82) than classifiers using individual datasets. Diarrhea-predominant IBS (IBS-D) demonstrated shifts in the metatranscriptome and metabolome including increased bile acids, polyamines, succinate pathway intermediates (malate, fumarate), and transcripts involved in fructose, mannose, and polyol metabolism compared to constipation-predominant IBS (IBS-C). A classifier incorporating metabolites and gene-normalized transcripts differentiated IBS-D from IBS-C with high accuracy (AUC 0.86). CONCLUSIONS: IBS is characterized by a multi-omics microbial signature indicating increased capacity to utilize fermentable carbohydrates-consistent with the clinical benefit of diets restricting this energy source-that also includes multiple previously unrecognized metabolites and metabolic pathways. These findings support the need for integrative assessment of microbial function to investigate the microbiome in IBS and identify novel microbiome-related therapeutic targets. Video Abstract.

Reproducible Microstructural Changes in the Brain Associated With the Presence and Severity of Urologic Chronic Pelvic Pain Syndrome (UCPPS): A 3-Year Longitudinal Diffusion Tensor Imaging Study From the MAPP Network.

Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn't clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N = 364) and healthy controls (HCs, N = 61) over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS. PERSPECTIVE: This longitudinal study identified reproducible, "disease-associated" patterns in altered mean diffusivity and abnormal microstructural connectivity in UCPPS comparing to HCs over 6 months. These differences were found in regions involved in sensory processing and integration and pain modulation, making it potentially amenable for clinical interventions that target synaptic and/or neuronal reorganization.

Sex-specific brain microstructural reorganization in irritable bowel syndrome.

ABSTRACT: Preliminary evidence suggests that there are sex differences in microstructural brain organization among individuals with irritable bowel syndrome (IBS). The aim of this study was to further investigate sex-dependent differences in brain microstructure and organization in a large sample of well-phenotyped participants with IBS compared with healthy controls. We hypothesized that female patients with IBS would show evidence for increased axonal strength and myelination within and between brain regions concerned with pain and sensory processing, when compared with males with IBS. We also hypothesized that female compared with male IBS subjects show greater levels of somatic awareness and sensory sensitivity consistent with multisystem sensory sensitivity. Diffusion tensor images and clinical assessments were obtained in 100 healthy controls (61 females) and 152 IBS (107 females) on a 3T Siemens Trio. Whole brain voxel-wise differences in fractional anisotropy, mean, radial and axial diffusivity, and track density as differences in somatic awareness and sensory sensitivity were assessed using the general linear model. Female compared with male IBS participants showed extensive microstructural alterations in sensorimotor, corticothalamic, and basal ganglia circuits involved in pain processing and integration of sensorimotor information. Together with the observed increases in symptom severity, somatic awareness, and sensory sensitivity, the findings support the hypotheses that the etiology and maintenance of symptoms in females with IBS may be driven by greater central sensitivity for multiple sensory stimuli.

A multi-omic brain gut microbiome signature differs between IBS subjects with different bowel habits.

Alterations of the brain-gut-microbiome system (BGM) have been implicated in the pathophysiology of irritable bowel syndrome (IBS), yet bowel habit-specific alterations have not been elucidated. In this cross-sectional study, we apply a systems biology approach to characterize BGM patterns related to predominant bowel habit. Fecal samples and resting state fMRI were obtained from 102 premenopausal women (36 constipation-predominant IBS (IBS-C), 27 diarrhea-predominant IBS (IBS-D), 39 healthy controls (HCs)). Data integration analysis using latent components (DIABLO) was used to integrate data from the phenome, microbiome, metabolome, and resting-state connectome to predict HCs vs IBS-C vs IBS-D. Bloating and visceral sensitivity, distinguishing IBS from HC, were negatively associated with beneficial microbes and connectivity involving the orbitofrontal cortex. This suggests that gut interactions may generate aberrant central autonomic and descending pain pathways in IBS. The connection between IBS symptom duration, key microbes, and caudate connectivity may provide mechanistic insight to the chronicity of pain in IBS. Compared to IBS-C and HCs, IBS-D had higher levels of many key metabolites including tryptophan and phenylalanine, and increased connectivity between the sensorimotor and default mode networks; thus, suggestingan influence on diarrhea, self-related thoughts, and pain perception in IBS-D ('bottom-up' mechanism). IBS-C's microbiome and metabolome resembled HCs, but IBS-C had increased connectivity in the default mode and salience networks compared to IBS-D, which may indicate importance of visceral signals, suggesting a more 'top-down' BGM pathophysiology. These BGM characteristics highlight possible mechanistic differences for variations in the IBS bowel habit phenome. This article is part of the Special Issue on 'Microbiome & the Brain: Mechanisms & Maladies'.

Symptom-associated alterations in functional connectivity in primary and secondary provoked vestibulodynia.

ABSTRACT: Primary provoked vestibulodynia (PVD) is marked by the onset of symptoms at first provoking vulvar contact, whereas secondary PVD refers to symptom onset after some period of painless vulvar contact. Different pathophysiological processes are believed to be involved in the development and maintenance of primary PVD and secondary PVD. The primary aim of this study was to test the hypotheses that the resting state functional connectivity of the brain and brain stem regions differs between these subtypes. Deep clinical phenotyping and resting state brain imaging were obtained in a large sample of a women with primary PVD (n = 46), those with secondary PVD (n = 68), and healthy control women (n = 94). The general linear model was used to test for differences in region-to-region resting state functional connectivity and psychosocial and symptom assessments. Direct statistical comparisons by onset type indicated that women with secondary PVD have increased dorsal attention-somatomotor network connectivity, whereas women with primary PVD predominantly show increased intrinsic resting state connectivity within the brain stem and the default mode network. Furthermore, compared with women with primary PVD, those with secondary PVD reported greater incidence of early life sexual abuse, greater pain catastrophizing, greater 24-hour symptom unpleasantness, and less sexual satisfaction. The findings suggest that women with secondary PVD show greater evidence for central amplification of sensory signals, whereas women with primary PVD have alterations in brain stem circuitry responsible for the processing and modulation of ascending and descending peripheral signals.

High Perceived Stress is Associated With Increased Risk of Ulcerative Colitis Clinical Flares.

BACKGROUND & AIMS: Although perceived stress (PS) has been associated with symptomatic flares in inflammatory bowel disease, clinical and physiological measures associated with perceived stress and flare are not known. The aim of this study was to identify physiological factors associated with perceived stress in ulcerative colitis (UC) subjects, and their relationship with flare. METHODS: Patients with UC in clinical remission (Simple Colitis Clinical Activity Index [SCCAI] score <5) underwent clinical and behavioral assessments, morning salivary cortisol measurements, autonomic nervous system activity testing (heart rate variability, electrodermal activity) at baseline with patient-reported SCCAI every 2 weeks over 1 to 2 years and fecal calprotectin at time of flare. Clinical flares (SCCAI ≥5) and biochemical flares (SCCAI ≥5 with fecal calprotectin ≥250 µg/g) were evaluated. RESULTS: One hundred ten patients with UC were enrolled, with mean follow-up of 65.6 weeks. Patients with UC with higher and lower PS were determined. Although the high PS group had 3.6 times higher odds of a clinical flare than the low PS group, no significant differences in biochemical flares were observed between the low and high PS groups. The high vs low PS group differed in tonic sympathetic arousal as indexed by significantly greater baseline electrodermal activity (4.3 vs 3.4 microsiemens; P = .026) in the high PS group, but not in terms of heart rate variability and morning cortisol levels. Increased fecal calprotectin was associated with cardioautonomic measures, suggesting lower parasympathetic activity. CONCLUSIONS: Increased PS assessed at baseline is associated with tonic sympathetic arousal and greater odds of clinical flares in patients with UC.

Colonic mucosal microbiota is associated with bowel habit subtype and abdominal pain in patients with irritable bowel syndrome.

Mucosal microbiota differ significantly from fecal microbiota and may play a different role in the pathophysiology of irritable bowel syndrome (IBS). The aims of this study were to determine if the composition of mucosal microbiota differed between IBS, or IBS bowel habit (BH) subtypes, and healthy controls (HCs). Sigmoid colon mucosal biopsies were obtained from 97 Rome-positive patients with IBS (28% IBS-constipation, 38% IBS-diarrhea, 24% IBS-mixed, and 10% IBS-unsubtyped) and 54 HCs, from which DNA was extracted. 16S rRNA gene sequencing and microbial composition analysis were performed. Group differences in α and ß diversity and taxonomic level differences were determined using linear regression while controlling for confounding variables. IBS BH subtype was associated with microbial α diversity (P = 0.0003) with significant differences seen in the mucosal microbiota of IBS-constipation versus IBS-diarrhea (P = 0.046). There were no significant differences in α or ß diversity in the mucosal microbiota of IBS versus HCs (P = 0.29 and 0.93, respectively), but metagenomic profiling suggested functional differences. The relative abundance of Prevotella_9 copri within IBS was significantly correlated with increased abdominal pain (r = 0.36, P = 0.0003), which has not been previously reported in IBS. Significant differences in the mucosal microbiota were present within IBS BH subtypes but not between IBS and HCs, supporting the possibility of IBS BH subtype-specific pathogenesis. Increased Prevotella copri may contribute to symptoms in patients with IBS.NEW & NOTEWORTHY Gut mucosal microbiota differs significantly from fecal microbiota in irritable bowel syndrome (IBS) and may play a different role in its pathophysiology. Investigation of colonic mucosal microbiota in the largest cohort of patients with IBS and healthy controls accounting for confounding variables, including diet demonstrated significant differences in mucosal microbiota between IBS bowel habit subtypes but not between IBS and healthy controls. In addition, the study reported gut microbiota is associated with abdominal pain in patients with IBS.

Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses Toward an Emotional Task in Healthy Subjects: A Randomized Clinical Trial.

Background: Evidence from preclinical studies suggests that probiotics affect brain function via the microbiome-gut-brain axis, but evidence in humans remains limited. Objective: The present proof-of-concept study investigated if a probiotic product containing a mixture of Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 (in total 3 × 109 CFU/day) affected functional brain responses in healthy subjects during an emotional attention task. Design: In this double-blinded, randomized, placebo-controlled crossover study (Clinicaltrials.gov, NCT03615651), 22 healthy subjects (24.2 ± 3.4 years, 6 males/16 females) were exposed to a probiotic intervention and a placebo for 4 weeks each, separated by a 4-week washout period. Subjects underwent functional magnetic resonance imaging while performing an emotional attention task after each intervention period. Differential brain activity and functional connectivity were assessed. Results: Altered brain responses were observed in brain regions implicated in emotional, cognitive and face processing. Increased activation in the orbitofrontal cortex, a region that receives extensive sensory input and in turn projects to regions implicated in emotional processing, was found after probiotic intervention compared to placebo using a cluster-based analysis of functionally defined areas. Significantly reduced task-related functional connectivity was observed after the probiotic intervention compared to placebo. Fecal microbiota composition was not majorly affected by probiotic intervention. Conclusion: The probiotic intervention resulted in subtly altered brain activity and functional connectivity in healthy subjects performing an emotional task without major effects on the fecal microbiota composition. This indicates that the probiotic effects occurred via microbe-host interactions on other levels. Further analysis of signaling molecules could give possible insights into the modes of action of the probiotic intervention on the gut-brain axis in general and brain function specifically. The presented findings further support the growing consensus that probiotic supplementation influences brain function and emotional regulation, even in healthy subjects. Future studies including patients with altered emotional processing, such as anxiety or depression symptoms are of great interest. Clinical Trial Registration: [http://clinicaltrials.gov/], identifier [NCT03615651].

The visceral sensitivity index: A novel tool for measuring GI-symptom-specific anxiety in inflammatory bowel disease.

BACKGROUND: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are chronic gastrointestinal (GI) disorders. GI symptom-specific anxiety (GSA) is the cognitive, affective, and behavioral response stemming from fear of GI symptoms. The Visceral Sensitivity Index (VSI) measures GSA and is validated in IBS and may be useful in IBD. METHODS: We compared VSI scores in IBD participants to IBS participants and healthy controls (HCs). Using validated questionnaires, we assessed the VSI's correlation with anxiety, health-related quality of life (HRQOL), and IBD activity. KEY RESULTS: We recruited 222 age- and sex-matched participants (74 IBD [23 Crohn's disease; 51 ulcerative colitis], 74 IBS, and 74 HCs). IBD and IBS participants had higher VSI scores compared with HCs (IBD = 26.62 ± 16.64, IBS = 38.83 ± 15.06; HCs = 3.42±5.06; all p's < 0.001). VSI scores were lower in IBD vs IBS (p < 0.001). In IBD, VSI modestly correlated with current anxiety (R = 0.35, p = 0.002) and the physical component of HRQOL (R = -0.45, p = 0.0001) but less with the mental component of HRQOL (R = -0.23, p = 0.05). CONCLUSIONS & INFERENCES: Our findings suggest the VSI is a useful measure in IBD. The VSI in IBD is related to general anxiety but is measuring a different construct and is not affected by the presence of trait anxiety. IBD patients have GSA that is associated with decreased HRQOL, which can negatively affect treatment compliance and other long-term disease outcomes. Future studies are needed to further validate the VSI in IBD and to assess its correlation with disease activity.