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Background:Neuroimaging studies have identified obesity-related differences in the brain's resting state activity. An imbalance between homeostatic and reward aspects of ingestive behaviour may contribute to obesity and food addiction. The interactions between early life adversity (ELA), the reward network and food addiction were investigated to identify obesity and sex-related differences, which may drive obesity and food addiction. Methods:Functional resting state magnetic resonance imaging was acquired in 186 participants (high body mass index [BMI]: ≥25: 53 women and 54 men; normal BMI: 18.50-24.99: 49 women and 30 men). Participants completed questionnaires to assess ELA (Early Traumatic Inventory) and food addiction (Yale Food Addiction Scale). A tripartite network analysis based on graph theory was used to investigate the interaction between ELA, brain connectivity and food addiction. Interactions were determined by computing Spearman rank correlations, thresholded at q

ObjectiveThe differential effect of GLP-1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite-related behaviours was investigated in women with normal weight compared with women with obesity.MethodsFollowing an 8-h fast, 19 female subjects (11 lean, 8 obese) participated in a 2-d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30-min post subcutaneous injection of 5 μg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug-induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus.ResultsWomen with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese.ConclusionsObesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP-1 analogues in therapeutic interventions.

Background/objectivesThe brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters.Subjects/methodsStructural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age.ResultsIn both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions.ConclusionsIn individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

BackgroundA majority of the subjects with irritable bowel syndrome (IBS) show increased behavioral and brain responses to expected and delivered aversive visceral stimuli during controlled rectal balloon distension, and during palpation of the sigmoid colon. We aimed to determine if altered brain responses to cued and uncued pain expectation are also seen in the context of a noxious somatic pain stimulus applied to the same dermatome as the sigmoid colon.MethodsA task-dependent functional magnetic resonance imaging technique was used to investigate the brain activity of 37 healthy controls (18 females) and 37 IBS subjects (21 females) during: (i) a cued expectation of an electric shock to the abdomen vs a cued safe condition; and (ii) an uncued cross-hair condition in which the threat is primarily based on context vs a cued safe condition.Key resultsRegions within the salience, attention, default mode, and emotional arousal networks were more activated by the cued abdominal threat condition and the uncued condition than in the cued safe condition. During the uncued condition contrasted to the cued safe condition, IBS subjects (compared to healthy control subjects) showed greater brain activations in the affective (amygdala, anterior insula) and attentional (middle frontal gyrus) regions, and in the thalamus and precuneus. These disease-related differences were primarily seen in female subjects.Conclusions & inferencesThe observed greater engagement of cognitive and emotional brain networks in IBS subjects during contextual threat may reflect the propensity of IBS subjects to overestimate the likelihood and severity of future abdominal pain.

BackgroundIncreased attention to gastrointestinal (GI) symptoms and disease-specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS.MethodsTo evaluate brain networks that support alerting, orienting, and executive attention, we employed the attention network test (ANT), a modified flanker task which measures the efficiency of functioning of core attentional networks, during functional magnetic resonance imaging in 15 IBS patients (mean age = 31 [11.96]) and 14 healthy controls (HCs; mean age = 31 [10.91]).Key resultsPatients with IBS, compared to HCs, showed shorter reaction times during the alerting and orienting conditions which were associated with greater activation of anterior midcingulate and insular cortices, and decreased activity in the right inferior frontal junction and supplementary motor cortex. Patients also showed activation in the dorsal medial prefrontal cortex and concurrent thalamic deactivation during the executive control portion of the ANT relative to HCs, but no group difference in reaction times were found. The activity in brain regions showing group differences during the ANT were associated with measures of GI-specific anxiety, pain catastrophizing, and fear of uncertainty. In IBS, activity in the anterior midcingulate during alerting correlated with duration of GI-symptoms and overall symptom severity.Conclusions & inferencesTogether, these results suggest that IBS patients have specific abnormalities in attentional network functioning and these deficits may underlie symptom-related anxiety, hypervigilance, and visceral hypersensitivity.

BackgroundStudies have demonstrated the existence of regional gray matter and white matter (WM) alterations in the brains of patients with irritable bowel syndrome (IBS), but the extent to which altered anatomical connectivity between brain regions is altered in IBS remains incompletely understood.MethodsIn this study, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were used to identify significant brain connectivity differences between IBS patients and healthy control (HC) subjects. Based on MRI and DTI volumes acquired from 66 IBS patients and 23 HC subjects, multivariate regression was used to investigate whether subject age, sex, cortical thickness, or the mean fractional anisotropy (FA) of WM connections innervating each location on the cortex could predict IBS diagnosis.Key resultsHC and IBS subjects were found to differ significantly within both left and right viscerotopic portions of the primary somatosensory cortex (S1), with the mean FA of WM bundles innervating S1 being the predictor variable responsible for these significant differences.Conclusions & inferencesThese preliminary findings illustrate how a chronic visceral pain syndrome and brain structure are related in the cohort examined, and because of their indication that IBS diagnosis is associated with anatomic neuropathology of potential neurological relevance in this patient sample.

Background/objectivesNeuroimaging studies in obese subjects have identified abnormal activation of key regions of central reward circuits, including the nucleus accumbens (NAcc), in response to food-related stimuli. We aimed to examine whether women with elevated body mass index (BMI) show structural and resting state (RS) functional connectivity alterations within regions of the reward network.Subjects/methodsFifty healthy, premenopausal women, 19 overweight and obese (high BMI=26-38 kg m(-2)) and 31 lean (BMI=19-25 kg m(-2)) were selected from the University of California Los Angeles' Oppenheimer Center for Neurobiology of Stress database. Structural and RS functional scans were collected. Group differences in grey matter volume (GMV) of the NAcc, oscillation dynamics of intrinsic brain activity and functional connectivity of the NAcc to regions within the reward network were examined.ResultsGMV of the left NAcc was significantly greater in the high BMI group than in the lean group (P=0.031). Altered frequency distributions were observed in women with high BMI compared with lean group in the left NAcc (P=0.009) in a medium-frequency (MF) band, and in bilateral anterior cingulate cortex (ACC) (P=0.014,

Context.-In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. Objective.-To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. Design and Setting.-Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. Participants and Intervention.-Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. Outcome Measures.-Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. Results.-In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. Conclusions.-We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo. [ABSTRACT FROM AUTHOR]

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.

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.

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., (© 2024. The Author(s).)

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 (β for indirect effect, 0.111; 95% CI, 0.013-0.210; P = .03), increased body fat composition (β, -0.141; 95% CI, -0.260 to -0.021; P = .02), and diminished positive affect (β, -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.

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., (Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation 2023.)

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., (© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

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., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests A.G. is a scientific advisor to Yamaha. All other authors declare no competing interests.

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., (© 2023. Springer Nature Limited.)

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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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'., Competing Interests: Declaration of competing interest AG is scientific advisor to Yamaha. EAM is a scientific advisory board member of Danone, Axial Biotherapeutics, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, Seed and APC Microbiome Ireland. All other authors have nothing to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 International Association for the Study of Pain.)

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 International Association for the Study of Pain.)

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., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (© 2022 John Wiley & Sons Ltd.)

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 β 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 β 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&#95;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.

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 × 10 9 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]., Competing Interests: LLS was employed by Pfizer Consumer Healthcare. This study received funding from Pfizer Consumer Healthcare. LLS was involved in study design and discussion of the results, but had no involvement in collection, analysis, interpretation of data or the decision to submit this article for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rode, Edebol Carlman, König, Repsilber, Hutchinson, Thunberg, Andersson, Persson, Kiselev, Lathrop Stern, Salomon, Mohammed, Labus and Brummer.)

Irritable bowel syndrome (IBS) is a common disorder of brain-gut interactions characterized by chronic abdominal pain, altered bowel movements, often accompanied by somatic and psychiatric comorbidities. We aimed to test the hypothesis that a baseline phenotype composed of multi-modal neuroimaging and clinical features predicts clinical improvement on the IBS Symptom Severity Scale (IBS-SSS) at 3 and 12 months without any targeted intervention. Female participants (N = 60) were identified as "improvers" (50-point decrease on IBS-SSS from baseline) or "non-improvers." Data integration analysis using latent components (DIABLO) was applied to a training and test dataset to determine whether a limited number of sets of multiple correlated baseline'omics data types, including brain morphometry, anatomical connectivity, resting-state functional connectivity, and clinical features could accurately predict improver status. The derived predictive models predicted improvement status at 3-months and 12-months with 91% and 83% accuracy, respectively. Across both time points, non-improvers were classified as having greater correlated morphometry, anatomical connectivity and resting-state functional connectivity characteristics within salience and sensorimotor networks associated with greater pain unpleasantness, but lower default mode network integrity and connectivity. This suggests that non-improvers have a greater engagement of attentional systems to perseverate on painful visceral stimuli, predicting IBS exacerbation. The ability of baseline multimodal brain-clinical signatures to predict symptom trajectories may have implications in guiding integrative treatment in the age of precision medicine, such as treatments targeted at changing attentional systems such as mindfulness or cognitive behavioral therapy., (© 2021. The Author(s).)

Background & Aims: Altered fecal microbiota have been reported in irritable bowel syndrome (IBS), although studies vary, which could be owing to dietary effects. Many IBS patients may eliminate certain foods because of their symptoms, which in turn may alter fecal microbiota diversity and composition. This study aimed to determine if dietary patterns were associated with IBS, symptoms, and fecal microbiota differences reported in IBS., Methods: A total of 346 IBS participants and 170 healthy controls (HCs) completed a Diet Checklist reflecting the diet(s) consumed most frequently. An exclusion diet was defined as a diet that eliminated food components by choice. Within this group, a gluten-free, dairy-free, or low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet was further defined as restrictive because they often are implicated in reducing symptoms. Stool samples were obtained from 171 IBS patients and 98 HCs for 16S ribosomal RNA gene sequencing and microbial composition analysis., Results: Having IBS symptoms was associated with consuming a restrictive diet (27.17% of IBS patients vs 7.65% of HCs; odds ratio, 3.25; 95% CI, 1.66-6.75; P value = .006). IBS participants on an exclusion or restrictive diet reported more severe IBS symptoms (P = .042 and .029, respectively). The composition of the microbiota in IBS patients varied depending on the diet consumed. IBS participants on an exclusion diet had a greater abundance of Lachnospira and a lower abundance of Eubacterium (q value, <.05), and those on a restrictive diet had a lower abundance of Lactobacillus (q value, <.05)., Conclusions: Restrictive diets likely are consumed more by IBS patients than HCs to reduce GI symptom severity. Dietary patterns influence the composition of the fecal microbiota and may explain some of the differences between IBS and HCs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC < IBS < HC) and increased eigenvector centrality in the visual network (UC > IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC., (© 2021. The Author(s).)

Background: Anorexia nervosa (AN) is a disorder characterized by an incapacitating fear of weight gain and by a disturbance in the way the body is experienced, facets that motivate dangerous weight loss behaviors. Multimodal neuroimaging studies highlight atypical neural activity in brain networks involved in interoceptive awareness and reward processing., Methods: The current study used resting-state neuroimaging to model the architecture of large-scale functional brain networks and characterize network properties of individual brain regions to clinical measures. Resting-state neuroimaging was conducted in 62 adolescents, 22 (21 female) with a history of AN and 40 (39 female) healthy controls (HCs). Sensorimotor and basal ganglia regions, as part of a 165-region whole-brain network, were investigated. Subject-specific functional brain networks were computed to index centrality. A contrast analysis within the general linear model covarying for age was performed. Correlations between network properties and behavioral measures were conducted (significance q < .05)., Results: Compared to HCs, AN had lower connectivity from sensorimotor regions, and greater connectivity from the left caudate nucleus to the right postcentral gyrus. AN demonstrated lower sensorimotor centrality, but higher basal ganglia centrality. Sensorimotor connectivity dyads and centrality exhibited negative correlations with body dissatisfaction and drive for thinness, two essential features of AN., Conclusions: These findings suggest that AN is associated with greater communication from the basal ganglia, and lower information propagation in sensorimotor cortices. This is consistent with the clinical presentation of AN, where individuals exhibit patterns of rigid habitual behavior that is not responsive to bodily needs, and seem "disconnected" from their bodies., (© 2022. The Author(s).)

Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD.

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There is growing recognition that bidirectional signaling between the digestive tract and the brain contributes to irritable bowel syndrome (IBS). We recently showed in a large randomized controlled trial that cognitive behavioral therapy (CBT) reduces IBS symptom severity. This study investigated whether baseline brain and gut microbiome parameters predict CBT response and whether response is associated with changes in the brain-gut-microbiome (BGM) axis., Methods: Eighty-four Rome III-diagnosed IBS patients receiving CBT were drawn from the Irritable Bowel Syndrome Outcome Study (IBSOS; ClinicalTrials.gov NCT00738920) for multimodal brain imaging and psychological assessments at baseline and after study completion. Fecal samples were collected at baseline and post-treatment from 34 CBT recipients for 16S rRNA gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acids. Clinical measures, brain functional connectivity and microstructure, and microbiome features associated with CBT response were identified by multivariate linear and negative binomial models., Results: At baseline, CBT responders had increased fecal serotonin levels, and increased Clostridiales and decreased Bacteroides compared to non-responders. A random forests classifier containing 11 microbial genera predicted CBT response with high accuracy (AUROC 0.96). Following treatment, CBT responders demonstrated reduced functional connectivity in regions of the sensorimotor, brainstem, salience, and default mode networks and changes in white matter in the basal ganglia and other structures. Brain changes correlated with microbiome shifts including Bacteroides expansion in responders., Conclusions: Pre-treatment intestinal microbiota and serotonin levels were associated with CBT response, suggesting that peripheral signals from the microbiota can modulate central processes affected by CBT that generate abdominal symptoms in IBS. CBT response is characterized by co-correlated shifts in brain networks and gut microbiome that may reflect top-down effects of the brain on the microbiome during CBT. Video abstract., (© 2021. The Author(s).)

Somatization, defined as the presence of multiple somatic symptoms, frequently occurs in irritable bowel syndrome (IBS) and may constitute the clinical manifestation of a neurobiological sensitization process. Brain imaging data was acquired with T1 weighted 3 tesla MRI, and gray matter morphometry were analyzed using FreeSurfer. We investigated differences in networks of structural covariance, based on graph analysis, between regional gray matter volumes in IBS-related brain regions between IBS patients with high and low somatization levels, and compared them to healthy controls (HCs). When comparing IBS low somatization (N = 31), IBS high somatization (N = 35), and HCs (N = 31), we found: (1) higher centrality and neighbourhood connectivity of prefrontal cortex subregions in IBS high somatization compared to healthy controls; (2) higher centrality of left cerebellum in IBS low somatization compared to both IBS high somatization and healthy controls; (3) higher centrality of the anterior insula in healthy controls compared to both IBS groups, and in IBS low compared to IBS high somatization. The altered structural covariance of prefrontal cortex and anterior insula in IBS high somatization implicates that prefrontal processes may be more important than insular in the neurobiological sensitization process associated with IBS high somatization.

Background: Enhanced perception of visceral stimuli is an important feature of Irritable Bowel Syndrome (IBS), but it is not known whether visceral sensitivity is associated with regional structural brain properties in IBS., Methods: Structural brain magnetic resonance imaging data from 216 women with IBS and 138 healthy women were parcellated with FreeSurfer to define regional gray matter morphometry (volume, cortical thickness, surface area and mean curvature) in the sensorimotor network. General linear models were used to detect group differences between IBS and health. In a second set of 48 female IBS patients, pain threshold, pain intensity ratings during rectal balloon distension, and reported levels of abdominal pain and bloating were correlated with brain regions that showed differences between IBS and health in the first data set., Key Results: Several statistically significant differences between IBS patients and healthy controls were found, mainly higher gray matter volume and cortical thickness in primary somatosensory cortex, secondary somatosensory cortex, and subcortical regions, and lesser gray matter volume, surface area and cortical thickness in posterior insula and superior frontal gyrus. Pain intensity ratings during rectal distension were associated with left primary somatosensory cortical thickness, and pain threshold was associated with right nucleus accumbens volume., Conclusions and Inferences: Regional gray matter differences in sensorimotor network are associated with visceral sensitivity and may represent neuroplastic changes in female IBS patients., (© 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Provoked vestibulodynia (PVD) is a chronic vulvar pain disorder characterized by hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Knowledge regarding pathophysiological mechanisms contributing to the etiology and production of symptoms in PVD remains incomplete but is considered multifactorial. Using a cross-sectional observational study design, data from untargeted metabolomic profiling of vaginal fluid and plasma in women with PVD and healthy women was combined with pain testing and brain imaging in women with PVD to test the hypotheses that women with PVD compared to healthy women show differences in vaginal and plasma metabolites involved in steroid hormone biosynthesis. Steroid hormone metabolites showing group differences were correlated with vulvar vestibular pain and vaginal muscle tenderness and functional connectivity of brain regions involved in pain processing in women with PVD to provide insight into the functional mechanisms linked to the identified alterations. Sensitivity analyses were also performed to determine the impact of hormonal contraceptive use on the study findings. Women with PVD compared to healthy controls had significant reductions primarily in vaginal fluid concentrations of androgenic, pregnenolone and progestin metabolites involved in steroidogenesis, suggesting localized rather than systemic effects in vagina and vulvar vestibule. The observed reductions in androgenic metabolite levels showed large effect size associations with increased vulvar vestibular pain and vulvar muscle tenderness and decreases in androgenic and progestin metabolites were associated with decreased connectivity strength in primary sensorimotor cortices. Women with PVD showed symptom-associated reductions in vaginal fluid concentrations of metabolites involved in the biosynthesis of steroid hormones previously shown to affect the integrity of vulvar and vaginal tissue and nociceptive processing. Deficiency of certain steroids may be an important mechanism contributing to the pathophysiology of symptoms in PVD may provide potential diagnostic markers that could lead to new targets for therapeutic intervention.

Objective: We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis (UC) participants who had a history of chronic gut inflammation, healthy controls (HCs) and a disease control group without gut inflammation (irritable bowel syndrome; IBS)., Design: Diffusion weighted imaging was conducted in age and sex-matched participants with UC, IBS, and HCs (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences., Results: UC participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to HCs (q < 0.05). Hub analyses revealed compromised hubness of the pallidus in UC and IBS compared to HCs which was replaced by increased hubness of the postcentral sulcus. Surprisingly, few differences in network matrices between UC and IBS were identified. In UC, centrality measures in the secondary somatosensory cortex were associated with depression (q < 0.03), symptom related anxiety (q < 0.04), trait anxiety (q < 0.03), and symptom duration (q < 0.05)., Conclusion: A history of UC is associated with neuroplastic changes in several brain networks, which are associated with symptoms of depression, trait and symptom-related anxiety, as well as symptom duration. When viewed together with the results from IBS subjects, these findings suggest that chronic gut inflammation as well as abdominal pain have a lasting impact on brain network organization, which may play a role in symptoms reported by UC patients, even when gut inflammation has subsided., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Alterations in brain-gut-microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood-brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.

Background: Irritable bowel syndrome (IBS) is a common and often debilitating chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Pharmacological treatments are often ineffective, leading to the development of a variety of behavioral interventions. Mindfulness-based stress reduction (MBSR) is one such program that has shown efficacy in reducing gastrointestinal (GI) symptoms and improving quality of life (QOL). This single-arm intervention study examines the association of clinical outcomes with changes in specific aspects of mindfulness., Methods: Adults with IBS (53 women, 15 men) participated in an 8-week MBSR class. Primary outcomes of GI symptom severity, quality of life, and GI-specific anxiety, as well as specific aspects of mindfulness using the Five Factor Mindfulness Questionnaire (FFMQ), were assessed at baseline, post-treatment, and 6-month follow-up., Key Results: Gastrointestinal symptom responder rate was 71%, and there was a significant pre-post treatment change for three of the five FFMQ scales. Regression analysis indicated that change in the Act with Awareness (P = .02) facet of mindfulness was the strongest predictor of GI symptom and QOL improvement., Conclusions & Inferences: Mindfulness-based stress reduction training was associated with robust improvements in GI symptoms and associated problems in participants with IBS. Although significant increases in 3 of the 5 measured facets of mindfulness were found, regression analyses suggest that increases in the ability to retain present moment focus and act with awareness may be particularly important for improving outcomes in individuals with IBS. These results may inform the refinement of mindfulness-based protocols specifically for treatment of IBS., (© 2020 John Wiley & Sons Ltd.)

Inflammatory bowel disease (IBD) is a chronic disease that is associated with aspects of brain anatomy and activity. In this preliminary MRI study, we investigated differences in brain structure and in functional connectivity (FC) of brain regions in 35 participants with Crohn's disease (CD) and 21 healthy controls (HC). Voxel-based morphometry (VBM) analysis was performed to contrast CD and HC structural images. Region of interest (ROI) analyses were run to assess FC for resting-state network nodes. Independent component analysis (ICA) identified whole brain differences in FC associated with resting-state networks. Though no structural differences were found, ROI analyses showed increased FC between the frontoparietal (FP) network and salience network (SN), and decreased FC between nodes of the default mode network (DMN). ICA results revealed changes involving cerebellar (CER), visual (VIS), and SN components. Differences in FC associated with sex were observed for both ROI analysis and ICA. Taken together, these changes are consistent with an influence of CD on the brain and serve to direct future research hypotheses., (Copyright © 2020 Kornelsen, Wilson, Labus, Witges, Mayer and Bernstein.)

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study, we tested the hypotheses that PVD compared with healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD vs HCs. In addition, disease specificity of GMV alterations were examined by comparing PVD with another chronic pain disorder. Finally, we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, and 29 irritable bowel syndrome [IBS]). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared with HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to patients with IBS, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional GMV alterations were associated with patient reports of pain during intercourse and muscle tenderness. The current findings provide further evidence that GMV is increased in PVD compared with HCs in several regions of the sensorimotor network and the hippocampus in patients with PVD. In addition, GMV distinct alterations in the sensorimotor network were identified between 2 pelvic pain disorders, PVD compared with IBS.

Pain is a highly complex and individualized experience with biopsychosocial components. Neuroimaging research has shown evidence of the involvement of the central nervous system in the development and maintenance of chronic pain conditions, including urological chronic pelvic pain syndrome (UCPPS). Furthermore, a history of early adverse life events (EALs) has been shown to adversely impact symptoms throughout childhood and into adulthood. However, to date, the role of EAL's in the central processes of chronic pain have not been adequately investigated. We studied 85 patients (56 females) with UCPPS along with 86 healthy controls (HCs) who had resting-state magnetic resonance imaging scans (59 females), and data on EALs as a part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Study. We used graph theory methods in order to investigate the impact of EALs on measures of centrality, which characterize information flow, communication, influence, and integration in a priori selected regions of interest. Patients with UCPPS exhibited lower centrality in the right anterior insula compared to HCs, a key node in the salience network. Males with UCPPS exhibited lower centrality in the right anterior insula compared the HC males. Females with UCPPS exhibited greater centrality in the right caudate nucleus and left angular gyrus compared to HC females. Males with UCPPS exhibited lower centrality in the left posterior cingulate, angular gyrus, middle temporal gyrus, and superior temporal sulcus, but greater centrality in the precuneus and anterior mid-cingulate cortex (aMCC) compared to females with UCPPS. Higher reports of EALs was associated with greater centrality in the left precuneus and left aMCC in females with UCPPS. This study provides evidence for disease and sex-related alterations in the default mode, salience, and basal ganglia networks in patients with UCPPS, which are moderated by EALs, and associated with clinical symptoms and quality of life (QoL)., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Evidence from preclinical and clinical studies suggests that interactions among the brain, gut, and microbiota may affect the pathophysiology of irritable bowel syndrome (IBS). As disruptions in central and peripheral serotonergic signaling pathways have been found in patients with IBS, we explored the hypothesis that the abundance of serotonin-modulating microbes of the order Clostridiales is associated with functional connectivity of somatosensory brain regions and gastrointestinal (GI) sensorimotor function., Methods: We performed a prospective study of 65 patients with IBS and 21 healthy individuals (controls) recruited from 2011 through 2013 at a secondary/tertiary care outpatient clinic in Sweden. Study participants underwent functional brain imaging, rectal balloon distension, a nutrient and lactulose challenge test, and assessment of oroanal transit time within a month. They also submitted stool samples, which were analyzed by 16S ribosomal RNA gene sequencing. A tripartite network analysis based on graph theory was used to investigate the interactions among bacteria in the order Clostridiales, connectivity of brain regions in the somatosensory network, and GI sensorimotor function., Results: We found associations between GI sensorimotor function and gut microbes in stool samples from controls, but not in samples from IBS patients. The largest differences between controls and patients with IBS were observed in the Lachnospiraceae incertae sedis, Clostridium XIVa, and Coprococcus subnetworks. We found connectivity of subcortical (thalamus, caudate, and putamen) and cortical (primary and secondary somatosensory cortices) regions to be involved in mediating interactions among these networks., Conclusions: In a comparison of patients with IBS and controls, we observed disruptions in the interactions between the brain, gut, and gut microbial metabolites in patients with IBS-these involve mainly subcortical but also cortical regions of brain. These disruptions may contribute to altered perception of pain in patients with IBS and may be mediated by microbial modulation of the gut serotonergic system.