Publications by authors named "Arpana Gupta"

57 Publications

Early life adversity predicts brain-gut alterations associated with increased stress and mood.

Neurobiol Stress 2021 Nov 25;15:100348. Epub 2021 May 25.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, USA.

Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.
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http://dx.doi.org/10.1016/j.ynstr.2021.100348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170500PMC
November 2021

Effect of Exclusion Diets on Symptom Severity and the Gut Microbiota in Patients with Irritable Bowel Syndrome.

Clin Gastroenterol Hepatol 2021 May 19. Epub 2021 May 19.

G Oppenheimer Center for Neurobiology of Stress and Resilience; Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, United States,. Electronic address:

Background & Aims: Altered fecal microbiota have been reported in IBS, although studies vary which could be due 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 aims were to determine if dietary patterns were associated with IBS, symptoms, and fecal microbiota differences reported in IBS.

Methods: 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 FODMAP diet was further defined as restrictive as they are often implicated to reduce symptoms. Stool samples were obtained from 171 IBS patients and 98 HCs for 16S rRNA 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; OR 3.25; 95% CI 1.66-6.75; p-value 0.006). IBS participants on an exclusion or restrictive diet reported more severe IBS symptoms (p=0.042 and p=0.029 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-values<0.05) and those on a restrictive diet had a lower abundance of Lactobacillus (q-value <0.05).

Conclusions: Restrictive diets are likely consumed more by IBS patients than HCs to reduce GI symptom severity. Dietary patterns influence the composition of fecal microbiota and may explain some of the differences between IBS and HCs.
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http://dx.doi.org/10.1016/j.cgh.2021.05.027DOI Listing
May 2021

Altered brain structural connectivity in patients with longstanding gut inflammation is correlated with psychological symptoms and disease duration.

Neuroimage Clin 2021 9;30:102613. Epub 2021 Mar 9.

G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, United States; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, United States; UCLA Microbiome Center, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nicl.2021.102613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050027PMC
March 2021

Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement.

Endocr Rev 2021 May;42(3):219-258

Diffusion and Connectomics In Precision Healthcare Research (DiCIPHR) lab, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

In May 2014, the National Institutes of Health (NIH) stated its intent to "require applicants to consider sex as a biological variable (SABV) in the design and analysis of NIH-funded research involving animals and cells." Since then, proposed research plans that include animals routinely state that both sexes/genders will be used; however, in many instances, researchers and reviewers are at a loss about the issue of sex differences. Moreover, the terms sex and gender are used interchangeably by many researchers, further complicating the issue. In addition, the sex or gender of the researcher might influence study outcomes, especially those concerning behavioral studies, in both animals and humans. The act of observation may change the outcome (the "observer effect") and any experimental manipulation, no matter how well-controlled, is subject to it. This is nowhere more applicable than in physiology and behavior. The sex of established cultured cell lines is another issue, in addition to aneuploidy; chromosomal numbers can change as cells are passaged. Additionally, culture medium contains steroids, growth hormone, and insulin that might influence expression of various genes. These issues often are not taken into account, determined, or even considered. Issues pertaining to the "sex" of cultured cells are beyond the scope of this Statement. However, we will discuss the factors that influence sex and gender in both basic research (that using animal models) and clinical research (that involving human subjects), as well as in some areas of science where sex differences are routinely studied. Sex differences in baseline physiology and associated mechanisms form the foundation for understanding sex differences in diseases pathology, treatments, and outcomes. The purpose of this Statement is to highlight lessons learned, caveats, and what to consider when evaluating data pertaining to sex differences, using 3 areas of research as examples; it is not intended to serve as a guideline for research design.
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http://dx.doi.org/10.1210/endrev/bnaa034DOI Listing
May 2021

Brain-Gut-Microbiome Interactions and Intermittent Fasting in Obesity.

Nutrients 2021 Feb 10;13(2). Epub 2021 Feb 10.

G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7378, USA.

The obesity epidemic and its metabolic consequences are a major public health problem both in the USA and globally. While the underlying causes are multifactorial, dysregulations within the brain-gut-microbiome (BGM) system play a central role. Normal eating behavior is coordinated by the tightly regulated balance between intestinal, extraintestinal and central homeostatic and hedonic mechanisms, resulting in stable body weight. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food has played a crucial role in shifting this balance towards hedonic eating through both central (disruptions in dopaminergic signaling) and intestinal (vagal afferent function, metabolic toxemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. The balance between homeostatic and hedonic eating behaviors is not only influenced by the amount and composition of the diet, but also by the timing and rhythmicity of food ingestion. Circadian rhythmicity affects both eating behavior and multiple gut functions, as well as the composition and interactions of the microbiome with the gut. Profound preclinical effects of intermittent fasting and time restricted eating on the gut microbiome and on host metabolism, mostly demonstrated in animal models and in a limited number of controlled human trials, have been reported. In this Review, we will discuss the effects of time-restricted eating on the BGM and review the promising effects of this eating pattern in obesity treatment.
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http://dx.doi.org/10.3390/nu13020584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916460PMC
February 2021

Alterations in reward network functional connectivity are associated with increased food addiction in obese individuals.

Sci Rep 2021 Feb 9;11(1):3386. Epub 2021 Feb 9.

G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity Program, CHS 42-210 MC737818, 10833 Le Conte Avenue, Los Angeles, USA.

Functional neuroimaging studies in obesity have identified alterations in the connectivity within the reward network leading to decreased homeostatic control of ingestive behavior. However, the neural mechanisms underlying sex differences in the prevalence of food addiction in obesity is unknown. The aim of the study was to identify functional connectivity alterations associated with: (1) Food addiction, (2) Sex- differences in food addiction, (3) Ingestive behaviors. 150 participants (females: N = 103, males: N = 47; food addiction: N = 40, no food addiction: N = 110) with high BMI ≥ 25 kg/m underwent functional resting state MRIs. Participants were administered the Yale Food Addiction Scale (YFAS), to determine diagnostic criteria for food addiction (YFAS Symptom Count ≥ 3 with clinically significant impairment or distress), and completed ingestive behavior questionnaires. Connectivity differences were analyzed using a general linear model in the CONN Toolbox and images were segmented using the Schaefer 400, Harvard-Oxford Subcortical, and Ascending Arousal Network atlases. Significant connectivities and clinical variables were correlated. Statistical significance was corrected for multiple comparisons at q < .05. (1) Individuals with food addiction had greater connectivity between brainstem regions and the orbital frontal gyrus compared to individuals with no food addiction. (2) Females with food addiction had greater connectivity in the salience and emotional regulation networks and lowered connectivity between the default mode network and central executive network compared to males with food addiction. (3) Increased connectivity between regions of the reward network was positively associated with scores on the General Food Cravings Questionnaire-Trait, indicative of greater food cravings in individuals with food addiction. Individuals with food addiction showed greater connectivity between regions of the reward network suggesting dysregulation of the dopaminergic pathway. Additionally, greater connectivity in the locus coeruleus could indicate that the maladaptive food behaviors displayed by individuals with food addiction serve as a coping mechanism in response to pathological anxiety and stress. Sex differences in functional connectivity suggest that females with food addiction engage more in emotional overeating and less cognitive control and homeostatic processing compared to males. These mechanistic pathways may have clinical implications for understanding the sex-dependent variability in response to diet interventions.
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http://dx.doi.org/10.1038/s41598-021-83116-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873272PMC
February 2021

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis.

Nutrients 2020 Nov 30;12(12). Epub 2020 Nov 30.

Division of Hematology and Oncology, University of California, Los Angeles, CA 90095, USA.

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition ( = 0.046) with lower microbial species richness (Chao1) ( = 0.032) and evenness (Shannon) ( = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics ( < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, = 0.036; brainstem, = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies.
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http://dx.doi.org/10.3390/nu12123701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761087PMC
November 2020

Association between pain sensitivity and gray matter properties in the sensorimotor network in women with irritable bowel syndrome.

Neurogastroenterol Motil 2021 04 10;33(4):e14027. Epub 2020 Nov 10.

Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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.
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http://dx.doi.org/10.1111/nmo.14027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047895PMC
April 2021

Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome.

Transl Psychiatry 2020 11 2;10(1):367. Epub 2020 Nov 2.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, CA, USA.

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.
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http://dx.doi.org/10.1038/s41398-020-01071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608552PMC
November 2020

Improvement in Uncontrolled Eating Behavior after Laparoscopic Sleeve Gastrectomy Is Associated with Alterations in the Brain-Gut-Microbiome Axis in Obese Women.

Nutrients 2020 Sep 24;12(10). Epub 2020 Sep 24.

The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Background: Bariatric surgery is proven to change eating behavior and cause sustained weight loss, yet the exact mechanisms underlying these changes are not clearly understood. We explore this in a novel way by examining how bariatric surgery affects the brain-gut-microbiome (BGM) axis.

Methods: Patient demographics, serum, stool, eating behavior questionnaires, and brain magnetic resonance imaging (MRI) were collected before and 6 months after laparoscopic sleeve gastrectomy (LSG). Differences in eating behavior and brain morphology and resting-state functional connectivity in core reward regions were correlated with serum metabolite and 16S microbiome data.

Results: LSG resulted in significant weight loss and improvement in maladaptive eating behaviors as measured by the Yale Food Addiction Scale (YFAS). Brain imaging showed a significant increase in brain volume of the putamen (.adj < 0.05) and amygdala (.adj < 0.05) after surgery. Resting-state connectivity between the precuneus and the putamen was significantly reduced after LSG (.adj = 0.046). This change was associated with YFAS symptom count. , , and were associated with reduced connectivity between these areas. Metabolomic profiles showed a positive correlation between this brain connection and a phosphatidylcholine metabolite.

Conclusion: Bariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites.
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http://dx.doi.org/10.3390/nu12102924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599899PMC
September 2020

A Distinct Brain-Gut-Microbiome Profile Exists for Females with Obesity and Food Addiction.

Obesity (Silver Spring) 2020 08;28(8):1477-1486

Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, Department of Medicine, Los Angeles, California, USA.

Background: Alterations in brain-gut-microbiome interactions have been implicated as an important factor in obesity. This study aimed to explore the relationship between food addiction (FA) and the brain-gut-microbiome axis, using a multi-omics approach involving microbiome data, metabolomics, and brain imaging.

Methods: Brain magnetic resonance imaging was obtained in 105 females. FA was defined by using the Yale Food Addiction Scale. Fecal samples were collected for sequencing and metabolomics. Statistical analysis was done by using multivariate analyses and machine learning algorithms.

Results: Of the females with obesity, 33.3% exhibited FA as compared with 5.3% and 0.0% of females with overweight and normal BMI, respectively (P = 0.0001). Based on a multilevel sparse partial least square discriminant analysis, there was a difference in the gut microbiome of females with FA versus those without. Differential abundance testing showed Bacteroides, Megamonas, Eubacterium, and Akkermansia were statistically associated with FA (q < 0.05). Metabolomics showed that indolepropionic acid was inversely correlated with FA. FA was also correlated with increased connectivity within the brain's reward network, specifically between the intraparietal sulcus, brain stem, and putamen.

Conclusions: This is the first study to examine FA along the brain-gut-microbiome axis and it supports the idea of targeting the brain-gut-microbiome axis for the treatment of FA and obesity.
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http://dx.doi.org/10.1002/oby.22870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494955PMC
August 2020

Study protocol of the Bergen brain-gut-microbiota-axis study: A prospective case-report characterization and dietary intervention study to evaluate the effects of microbiota alterations on cognition and anatomical and functional brain connectivity in patients with irritable bowel syndrome.

Medicine (Baltimore) 2020 Sep;99(37):e21950

National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway.

Introduction: Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal (GI) symptoms, recently described as a disturbance of the brain-gut-microbiota (BGM) axis. To gain a better understanding of the mechanisms underlying the poorly understood etiology of IBS, we have designed a multifaceted study that aim to stratify the complex interaction and dysfunction between the brain, the gut, and the microbiota in patients with IBS.

Methods: Deep phenotyping data from patients with IBS (n = 100) and healthy age- (between 18 and 65) and gender-matched controls (n = 40) will be collected between May 2019 and December 2021. Psychometric tests, questionnaires, human biological tissue/samples (blood, faeces, saliva, and GI biopsies from antrum, duodenum, and sigmoid colon), assessment of gastric accommodation and emptying using transabdominal ultrasound, vagal activity, and functional and structural magnetic resonance imaging (MRI) of the brain, are included in the investigation of each participant. A subgroup of 60 patients with IBS-D will be further included in a 12-week low FODMAP dietary intervention-study to determine short and long-term effects of diet on GI symptoms, microbiota composition and functions, molecular GI signatures, cognitive, emotional and social functions, and structural and functional brain signatures. Deep machine learning, prediction tools, and big data analyses will be used for multivariate analyses allowing disease stratification and diagnostic biomarker detection.

Discussion: To our knowledge, this is the first study to employ unsupervised machine learning techniques and incorporate systems-based interactions between the central and the peripheral components of the brain-gut-microbiota axis at the levels of the multiomics, microbiota profiles, and brain connectome of a cohort of 100 patients with IBS and matched controls; study long-term safety and efficacy of the low-FODMAP diet on changes in nutritional status, gut microbiota composition, and metabolites; and to investigate changes in the brain and gut connectome after 12 weeks strict low-FODMAP-diet in patients with IBS. However, there are also limitations to the study. As a restrictive diet, the low-FODMAP diet carries risks of nutritional inadequacy and may foster disordered eating patterns. Strict FODMAP restriction induces a potentially unfavourable gut microbiota, although the health effects are unknown.

Trial Registration Number: NCT04296552 (ClinicalTrials.gov).
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http://dx.doi.org/10.1097/MD.0000000000021950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489588PMC
September 2020

Brain-gut-microbiome interactions in obesity and food addiction.

Nat Rev Gastroenterol Hepatol 2020 11 27;17(11):655-672. Epub 2020 Aug 27.

G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity Program, University of California Los Angeles, Los Angeles, CA, USA.

Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis.
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http://dx.doi.org/10.1038/s41575-020-0341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841622PMC
November 2020

The Role of Resilience in Irritable Bowel Syndrome, Other Chronic Gastrointestinal Conditions, and the General Population.

Clin Gastroenterol Hepatol 2020 Aug 21. Epub 2020 Aug 21.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Background & Aims: Resilience is the ability to adapt positively to stress and adversity. It is a potential therapeutic target as it is reduced in irritable bowel syndrome (IBS) compared to healthy controls and associated with worse symptom severity and poorer quality of life. The aim of this study was to examine if these findings are generalizable by comparing resilience between IBS versus the general population and other chronic gastrointestinal (GI) conditions.

Methods: Participants in the general population completed an online survey containing questionnaires measuring demographics, diagnosis of IBS and other GI conditions, symptom severity, psychological symptoms, resilience, and early adverse life events (EALs). IBS was defined as having a physician diagnosis of IBS and/or meeting Rome criteria without co-morbid GI disease. All others were included in the general population group. The chronic GI conditions group included those with inflammatory bowel disease, celiac disease and/or microscopic colitis.

Results: Resilience was lower in IBS (n = 820) than the general population (n = 1026; p < 0.001) and associated with worse IBS symptom severity (p < 0.05). Global mental health affected resilience differently in IBS compared to the general population (all p's < 0.05). EALs were associated with decreased ability to bounce back from adversity in both IBS and the general population (p < 0.001). Resilience scores were similar in IBS and other chronic GI conditions that present with similar symptoms.

Conclusions: Resilience is lower compared to the general U.S. population but does not appear to be specific to IBS as it is comparable to other chronic GI conditions. Low resilience negatively affects symptom severity and mental health and thus, may serve as a novel therapeutic target.
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http://dx.doi.org/10.1016/j.cgh.2020.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897330PMC
August 2020

Importance of trauma-related fear in patients with irritable bowel syndrome and early adverse life events.

Neurogastroenterol Motil 2020 09 17;32(9):e13896. Epub 2020 Jun 17.

G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background: Although early adverse life events (EALs) are prevalent among patients with irritable bowel syndrome (IBS), the impact of fear or dissociation experienced during the trauma has not been evaluated. We investigated the prevalence of fear at the time of trauma and its association with IBS status among individuals with early-life trauma before the age of 18.

Methods: Among participants with ≥1 EAL, association of fear and dissociation with IBS status was determined with logistic regression, and improvement in prediction of IBS over ETI score alone was determined with the likelihood ratio test. Controlling for age, sex, and IBS status, we then examined the association of each EAL with reported fear.

Key Results: Compared to healthy controls (HCs), IBS subjects reported a higher prevalence of fear (60.4% vs 36.2%, P < .0005) and dissociation (23.5% vs 13.0%, P < .0005) at the time of EAL. Fear, but not dissociation, improved prediction of IBS over the total number of EALs (odds ratio = 2.00, P < .0001).

Conclusions And Inferences: This study highlights the importance of EAL-related factors such as fear in addition to the presence or absence of EALs in IBS pathophysiology.
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http://dx.doi.org/10.1111/nmo.13896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483907PMC
September 2020

Postmenopausal women with irritable bowel syndrome (IBS) have more severe symptoms than premenopausal women with IBS.

Neurogastroenterol Motil 2020 10 29;32(10):e13913. Epub 2020 May 29.

Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background: Although irritable bowel syndrome (IBS) is more common in women, little is known about the role of hormonal changes and menopause in IBS. This study aimed to evaluate for differences in gastrointestinal (GI) and psychological symptoms between pre- and postmenopausal women with IBS compared to age-matched men with IBS.

Methods: Patients with Rome-positive IBS were identified. Premenopausal women were <45 years of age with regular menses. Postmenopausal women were ≥45 years without menses for at least 1 year. Younger men were <45 years, and older men were ≥45 years. Questionnaires measured severity of IBS symptoms, somatic symptoms, health-related quality of life (HRQOL), and psychological symptoms. Multivariable linear or logistic regressions evaluating relationships between age and sex were performed.

Key Results: 190 premenopausal women (mean age 30.25 years), 52 postmenopausal women (mean age 54.38 years), 190 men <45 years (mean age 30.45 years), and 52 men ≥45 years (mean age 53.37 years) were included. Postmenopausal IBS women had greater severity of IBS symptoms (P = .003) and worse physical HRQOL (P = .048) compared to premenopausal women. No differences were observed between age-matched older and younger IBS men. Constipation increased with age for both sexes but was the principal IBS subtype in women only.

Conclusions And Inferences: Postmenopausal women with IBS have more severe IBS symptoms than premenopausal women, while no comparable age-related changes were seen in IBS men. The modulatory effect of female sex hormones on brain-gut interactions which affect visceral perception and GI function likely contributes to these findings.
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http://dx.doi.org/10.1111/nmo.13913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529855PMC
October 2020

Chronic pain in children: structural and resting-state functional brain imaging within a developmental perspective.

Pediatr Res 2020 12 2;88(6):840-849. Epub 2019 Dec 2.

UCLA Pediatric Pain Program, Department of Pediatrics, David Geffen School of Medicine at UCLA, 650 Charles E. Young South #12-096 CHS, Los Angeles, CA, USA.

Chronic pain is a major public health problem in the United States costing $635 billion annually. Hospitalizations for chronic pain in childhood have increased almost tenfold in the past decade, without breakthroughs in novel treatment strategies. Findings from brain imaging studies using structural and resting-state fMRI could potentially help personalize treatment to address this costly and prevalent health problem by identifying the underlying brain pathways that contribute, facilitate, and maintain chronic pain. The aim of this review is to synthesize structural and resting-state network pathology identified by recent brain imaging studies in pediatric chronic pain populations and discuss the potential impact of chronic pain on cortical development. Sex differences as well as treatment effects on these cortical alterations associated with symptom changes are also summarized. This area of research is still in its infancy with currently limited evidence available from a small number of studies, some of which suffer from limitations such as small sample size and suboptimal methodology. The identification of brain signatures of chronic pain in children may help to develop new pathways for future research as well as treatment strategies.
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http://dx.doi.org/10.1038/s41390-019-0689-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263945PMC
December 2020

Impact of early adverse life events and sex on functional brain networks in patients with urological chronic pelvic pain syndrome (UCPPS): A MAPP Research Network study.

PLoS One 2019 20;14(6):e0217610. Epub 2019 Jun 20.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, United States of America.

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).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217610PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586272PMC
February 2020

Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis.

Microbiome 2019 03 21;7(1):45. Epub 2019 Mar 21.

G. Oppenheimer Center for Neurobiology of Stress & Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA CHS 42-210, MC737818, 10833 Le Conte Avenue, Los Angeles, CA, 90095-7378, USA.

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.
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http://dx.doi.org/10.1186/s40168-019-0656-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429755PMC
March 2019

Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study.

Pain 2019 07;160(7):1529-1540

Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, UCLA, Los Angeles, CA, United States.

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.
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http://dx.doi.org/10.1097/j.pain.0000000000001532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586504PMC
July 2019

Altered Brain Structure and Functional Connectivity and Its Relation to Pain Perception in Girls With Irritable Bowel Syndrome.

Psychosom Med 2019 Feb/Mar;81(2):146-154

From the Pediatric Pain and Palliative Care Program (Bhatt, Zeltzer, Tsao), Department of Pediatrics at UCLA, Los Angeles, California; David Geffen School of Medicine at UCLA (Bhatt, Gupta, Labus, Zeltzer, Tsao, Tillisch), Los Angeles, California; G. Oppenheimer Family Center for Neurobiology of Stress and Resilience at UCLA (Gupta, Labus, Tillisch), Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA (Gupta, Labus, Tillisch); VA Greater Los Angeles Healthcare System (Tillisch), Los Angeles, California; and Department of Pediatrics (Shulman), Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.

Objective: Imaging studies in adults with irritable bowel syndrome (IBS) have shown both morphological and resting state (RS) functional connectivity (FC) alterations related to cortical modulation of sensory processing. Because analogous differences have not been adequately investigated in children, this study compared gray matter volume (GMV) and RS-FC between girls with IBS and healthy controls (HC) and tested the correlation between brain metrics and laboratory-based pain thresholds (Pth).

Methods: Girls with Rome III criteria IBS (n = 32) and matched HCs (n = 26) were recruited. In a subset of patients, Pth were determined using a thermode to the forearm. Structural and RS scans were acquired. A voxel-based general linear model, adjusting for age, was applied to compare differences between groups. Seeds were selected from regions with group GMV differences for a seed-to-voxel whole brain RS-FC analysis. Significance for analyses was considered at p < .05 after controlling for false discovery rate. Significant group differences were correlated with Pth.

Results: Girls with IBS had lower GMV in the thalamus, caudate nucleus, nucleus accumbens, anterior midcingulate (aMCC), and dorsolateral prefrontal cortex. They also exhibited lower RS-FC between the aMCC and the precuneus, but greater connectivity between the caudate nucleus and precentral gyrus. Girls with IBS had higher Pth with a moderate effect size (t(22.81) = 1.63, p = .12, d = 0.64) and lower thalamic GMV bilaterally was correlated with higher Pth (left: r = -.62, p(FDR) = .008; right: r = -.51, p(FDR) = .08).

Conclusions: Girls with IBS had lower GMV in the PFC, basal ganglia, and aMCC, as well as altered FC between multiple brain networks, suggesting that structural changes related to IBS occur early in brain development. Girls with IBS also showed altered relationships between pain sensitivity and brain structure.
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http://dx.doi.org/10.1097/PSY.0000000000000655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355369PMC
April 2020

Risk and Protective Factors Related to Early Adverse Life Events in Irritable Bowel Syndrome.

J Clin Gastroenterol 2020 01;54(1):63-69

Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles.

Background: Irritable bowel syndrome (IBS) is a stress-sensitive disorder of brain-gut interactions associated with a higher prevalence of early adverse life events (EALs). However, it is incompletely understood how trauma severity or disclosure influence the risk of developing IBS or symptom severity.

Aims: To determine whether (1) IBS patients report a greater number of EALs compared with healthy controls; (2) trauma severity and first age of EAL increase the odds of IBS; (3) confiding in others reduces the odds of IBS; (4) the number, trauma severity, and first age of EAL are associated with symptom severity; (5) sex differences exist.

Methods: In total, 197 IBS patients (72% women, mean age=30.28 y) and 165 healthy controls (59% women, mean age=30.77 y) completed the Childhood Traumatic Events Scale, measuring severity of EALs and degree of confiding in others. Regression analyses were used to predict IBS status from EALs and association between gastrointestinal symptoms and EALs.

Results: A greater number of EALs [odds ratio (OR)=1.36, 95% confidence interval (CI), 1.14-1.62; P<0.001] and higher perceived trauma severity (OR=1.13, 95% CI, 1.08-1.19; P<0.001) were associated with increased odds of IBS. Confiding in others decreased the odds of having IBS (OR=0.83, 95% CI, 0.72-0.96; P=0.012). The first age of EAL was not predictive of IBS. No sex differences were found.

Conclusions: Assessing the traumatic severity of EALs and amount of confiding in others is important as they can affect the risk of having IBS. Our findings emphasize early intervention to improve health outcomes in individuals with EALs.
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http://dx.doi.org/10.1097/MCG.0000000000001153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802286PMC
January 2020

Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study.

Ann Behav Med 2018 09;52(10):865-877

Department of Psychological and Brain Sciences and Urology, University of Iowa, Iowa City, IA, USA.

Background: Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS).

Purpose: We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation.

Methods: For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being.

Results: ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year.

Conclusions: These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS.

Clinical Trial Registration: NCT01098279.
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http://dx.doi.org/10.1093/abm/kax060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135957PMC
September 2018

Influence of Early Life, Diet, and the Environment on the Microbiome.

Clin Gastroenterol Hepatol 2019 01 7;17(2):231-242. Epub 2018 Sep 7.

Vatche and Tamar Manoukin Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles, Los Angeles, California. Electronic address:

Advances in sequencing technology and bioinformatics have greatly enhanced our ability to understand the human microbiome. Over the last decade, a growing body of literature has linked nutrition and the environment to the microbiome and is now thought to be an important contributor to overall health. This paper reviews the literature from the past 10 years to highlight the influence of environmental factors such as diet, early life adversity and stress in shaping and modifying our microbiome towards health and disease. The review shows that many factors such as the mode of delivery, breast milk, stress, diet and medications can greatly influence the development of our gut microbiome and potentially make us more prone to certain diseases. By incorporating environmental factors into models that study the microbiome in the setting of health and disease, may provide a better understanding of disease and potentially new areas of treatment. To highlight this, we will additionally explore the role of the environment and the microbiome in the development of obesity and functional bowel disorders.
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http://dx.doi.org/10.1016/j.cgh.2018.08.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422042PMC
January 2019

Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects.

PLoS One 2018 6;13(8):e0201772. Epub 2018 Aug 6.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, CA, United States of America.

Objective: A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions play an important role in human health and disease, including hedonic food intake and obesity. We performed a tripartite network analysis based on graph theory to test the hypothesis that microbiota-derived fecal metabolites are associated with connectivity of key regions of the brain's extended reward network and clinical measures related to obesity.

Methods: DTI and resting state fMRI imaging was obtained from 63 healthy subjects with and without elevated body mass index (BMI) (29 males and 34 females). Subjects submitted fecal samples, completed questionnaires to assess anxiety and food addiction, and BMI was recorded.

Results: The study results demonstrate associations between fecal microbiota-derived indole metabolites (indole, indoleacetic acid, and skatole) with measures of functional and anatomical connectivity of the amygdala, nucleus accumbens, and anterior insula, in addition to BMI, food addiction scores (YFAS) and anxiety symptom scores (HAD Anxiety).

Conclusions: The findings support the hypothesis that gut microbiota-derived indole metabolites may influence hedonic food intake and obesity by acting on the extended reward network, specifically the amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit. These cross sectional, data-driven results provide valuable information for future mechanistic studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078307PMC
January 2019

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

J Pain 2018 05 31;19(5):528.e1-528.e15. Epub 2018 Jan 31.

G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California; David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs.

Perspective: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.
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http://dx.doi.org/10.1016/j.jpain.2017.12.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927835PMC
May 2018

Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity.

Obesity (Silver Spring) 2018 02 27;26(2):340-350. Epub 2017 Dec 27.

Ingestive Behavior and Obesity Program, Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and Resilience, Los Angeles, California, USA.

Objective: This study aimed to characterize obesity-related sex differences in the intrinsic activity and connectivity of the brain's reward networks.

Methods: Eighty-six women (n = 43) and men (n = 43) completed a 10-minute resting functional magnetic resonance imaging scan. Sex differences and commonalities in BMI-related frequency power distribution and reward seed-based connectivity were investigated by using partial least squares analysis.

Results: For whole-brain activity in both men and women, increased BMI was associated with increased slow-5 activity in the left globus pallidus (GP) and substantia nigra. In women only, increased BMI was associated with increased slow-4 activity in the right GP and bilateral putamen. For seed-based connectivity in women, increased BMI was associated with reduced slow-5 connectivity between the left GP and putamen and the emotion and cortical regulation regions, but in men, increased BMI was associated with increased connectivity with the medial frontal cortex. In both men and women, increased BMI was associated with increased slow-4 connectivity between the right GP and bilateral putamen and the emotion regulation and sensorimotor-related regions.

Conclusions: The stronger relationship between increased BMI and decreased connectivity of core reward network components with cortical and emotion regulation regions in women may be related to the greater prevalence of emotional eating. The present findings suggest the importance of personalized treatments for obesity that consider the sex of the affected individual.
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http://dx.doi.org/10.1002/oby.22060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783781PMC
February 2018

Brain Structure and Response to Emotional Stimuli as Related to Gut Microbial Profiles in Healthy Women.

Psychosom Med 2017 Oct;79(8):905-913

From the Oppenheimer Center for Neurobiology of Stress and Resilience (Tillisch, Mayer, Gupta, Gill, Labus), Departments of Medicine (Tillisch, Mayer, Gupta, Labus), Psychiatry (Mayer, Gupta), Division of Digestive Diseases, David Geffen School of Medicine at UCLA (Tillisch, Mayer, Gupta, Labus), UCLA Microbiome Center, Ahmanson-Lovelace Brain Mapping Center, UCLA (Mayer), Integrative Medicine, GLA VHA (Tillisch), UCLA Brain Research Institute (Labus), Los Angeles, CA; Danone Research (Brazeilles, Le Nevé, Derrien), Palaiseau, France; Microbiome & Human Health Innovation (van Hylckama Vlieg), Hoersholm, Denmark; and Symrise Group (Guyonnet), Clichy-la-Garenne, France.

Objective: Brain-gut-microbiota interactions may play an important role in human health and behavior. Although rodent models have demonstrated effects of the gut microbiota on emotional, nociceptive, and social behaviors, there is little translational human evidence to date. In this study, we identify brain and behavioral characteristics of healthy women clustered by gut microbiota profiles.

Methods: Forty women supplied fecal samples for 16S rRNA profiling. Microbial clusters were identified using Partitioning Around Medoids. Functional magnetic resonance imaging was acquired. Microbiota-based group differences were analyzed in response to affective images. Structural and diffusion tensor imaging provided gray matter metrics (volume, cortical thickness, mean curvature, surface area) as well as fiber density between regions. A sparse Partial Least Square-Discrimination Analysis was applied to discriminate microbiota clusters using white and gray matter metrics.

Results: Two bacterial genus-based clusters were identified, one with greater Bacteroides abundance (n = 33) and one with greater Prevotella abundance (n = 7). The Prevotella group showed less hippocampal activity viewing negative valences images. White and gray matter imaging discriminated the two clusters, with accuracy of 66.7% and 87.2%, respectively. The Prevotella cluster was associated with differences in emotional, attentional, and sensory processing regions. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus.

Conclusions: These results support the concept of brain-gut-microbiota interactions in healthy humans. Further examination of the interaction between gut microbes, brain, and affect in humans is needed to inform preclinical reports that microbial modulation may affect mood and behavior.
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http://dx.doi.org/10.1097/PSY.0000000000000493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089374PMC
October 2017

Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery.

Psychosom Med 2017 Oct;79(8):880-887

From the Ingestive Behavior and Obesity Program (Sanmiguel, Gupta, Ju, Stains, Coveleskie, Mayer, Labus), Oppenheimer Center for Neurobiology of Stress & Resilience; Department of Surgery (Balioukova, Chen, Dutson), Center for Obesity and Metabolic Health; UCLA Microbiome Center (Sanmiguel, Jacobs, Lagishetty, Mayer, Labus); and David Geffen School of Medicine at UCLA (Sanmiguel, Jacobs, Gupta, Ju, Stains, Lagishetty, Balioukova, Chen, Dutson, Mayer, Labus), Los Angeles, California.

Objective: Weight loss surgery results in significant changes in the anatomy, function, and intraluminal environment of the gastrointestinal tract affecting the gut microbiome. Although bariatric surgery results in sustained weight loss, decreased appetite, and hedonic eating, it is unknown whether the surgery-induced alterations in gut microbiota play a role in the observed changes in hedonic eating. We explored the following hypotheses: (1) laparoscopic sleeve gastrectomy (LSG) results in changes in gut microbial composition; (2) alterations in gut microbiota are related to weight loss; (3) alterations in gut microbiome are associated with changes in appetite and hedonic eating.

Methods: Eight obese women underwent LSG. Their body mass index, body fat mass, food intake, hunger, hedonic eating scores, and stool samples were obtained at baseline and 1-month postsurgery. 16S ribosomal RNA gene sequencing was performed on stool samples. DESeq2 changes in microbial abundance. Multilevel-sparse partial least squares discriminant analysis was applied to genus-level abundance for discriminative microbial signatures.

Results: LSG resulted in significant reductions in body mass index, food intake, and hedonic eating. A microbial signature composed of five bacterial genera discriminated between pre- and postsurgery status. Several bacterial genera were significantly associated with weight loss (Bilophila, q = 3E-05; Faecalibacterium q = 4E-05), lower appetite (Enterococcus, q = 3E-05), and reduced hedonic eating (Akkermansia, q = .037) after surgery.

Conclusions: In this preliminary analysis, changes in gut microbial abundance discriminated between pre- and postoperative status. Alterations in gut microbiome were significantly associated with weight loss and with reduced hedonic eating after surgery; however, a larger sample is needed to confirm these findings.
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http://dx.doi.org/10.1097/PSY.0000000000000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628115PMC
October 2017

Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome.

Microbiome 2017 05 1;5(1):49. Epub 2017 May 1.

Division of Digestive Diseases, David Geffen School at UCLA, Los Angeles, CA, 90095, USA.

Background: Preclinical and clinical evidence supports the concept of bidirectional brain-gut microbiome interactions. We aimed to determine if subgroups of irritable bowel syndrome (IBS) subjects can be identified based on differences in gut microbial composition, and if there are correlations between gut microbial measures and structural brain signatures in IBS.

Methods: Behavioral measures, stool samples, and structural brain images were collected from 29 adult IBS and 23 healthy control subjects (HCs). 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. The metagenomic content of samples was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). T1-weighted brain images were acquired on a Siemens Allegra 3T scanner, and morphological measures were computed for 165 brain regions.

Results: Using unweighted Unifrac distances with hierarchical clustering on microbial data, samples were clustered into two IBS subgroups within the IBS population (IBS1 (n = 13) and HC-like IBS (n = 16)) and HCs (n = 23) (AUROC = 0.96, sensitivity 0.95, specificity 0.67). A Random Forest classifier provided further support for the differentiation of IBS1 and HC groups. Microbes belonging to the genera Faecalibacterium, Blautia, and Bacteroides contributed to this subclassification. Clinical features distinguishing the groups included a history of early life trauma and duration of symptoms (greater in IBS1), but not self-reported bowel habits, anxiety, depression, or medication use. Gut microbial composition correlated with structural measures of brain regions including sensory- and salience-related regions, and with a history of early life trauma.

Conclusions: The results confirm previous reports of gut microbiome-based IBS subgroups and identify for the first time brain structural alterations associated with these subgroups. They provide preliminary evidence for the involvement of specific microbes and their predicted metabolites in these correlations.
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http://dx.doi.org/10.1186/s40168-017-0260-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410709PMC
May 2017
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