Analysis of brain networks and fecal metabolites reveals brain-gut alterations in premenopausal females with irritable bowel syndrome.
ABSTRACT: 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?
Project description:Irritable bowel syndrome (IBS) is a chronic functional disorder and its development may be linked, directly and indirectly, to intestinal dysbiosis. Here we investigated the interactions between IBS symptoms and the gut microbiome, including the relation to rifaximin (1200 mg daily; 11.2 g per a treatment). We recruited 72 patients, including 31 with IBS-D (diarrhea), 11 with IBS-C (constipation), and 30 with IBS-M (mixed constipation and diarrhea) and 30 healthy controls (HCs). Of them, 68%, 64%, and 53% patients with IBS-D, IBS-C, and IBS-M, respectively, achieved 10-12 week-term improvement after the rifaximin treatment. Stool samples were collected before and after the treatment, and fecal microbiotic profiles were analyzed by deep sequencing of 16S rRNA, while stool metabolic profiles were studied by hydrogen 1-nuclear magnetic resonance ((1)H-NMR) and gas chromatography-mass spectrometry (GC-MS). Of 26 identified phyla, only Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria were consistently found in all samples. Bacteroidetes was predominant in fecal samples from HCs and IBS-D and IBS-M subjects, whereas Firmicutes was predominant in samples from IBS-C subjects. Species richness, but not community diversity, differentiated all IBS patients from HCs. Metabolic fingerprinting, using NMR spectra, distinguished HCs from all IBS patients. Thirteen metabolites identified by GC-MS differed HCs and IBS patients. However, neither metagenomics nor metabolomics analyses identified significant differences between patients with and without improvement after treatment.
Project description:The goal of this study was to determine if fecal metabolite and microbiota profiles can serve as biomarkers of human intestinal diseases, and to uncover possible gut microbe-metabolite associations. We employed proton nuclear magnetic resonance to measure fecal metabolites of healthy children and those diagnosed with diarrhea-predominant irritable bowel syndrome (IBS-D). Metabolite levels were associated with fecal microbial abundances. Using several ordination techniques, healthy and irritable bowel syndrome (IBS) samples could be distinguished based on the metabolite profiles of fecal samples, and such partitioning was congruent with the microbiota-based sample separation. Measurements of individual metabolites indicated that the intestinal environment in IBS-D was characterized by increased proteolysis, incomplete anaerobic fermentation and possible change in methane production. By correlating metabolite levels with abundances of microbial genera, a number of statistically significant metabolite-genus associations were detected in stools of healthy children. No such associations were evident for IBS children. This finding complemented the previously observed reduction in the number of microbe-microbe associations in the distal gut of the same cohort of IBS-D children.
Project description:BACKGROUND:Recent studies indicate that gut microbiota disorders potentially contribute to the pathogenesis of irritable bowel syndrome (IBS), which can be partly reflected by fecal short-chain fatty acids (SCFAs) generated from gut microbiota. Previous studies on SCFA alterations in patients with IBS have yielded conflicting results. No prior systematic review has been conducted on the alterations in fecal SCFAs in IBS patients. AIMS:We performed a meta-analysis to explore and clarify alterations in fecal SCFAs in IBS patients. METHODS:Case-control studies, randomized controlled trials (RCTs), and self-controlled studies were identified through electronic database searches. The standardized mean difference (SMD) with 95% confidence interval (CI) in fecal SCFA levels between different groups was calculated. RESULTS:The proportion of fecal propionate in patients with IBS was significantly higher than in healthy controls (HCs) (SMD = 0.44, 95% CI = 0.12, 0.76). A subgroup analysis showed that the concentration of fecal propionate (SMD = -0.91, 95% CI = -1.41, -0.41) and butyrate (SMD = -0.53, 95% CI = -1.01, -0.04) in patients with constipation-predominant IBS (IBS-C) was significantly lower than that in HCs, and the concentration of fecal butyrate in patients with diarrhea-predominant IBS (IBS-D) was higher than that in HCs (SMD = 0.34, 95% CI = 0.00, 0.67). Finally, we found that restricted diets correlated with fecal butyrate reduction in IBS (SMD = -0.26, 95% CI = -0.51, -0.01). CONCLUSIONS:In terms of fecal SCFAs, there were differences between patients with IBS and HCs. In IBS-C patients, propionate and butyrate were reduced, whereas butyrate was increased in IBS-D patients in comparison to HCs. Propionate and butyrate could be used as biomarkers for IBS diagnosis.
Project description:Irritable bowel syndrome (IBS) is a common gastrointestinal dysfunctional disease. The pathophysiology of IBS is, however, largely unknown. This study aimed to determine whether evaluation of fecal metabolite and microbiota profiles may offer an opportunity to identify a novel pathophysiological target for IBS, and to reveal possible gut microbe-metabolite associations. By using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) and 16S rRNA gene sequencing, we measured fecal metabolites and microbiota of the control and water avoidance stress (WAS)-induced IBS rats. We found a significantly differential metabolite profile between the IBS and control groups; a cluster of metabolites was also found to be significantly associated with the amount of defecations. Moreover, the WAS group exhibited a decreased alpha diversity of the microbial population as compared to the control group. However, the characteristics of gut microbiota could not differentiate the IBS group from the control group. Correlation of the metabolite level with the number of microbial genera showed no significant association between the control and IBS groups. This study provides a global perspective on metabolomics and microbiota profiling in WAS-induced IBS model and a theoretical basis for research on the pathophysiology of IBS.
Project description:<h4>Background/aims</h4>Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels.<h4>Methods</h4>Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified.<h4>Results</h4>Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (<i>P</i> = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively).<h4>Conclusion</h4>Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.
Project description:Background and Aims: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. However, the underlying mechanism of IBS is not fully understood. The aim of this study was to investigate potential mechanism and novel biomarkers of IBS through evaluation of the metabolomic and microbiologic profile. Methods: Fecal samples were collected from 15 irritable bowel syndrome patients and 15 healthy controls. By using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) and 16S rDNA amplicon sequencing, fecal metabolites and microbiota of healthy controls and the IBS patients were measured. Results: IBS patients had a significantly differential metabolite profile as compared to healthy controls, and 4 clusters with 31 metabolites, including a group of amino acids and fatty acids, were significantly up-regulated as compared to the healthy controls. In addition, 19 microbes were significantly up-regulated, and 12 microbes were down-regulated in the IBS group, when compared with the healthy controls. Some clusters of fecal metabolites or microorganisms were significantly correlated with the severity of IBS symptoms, such as the frequency of abdominal pain/discomfort and the number of bowel movements. Correlation of the metabolite levels with abundances of microbial genera showed some statistically significant metabolite-microbe associations. Four differentially abundant amino acids clustered together were positively correlated with some microbes, including Lachnospira, Clostridium, and so on. Conclusion: The finding of this study puts a global perspective on metabolomics and microbiota profiling in IBS patients and provides a theoretical basis for future research on pathophysiology of IBS.
Project description:Although intestinal dysbiosis is well established in Crohn's disease (CD), little is known about the microbial metabolic activity of CD patients. In this study, we compared the metabolite patterns of the CD patients with profiles from healthy controls (HCs) and correlated them to disease activity and bacterial composition. In addition, the influence of the prebiotic oligofructose-enriched inulin (OF-IN) on the CD metabolites profile was evaluated.Sixty-seven inactive and moderately active CD patients were included in a double-blinded randomized placebo controlled trial (RCT). Patients consumed either 10?g OF-IN or 10?g placebo twice per day for 4 weeks. They collected a fecal sample before the start of the study (baseline) and after the treatment period. In addition, fecal samples were obtained from 40 HCs. The metabolite profile was assessed using gas chromatography-mass spectrometry.The number of fecal metabolites was significantly higher in HCs than in CD patients (P<0.001). Forty compounds differed between CD patients and HCs. When correlating the metabolite levels to disease activity, significantly lower levels of butyrate, pentanoate, hexanoate, heptanoate, and p-cresol were found in active patients as compared with HCs. In the RCT, no significant changes in the metabolite pattern were found in patients randomized to placebo. In patients receiving OF-IN (per protocol; n=21), the relative levels of acetaldehyde (P=0.0008) and butyrate (P=0.0011) were significantly increased as compared with baseline.We identified medium chain fatty acids and p-cresol as differentiating metabolites toward CD disease status and as compared with HCs. In addition, OF-IN intake primarily increased the carbohydrate fermentation metabolites butyrate and acetaldehyde.
Project description:Greater responsiveness of emotional arousal circuits in relation to delivered visceral pain has been implicated as underlying central pain amplification in irritable bowel syndrome (IBS), with female subjects showing greater responses than male subjects. Functional magnetic resonance imaging was used to measure neural responses to an emotion recognition paradigm, using faces expressing negative emotions (fear and anger). Sex and disease differences in the connectivity of affective and modulatory cortical circuits were studied in 47 IBS (27 premenopausal female subjects) and 67 healthy control subjects (HCs; 38 premenopausal female subjects). Male subjects (IBS+HC) showed greater overall brain responses to stimuli than female subjects in prefrontal cortex, insula, and amygdala. Effective connectivity analyses identified major sex- and disease-related differences in the functioning of brain networks related to prefrontal regions, cingulate, insula, and amygdala. Male subjects had stronger connectivity between anterior cingulate subregions, amygdala, and insula, whereas female subjects had stronger connectivity to and from the prefrontal modulatory regions (medial/dorsolateral cortex). Male IBS subjects demonstrate greater engagement of cortical and affect-related brain circuitry compared to male control subjects and female subjects, when viewing faces depicting emotions previously shown to elicit greater behavioral and brain responses in male subjects.
Project description:Alterations in gray matter (GM) density/volume and cortical thickness (CT) have been demonstrated in small and heterogeneous samples of subjects with differing chronic pain syndromes, including irritable bowel syndrome (IBS). Aggregating across 7 structural neuroimaging studies conducted at University of California, Los Angeles, Los Angeles, CA, USA, between August 2006 and April 2011, we examined group differences in regional GM volume in 201 predominantly premenopausal female subjects (82 IBS, mean age: 32±10 SD, 119 healthy controls [HCs], 30±10 SD). Applying graph theoretical methods and controlling for total brain volume, global and regional properties of large-scale structural brain networks were compared between the group with IBS and the HC group. Relative to HCs, the IBS group had lower volumes in the bilateral superior frontal gyrus, bilateral insula, bilateral amygdala, bilateral hippocampus, bilateral middle orbital frontal gyrus, left cingulate, left gyrus rectus, brainstem, and left putamen. Higher volume was found in the left postcentral gyrus. Group differences were no longer significant for most regions when controlling for the Early Trauma Inventory global score, with the exception of the right amygdala and the left postcentral gyrus. No group differences were found for measures of global and local network organization. Compared to HCs, in patients with IBS, the right cingulate gyrus and right thalamus were identified as being significantly more critical for information flow. Regions involved in endogenous pain modulation and central sensory amplification were identified as network hubs in IBS. Overall, evidence for central alterations in patients with IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks.
Project description:BACKGROUND:Short-chain fatty acids (SCFAs) alteration have been reported in irritable bowel syndrome (IBS), but the results are conflicting. Our study aims to explore the alteration of SCFAs in patients with diarrhea-predominant IBS (IBS-D) and their potential role in the occurrence and development of IBS. METHODS:We recruited patients with IBS-D defined by Rome IV criteria and age-and-gender matched healthy controls (HCs). A headspace solid-phase microextraction gas chromatography-mass spectrometric (HS-SPME-GC-MS) method was developed for the analysis of acetic, propionic and butyric acid in feces and serum. RESULTS:Compared with HCs, the levels of the serum propionate (2.957?±?0.157 vs 2.843?±?0.098?mmol/L, P?=?0.012) and butyrate (2.798?±?0.126 vs 2.697?±?0.077?mmol/L, P?=?0.012) were significantly higher in IBS-D group. No significant differences were found among two groups with regard to the concentration of fecal acetate (4.953?±?1.065 vs 4.774?±?1.465?mg/g, P?=?0.679), propionate (6.342?±?1.005 vs 6.282?±?1.077?mg/g, P?=?0.868) and butyrate (2.984?±?0.512 vs 3.071?±?0.447?mg/g, P?=?0.607). CONCLUSIONS:Metabolites of gut microbiota, the propionic and butyric acid, are increased in patients with IBS-D in serum but not in feces. It suggests that propionic and butyric acid might be associated with the occurrence and development of IBS.