Altered appetite in Crohn’s Disease: deconstructing the enteroendocrine axis using fMRI

Reduced appetite has been observed in patients with ileal Crohn’s disease, which has been attributed to the upregulation of enteroendocrine cells and the consequent increase of satiety hormones secretion, therefore possibly negatively affecting appetite signalling to the central nervous system. The specific hypotheses to be tested in this thesis were that Crohn’s disease patients with ileal inflammation, when compared with Crohn’s disease patients with colonic inflammation and healthy controls, will show A) an alteration in brain-gut stimulation, B) an increase in the postprandial plasma enteroendocrine peptides response (CCK, GLP-1 and PYY) with associated alteration in appetite scores, C) a change in eating behaviour, and D) an alteration in brain structure and resting-state functional connectivity. Ileal Crohn’s disease patients showed greater fasting GLP-1 concentrations compared with healthy controls. No difference was found between ileal and colonic Crohn’s disease patients in the fasting and postprandial concentrations of GLP-1, CCK and PYY. The ileal Crohn’s disease patients showed a greater postprandial decrease in neuronal activity in the right superior frontal gyrus in the default mode network in response to saline compared with the fat meal. The mechanism underlying this phenomenon is unclear and requires further investigation. Greater neuronal activity was found in areas including the cerebellum, hippocampus, posterior cingulate gyrus, middle temporal gyrus, thalamus and medulla in response to fat, which is in line with the previous literature. The fat induced greater activity of the posterior cingulate gyrus, was driven by Crohn’s disease patients, with colonic Crohn’s disease patients showing stronger activation in this region compared with the ileal Crohn’s disease patients. This finding may be linked with abdominal pain or GLP-1 elevations, which remains to be investigated. Stronger hedonic control of food intake was observed in the ileal CD patients compared with healthy controls, based on their explicit wanting/liking appeal bias for high-fat foods, however, this was not translated into actual increased calorie intake, perhaps because of fear of triggering or worsening symptoms. Ileal CD patients also exhibited greater impulsivity compared with colonic CD patients. These findings indicate that eating behaviour in ileal Crohn’s disease patients is likely to be impulse and reward-driven to alleviate symptoms such as low mood, abdominal pain and chronic fatigue. Therefore, a complex interplay of gut peptides, psychological factors, disease related symptoms, inflammatory burden may ultimately guide eating behaviour in ileal CD patients. Grey matter and white matter volume atrophy and cortical thinning were found in active Crohn’s disease patients in regions such as the precentral gyrus (motor cortex) and the postcentral gyrus. The relative atrophy of the motor cortex could be a possible central cause of fatigue in Crohn’s disease patients. Alterations were found in the resting-state functional connectivity between Crohn’s disease patients and healthy controls in the networks implicated in cognition, attention, emotion and pain. These findings may reflect neuroplasticity effects in response to chronic inflammation and disease symptoms such as abdominal pain and fatigue. This work was carried out between June 2015 and September 2019 at the National Institute of Health Research,Nottingham Biomedical Research Centre at the Queens Medical Centre Campus and the Sir Peter Mansfield Imaging Centre Nottingham.All work described in this thesis was performed by the author, except where indicated

The Gut–Brain Axis and Its Role in Controlling Eating Behavior in Intestinal Inflammation

Malnutrition represents a major problem in the clinical management of the inflammatorybowel disease (IBD). Presently, our understanding of the cross-link between eating behavior andintestinal inflammation is still in its infancy. Crohn’s disease patients with active disease exhibit stronghedonic desires for food and emotional eating patterns possibly to ameliorate feelings of low mood,anxiety, and depression. Impulsivity traits seen in IBD patients may predispose them to palatablefood intake as an immediate reward rather than concerns for future health. The upregulation ofenteroendocrine cells (EEC) peptide response to food intake has been described in ileal inflammation,which may lead to alterations in gut–brain signaling with implications for appetite and eatingbehavior. In summary, a complex interplay of gut peptides, psychological, cognitive factors, diseaserelatedsymptoms, and inflammatory burden may ultimately govern eating behavior in intestinalinflammation

An examination of resting-state functional connectivity in patients with active Crohn’s disease

Background: Alterations in resting state functional connectivity (rs-FC) in Crohn’s Disease (CD) have been documented in default mode network (DMN) and frontal parietal network (FPN) areas, visual, cerebellar, salience and attention resting-state-networks (RSNs), constituting a CD specific neural phenotype. To date, most studies are in patients in remission, with limited studies in active disease. Methods: 25 active CD cases and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited to a resting-state-functional Magnetic Resonance Imaging (rs-fMRI) study. Active disease was defined as C-reactive protein>5mg/dl, faecal calprotectin>250μg/g, or through ileocolonoscopy or MRE. rs-fMRI data were analysed using independent component analysis (ICA) and dual regression. Differences in RSNs between HCs and active CD were assessed, and rs-FC was associated with disease duration and abdominal pain. Results: Increased connectivity in the FPN (fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) and visual RSN (orbital frontal cortex) were observed in CD versus HC. Decreased activity was observed in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) in CD versus HCs. Greater abdominal pain scores were associated with lower connectivity in the precuneus (visual network) and parietal operculum (salience network), and higher connectivity in the cerebellum (frontal network). Greater disease duration was associated with greater connectivity in the middle temporal gyrus and planum temporale (visual network). Conclusion: Alterations in rs-FC in active CD in RSNs implicated in cognition, attention, emotion, and pain may represent neural correlates of chronic systemic inflammation, abdominal pain, disease duration, and severity

The relationship between Central Nervous System morphometry changes and key symptoms in Crohn’s disease

Alterations in grey matter volume (GMV) and cortical thickness (CT) in Crohn’s disease (CD) patients has been previously documented. However, the findings are inconsistent, and not a true representation of CD burden, as only CD patients in remission have been studied thus far. We investigate alterations in brain morphometry in patients with active CD and those in remission, and study relationships between brain structure and key symptoms of fatigue, abdominal pain, and extraintestinal manifestations (EIM).Magnetic Resonance Imaging brain scans were collected in 89 participants; 34 CD participants with active disease, 13 CD participants in remission and 42 healthy controls (HCs); Voxel based morphometry (VBM) assessed GMV and white matter volume (WMV), and surface-based analysis assessed cortical thickness (CT).We show a significant reduction in global cerebrospinal fluid (CSF) volume in CD participants compared with HCs, as well as, a reduction in regional GMV, WMV and CT in the left precentral gyrus (motor cortex), and an increase in GMV in the frontal brain regions in CD compared with HCs. Atrophy of the supplementary motor area (SMA) was associated with greater fatigue in CD. We also show alterations in brain structure in multiple regions in CD associated with abdominal pain and extraintestinal inflammations (EIMs).These brain structural alterations likely reflect neuroplasticity to a chronic systemic inflammatory response, abdominal pain, EIMs and fatigue. These findings will aid our understanding of the cross-linking between chronic inflammation, brain structural changes and key unexplained CD symptomatology like fatigue

An examination of resting-state functional connectivity in patients with active Crohn’s disease

BackgroundAlterations in resting state functional connectivity (rs-FC) in Crohn’s Disease (CD) have been documented in default mode network (DMN) and frontal parietal network (FPN) areas, visual, cerebellar, salience and attention resting-state-networks (RSNs), constituting a CD specific neural phenotype. To date, most studies are in patients in remission, with limited studies in active disease.MethodsTwenty five active CD cases and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited to a resting-state-functional Magnetic Resonance Imaging (rs-fMRI) study. Active disease was defined as C-reactive protein>5 mg/dL, faecal calprotectin>250 μg/g, or through ileocolonoscopy or MRE. rs-fMRI data were analysed using independent component analysis (ICA) and dual regression. Differences in RSNs between HCs and active CD were assessed, and rs-FC was associated with disease duration and abdominal pain.ResultsIncreased connectivity in the FPN (fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) and visual RSN (orbital frontal cortex) were observed in CD versus HC. Decreased activity was observed in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) in CD versus HCs. Greater abdominal pain scores were associated with lower connectivity in the precuneus (visual network) and parietal operculum (salience network), and higher connectivity in the cerebellum (frontal network). Greater disease duration was associated with greater connectivity in the middle temporal gyrus and planum temporale (visual network).ConclusionAlterations in rs-FC in active CD in RSNs implicated in cognition, attention, emotion, and pain may represent neural correlates of chronic systemic inflammation, abdominal pain, disease duration, and severity

Parent-reported child appetite moderates relationships between child genetic obesity risk and parental feeding practices

BackgroundFood parenting practices are associated with child weight. Such associations may reflect the effects of parents' practices on children's food intake and weight. However, longitudinal, qualitative, and behavioral genetic evidence suggests these associations could, in some cases, reflect parents' response to children's genetic risk for obesity, an instance of gene–environment correlation. We tested for gene–environment correlations across multiple domains of food parenting practices and explored the role of parent-reported child appetite in these relationships.Materials and methodsData on relevant variables were available for N = 197 parent–child dyads (7.54 ± 2.67 years; 44.4% girls) participating in RESONANCE, an ongoing pediatric cohort study. Children's body mass index (BMI) polygenic risk score (PRS) were derived based on adult GWAS data. Parents reported on their feeding practices (Comprehensive Feeding Practices Questionnaire) and their child's eating behavior (Child Eating Behavior Questionnaire). Moderation effects of child eating behaviors on associations between child BMI PRS and parental feeding practices were examined, adjusting for relevant covariates.ResultsOf the 12 parental feeding practices, 2 were associated with child BMI PRS, namely, restriction for weight control (β = 0.182, p = 0.011) and teaching about nutrition (β = −0.217, p = 0.003). Moderation analyses demonstrated that when children had high genetic obesity risk and showed moderate/high (vs. low) food responsiveness, parents were more likely to restrict food intake to control weight.ConclusionOur results indicate that parents may adjust their feeding practices in response to a child's genetic propensity toward higher or lower bodyweight, and the adoption of food restriction to control weight may depend on parental perceptions of the child's appetite. Research using prospective data on child weight and appetite and food parenting from infancy is needed to further investigate how gene–environment relationships evolve through development

An examination of appetite and disordered eating in active Crohn’s disease

Background: Crohn’s disease (CD) patients suffer from nutritional deficiencies when in active disease. We aim to examine calorific intake, macronutrient choice and disordered eating behaviour in patients with active CD. Methods: CD patients with matched healthy volunteers (HV) were recruited. Active disease was defined by faecal calprotectin >250ug/g, C-reactive protein >5mg/dl, or active disease seen on endoscopy or imaging. Symptoms were quantified by Harvey-Bradshaw Index (HBI). Calorific intake was assessed by 24-h dietary recall. Disordered eating was assessed using validated questionnaires [Binge Eating Scale (BES); Power of Food Scale (PFS); Control of Eating Questionnaire (CoEQ); Dutch Eating Behaviour Questionnaire (DEBQ); Three Factor Eating Questionnaire (TFEQ)]. Results: 30 CD (18M:12F, Age:32.3±2.19, BMI:24.9±0.8) and 31 matched HV (19M:12F, Age:32.8±2.0, BMI:24.7±0.5) were recruited. Mean faecal calprotectin was 1032.5±176µg/g,C-reactive protein 83.8±47.1mg/L and HBI 4.8±1. There were no significant differences in calorific intake between groups. Protein intake was lower in the CD cohort (p=0.03). Hospital Anxiety and Depression score was higher (p=0.01) and CoEQ-Positive Mood (p=0.001) lower in CD. CD were characterised by higher BES (p=0.01) and lower CoEQ Craving Control (p=0.027) with greater craving for Sweet (p=0.043), Savoury (p=0.021) foods. PFS food present (p=0.005), DEBQ Emotional (p=<0.001) and External Eating (p=0.022) were significantly higher than HV. Conclusions: Reduced protein consumption and more prevalent disordered eating behaviour traits were present in CD. Greater binge eating and decreased control of cravings may be attributed to lower mood and higher anxiety observed. Patients may benefit from stronger psychological support with firm dietetic advice for healthy eating

Altered appetite in Crohn’s Disease: deconstructing the enteroendocrine axis using fMRI

Reduced appetite has been observed in patients with ileal Crohn’s disease, which has been attributed to the upregulation of enteroendocrine cells and the consequent increase of satiety hormones secretion, therefore possibly negatively affecting appetite signalling to the central nervous system. The specific hypotheses to be tested in this thesis were that Crohn’s disease patients with ileal inflammation, when compared with Crohn’s disease patients with colonic inflammation and healthy controls, will show A) an alteration in brain-gut stimulation, B) an increase in the postprandial plasma enteroendocrine peptides response (CCK, GLP-1 and PYY) with associated alteration in appetite scores, C) a change in eating behaviour, and D) an alteration in brain structure and resting-state functional connectivity. Ileal Crohn’s disease patients showed greater fasting GLP-1 concentrations compared with healthy controls. No difference was found between ileal and colonic Crohn’s disease patients in the fasting and postprandial concentrations of GLP-1, CCK and PYY. The ileal Crohn’s disease patients showed a greater postprandial decrease in neuronal activity in the right superior frontal gyrus in the default mode network in response to saline compared with the fat meal. The mechanism underlying this phenomenon is unclear and requires further investigation. Greater neuronal activity was found in areas including the cerebellum, hippocampus, posterior cingulate gyrus, middle temporal gyrus, thalamus and medulla in response to fat, which is in line with the previous literature. The fat induced greater activity of the posterior cingulate gyrus, was driven by Crohn’s disease patients, with colonic Crohn’s disease patients showing stronger activation in this region compared with the ileal Crohn’s disease patients. This finding may be linked with abdominal pain or GLP-1 elevations, which remains to be investigated. Stronger hedonic control of food intake was observed in the ileal CD patients compared with healthy controls, based on their explicit wanting/liking appeal bias for high-fat foods, however, this was not translated into actual increased calorie intake, perhaps because of fear of triggering or worsening symptoms. Ileal CD patients also exhibited greater impulsivity compared with colonic CD patients. These findings indicate that eating behaviour in ileal Crohn’s disease patients is likely to be impulse and reward-driven to alleviate symptoms such as low mood, abdominal pain and chronic fatigue. Therefore, a complex interplay of gut peptides, psychological factors, disease related symptoms, inflammatory burden may ultimately guide eating behaviour in ileal CD patients. Grey matter and white matter volume atrophy and cortical thinning were found in active Crohn’s disease patients in regions such as the precentral gyrus (motor cortex) and the postcentral gyrus. The relative atrophy of the motor cortex could be a possible central cause of fatigue in Crohn’s disease patients. Alterations were found in the resting-state functional connectivity between Crohn’s disease patients and healthy controls in the networks implicated in cognition, attention, emotion and pain. These findings may reflect neuroplasticity effects in response to chronic inflammation and disease symptoms such as abdominal pain and fatigue. This work was carried out between June 2015 and September 2019 at the National Institute of Health Research,Nottingham Biomedical Research Centre at the Queens Medical Centre Campus and the Sir Peter Mansfield Imaging Centre Nottingham.All work described in this thesis was performed by the author, except where indicated

Bioavailability of iron multi-amino acid chelate preparation in mice and human duodenal HuTu 80 cells

AbstractStrategies for preventing Fe deficiency include Fe supplementation and Fe fortification of foods. The absorption, metabolism and chemical characteristics of Fe multi-amino acid chelate (IMAAC) are not known. Absorption of IMAAC was compared with FeSO4in Fe-depleted mice andin vitrochemical studies of the Fe supplement was performed in HuTu 80 cells. Hb repletion study was carried out in Fe-deficient CD1 mice that were fed for 10 d a diet supplemented with ferrous IMAAC or FeSO4. A control group of Fe-replete mice was fed a diet with adequate Fe concentrations throughout the study. Tissues were collected from the mice, and the expression of Fe-related genes was determined by quantitative PCR. Ferric reductase and Fe uptake were evaluated in HuTu 80 cells. Supplementation of the diet with FeSO4or IMAAC significantly increased Hb levels (P&lt;0·001) in Fe-deficient mice from initial 93·9 (SD10·8) or 116·2 (SD9·1) to 191 (SD0·7) or 200 (SD0·5) g/l, respectively. Initial and final Hb for the Fe-deficient control group were 87·4 (SD6·7) and 111 (SD11·7) g/l, respectively. Furthermore, the liver non-haem Fe of both supplement groups increased significantly (P&lt;0·001). IMAAC was more effective at restoring Fe in the spleen compared with FeSO4(P&lt;0·005). Gene expression showed the IMAAC supplement absorption is regulated by the body’s Fe status as it significantly up-regulated hepcidin (P&lt;0·001) and down-regulated duodenal cytochrome b mRNA (P&lt;0·005), similar to the effects seen with FeSO4. A significant proportion of Fe in IMAAC is reduced by ascorbic acid. Fe absorption in mice and cells was similar for both IMAAC and FeSO4and both compounds induce and regulate Fe metabolism genes similarly in the maintenance of homeostasis in mice.</jats:p

An examination of resting-state functional connectivity in patients with active Crohn's disease

Background: Alterations in resting state functional connectivity (rs-FC) in Crohn’s Disease (CD) have been documented in default mode network (DMN) and frontal parietal network (FPN) areas, visual, cerebellar, salience and attention resting-state-networks (RSNs), constituting a CD specific neural phenotype. To date, most studies are in patients in remission, with limited studies in active disease. Methods: 25 active CD cases and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited to a resting-state-functional Magnetic Resonance Imaging (rs-fMRI) study. Active disease was defined as C-reactive protein>5mg/dl, faecal calprotectin>250μg/g, or through ileocolonoscopy or MRE. rs-fMRI data were analysed using independent component analysis (ICA) and dual regression. Differences in RSNs between HCs and active CD were assessed, and rs-FC was associated with disease duration and abdominal pain. Results: Increased connectivity in the FPN (fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) and visual RSN (orbital frontal cortex) were observed in CD versus HC. Decreased activity was observed in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) in CD versus HCs. Greater abdominal pain scores were associated with lower connectivity in the precuneus (visual network) and parietal operculum (salience network), and higher connectivity in the cerebellum (frontal network). Greater disease duration was associated with greater connectivity in the middle temporal gyrus and planum temporale (visual network). Conclusion: Alterations in rs-FC in active CD in RSNs implicated in cognition, attention, emotion, and pain may represent neural correlates of chronic systemic inflammation, abdominal pain, disease duration, and severity