Kristen Coveleskie

The HTR3A Polymorphism c. -42C>T Is Associated With Amygdala Responsiveness in Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS 5-Hydroxytryptamine (5-HT)3 receptor (5-HT3R) antagonists are effective in treating patients with irritable bowel syndrome (IBS) and have anxiolytic effects. Their therapeutic effects are related, in part, to reducing amygdala engagement during expected visceral pain. A single nucleotide polymorphism in HTR3A, c.-42C>T;(C178T; rs1062613), is associated with altered reactivity of the amygdala during emotional face processing in healthy subjects (controls). We evaluated the influence of this single nucleotide polymorphism on amygdala reactivity to emotional faces and nonemotional stimuli in female patients with IBS and controls. METHODS We measured brain responses during an affect-matching paradigm in 54 women (26 with IBS, 29 controls) using functional magnetic resonance imaging. We examined associations between HTR3A c.-42C>T genotype (C/C vs T carrier) and responses in amygdala and other regions of brain that expressed high levels of 5-HT3R. RESULTS The C/C genotype was associated with greater anxiety symptoms in patients with IBS and controls and increased activation of the amygdala under emotional and nonemotional conditions. Among patients with IBS, C/C genotype was associated with greater symptom ratings. A subset of IBS patients with the C/C genotype had increased amygdala responses to nonemotional stimuli, compared with other subjects with C/C genotype. CONCLUSIONS Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared with T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and nonemotional tasks. This polymorphism was associated with severity of IBS symptoms. Although this genotype is not sufficient for diagnosis of IBS, it is associated with severity of symptoms.

Sex Differences in Emotion-related Cognitive Processes in Irritable Bowel Syndrome and Healthy Control Subjects

Summary Sex differences in the engagement of brain networks in response to negative emotional faces were investigated. Male irritable bowel syndrome subjects demonstrated differential engagement of emotional arousal circuits. Abstract 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.

Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women.

BACKGROUND & AIMS The study of intrinsic fluctuations in the blood oxygen level-dependent signal of functional magnetic resonance imaging can provide insight into the effect of physiologic states on brain processes. In an effort to better understand the brain-gut communication induced by the absorption and metabolism of nutrients in healthy lean and obese individuals, we investigated whether ingestion of nutritive and non-nutritive sweetened beverages differentially engages the hypothalamus and brainstem vagal pathways in lean and obese women. METHODS In a 2-day, double-blind crossover study, 11 lean and 11 obese healthy women underwent functional magnetic resonance imaging scans after ingestion of 2 beverages of different sucrose content, but identical sweetness. During scans, subjects rested with eyes closed. RESULTS Blood oxygen level-dependent fluctuations demonstrated significantly greater power in the highest frequency band (slow-3: 0.073-0.198 Hz) after ingestion of high-sucrose compared with low-sucrose beverages in the nucleus tractus solitarius for both groups. Obese women had greater connectivity between the right lateral hypothalamus and a reward-related brain region and weaker connectivity with homeostasis and gustatory-related brain regions than lean women. CONCLUSIONS In a functional magnetic resonance imaging study, we observed sucrose-related changes in oscillatory dynamics of blood oxygen level-dependent fluctuations in brainstem and hypothalamus in lean and obese women. The observed frequency changes are consistent with a rapid vagally mediated mechanism due to nutrient absorption, rather than sweet taste receptor activation. These findings provide support for altered interaction between homeostatic and reward networks in obese individuals.

Differences in brain responses between lean and obese women to a sweetened drink

Ingestion of sweet food is driven by central reward circuits and restrained by endocrine and neurocrine satiety signals. The specific influence of sucrose intake on central affective and reward circuitry and alterations of these mechanisms in the obese are incompletely understood. For this, we hypothesized that (i) similar brain regions are engaged by the stimulation of sweet taste receptors by sucrose and by non‐nutrient sweeteners and (ii) during visual food‐related cues, obese subjects show greater brain responses to sucrose compared with lean controls.

Surgically induced changes in gut microbiome and hedonic eating as related to weight loss: Preliminary findings in obese women undergoing bariatric surgery.

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.

The Effect of the GLP-1 analogue Exenatide on Functional Connectivity within an NTS-Based Network in Females With and Without Obesity

The 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.

38 Effect of the GLP-1 Analogue Exenatide on Functional Connectivity Within Hedonic and Homeostatic Brain Networks in Lean and Obese Women

G A A b st ra ct s developed pulmonary embolism. Percentage total body weight loss (TBWL) was 14.2 ± 3.3%, 15.4 ± 6%, 17 ± 8%, and 14 ± 12% at 3, 6, 9, 12 months, respectively (p=0.002). Fifty percent of subjects had a good response to ESG at 12 months with an average weight loss of 22 ± 5 kg representing 80 ± 12% excess weight loss (%EWL). Forty percent of the cohort had minimal response to ESG at 12 months with and average weight loss of only 3.2 ± 2.8 kg, and one subject was lost to follow-up. Patients reported improvement in all domains of eating behavior (cognitive restraint [p=0.02], emotional eating [p=0.006], and uncontrolled eating [p=0.06] assessed by TFEQ21. Repeat upper endoscopy at 3 months showed intact sleeve gastroplasty with formation of fibrotic bridges. ESG significantly alters satiation with lower caloric intake to reach maximum fullness leading to termination of the meal from 1086±302 kcal pre-ESG to 446±198 kcal post-ESG (p= 0.003). Furthermore, ESG significantly delays gastric emptying of solids with an 82 minute (79%) increase in time to empty 50% of the ingested meal (p=0.03). ESG improves insulin sensitivity (p= 0.05). Serum leptin significantly decreases after ESG (p <0.001); however, ghrelin levels fail to increase despite significant weight loss. Conclusions: ESG appear to produce significant weight loss and perturbations in gastric function and eating behavior in a significant portion of subjects.