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Melatonin in the gastrointestinal tract
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.ORCID iD: 0000-0003-2746-2726
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Melatonin is recognised as the pineal hormone regulating sleep and circadian rhythm. It has also been identified in peripheral tissues (mainly in animals) and thought to display a variety of actions, including anti-inflammatory properties, regulation of gastrointestinal (GI) functions, glucose homeostasis and beneficial effects in different tumour types. Patients with irritable bowel disorder commonly exhibit psychiatric co-morbidity and disturbances of the gut-brain axis have been proposed to play a role in these disorders. The focus of this thesis was to study melatonin and melatonin receptors in the normal human GI tract, the pancreas and small intestinal neuroendocrine tumours. The thesis also explores the complex relationship between GI symptoms and underlying psychiatric traits in the context of elevated levels of peripheral melatonin during waking hours.

In paper I-II, tissue samples from the normal human GI tract and pancreas and tumour tissue from small intestinal neuroendocrine tumours were analysed for expression of melatonin and melatonin receptors using immunohistochemistry. For tumour patients, melatonin was also analysed in plasma and set in relation to symptoms and outcome. In paper III-IV, a cohort of young adults (18-25 years) seeking psychiatric care was examined for GI symptoms, melatonin levels in saliva, depressive symptoms and anxiety traits. Psychiatric assessments were performed using structured or semi structured interviews. Depressive symptoms were measured using the self-rating version of the Montgomery-Åsberg Depression Rating Scale; GI symptoms were measured using the Gastrointestinal Symptoms Rating Scale for Irritable Bowel Syndrome; and personality traits were evaluated using the Swedish Universities Scales of Personality.

Melatonin and melatonin receptors were widely expressed in the normal human gut and pancreas (paper I) but even in small intestinal neuroendocrine tumours known to produce serotonin (paper II). The intensity of the melatonin immunoreactivity in tumour tissue was found to correlate with lower proliferation index. After treatment, plasma levels of melatonin were reduced in tumour patients. Young adult patients seeking psychiatric care reported more GI symptoms than healthy controls, regardless of the currently active psychotropic medication. The level of GI symptoms was associated with severity of depressive symptoms and trait anxiety (paper III). Higher postprandial levels of melatonin were associated with the GI symptoms of bloating and pain (paper IV).

In summary, these findings demonstrate the widespread presence of melatonin in the human gut and confirm a link between melatonin, psychiatric health and GI symptoms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1616
Keywords [en]
melatonin, MT1, MT2, gastointestinal tract, small intestinal neuroendocrine tumours, IBS, depression, anxiety, personality and affective disorder
National Category
Psychiatry Endocrinology and Diabetes Gastroenterology and Hepatology Cancer and Oncology
Research subject
Medical Science; Psychiatry
Identifiers
URN: urn:nbn:se:uu:diva-396347ISBN: 978-91-513-0814-2 (print)OAI: oai:DiVA.org:uu-396347DiVA, id: diva2:1371005
Public defence
2020-01-17, Humanistiska teatern, Thunbergsvägen 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-12-18 Created: 2019-11-18 Last updated: 2020-01-13
List of papers
1. Human Gastroenteropancreatic Expression of Melatonin and Its Receptors MT1 and MT2
Open this publication in new window or tab >>Human Gastroenteropancreatic Expression of Melatonin and Its Receptors MT1 and MT2
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0120195Article in journal (Refereed) Published
Abstract [en]

Background and Aim The largest source of melatonin, according to animal studies, is the gastrointestinal (GI) tract but this is not yet thoroughly characterized in humans. This study aims to map the expression of melatonin and its two receptors in human GI tract and pancreas using microarray analysis and immunohistochemistry. Method Gene expression data from normal intestine and pancreas and inflamed colon tissue due to ulcerative colitis were analyzed for expression of enzymes relevant for serotonin and melatonin production and their receptors. Sections from paraffin-embedded normal tissue from 42 individuals, representing the different parts of the GI tract (n= 39) and pancreas (n= 3) were studied with immunohistochemistry using antibodies with specificity for melatonin, MT1 and MT2 receptors and serotonin. Results Enzymes needed for production of melatonin are expressed in both GI tract and pancreas tissue. Strong melatonin immunoreactivity (IR) was seen in enterochromaffin (EC) cells partially co-localized with serotonin IR. Melatonin IR was also seen in pancreas islets. MT1 and MT2 IR were both found in the intestinal epithelium, in the submucosal and myenteric plexus, and in vessels in the GI tract as well as in pancreatic islets. MT1 and MT2 IR was strongest in the epithelium of the large intestine. In the other cell types, both MT2 gene expression and IR were generally elevated compared to MT1. Strong MT2, IR was noted in EC cells but not MT1 IR. Changes in gene expression that may result in reduced levels of melatonin were seen in relation to inflammation. Conclusion Widespread gastroenteropancreatic expression of melatonin and its receptors in the GI tract and pancreas is in agreement with the multiple roles ascribed to melatonin, which include regulation of gastrointestinal motility, epithelial permeability as well as enteropancreatic cross-talk with plausible impact on metabolic control.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-252709 (URN)10.1371/journal.pone.0120195 (DOI)000352134700057 ()25822611 (PubMedID)
Available from: 2015-05-12 Created: 2015-05-11 Last updated: 2019-11-18Bibliographically approved
2. Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours
Open this publication in new window or tab >>Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours
Show others...
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164354Article in journal (Refereed) Published
Abstract [en]

Background/ Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.

National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:uu:diva-310013 (URN)10.1371/journal.pone.0164354 (DOI)000385505800057 ()27736994 (PubMedID)
Funder
Swedish Society of MedicineSwedish Cancer Society
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2019-11-18Bibliographically approved
3. Gastrointestinal symptoms, depression and trait anxiety in young adults seeking psychiatric care
Open this publication in new window or tab >>Gastrointestinal symptoms, depression and trait anxiety in young adults seeking psychiatric care
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and aim: Patients with functional gastrointestinal (GI) disorders have a high psychiatric co-morbidity, especially for mood and anxiety disorders. This study aimed to investigate and characterise GI symptoms in relation to depressive symptoms and trait anxiety in a well-defined population of young adult outpatients seeking psychiatric care.

Material and methods: Patients, aged 18-25 years from the Uppsala Psychiatric Patient Samples (UPP) cohort seeking psychiatric care for primarily mood and anxiety disorders (n=491) were compared with healthy controls (n=85) for GI symptoms (measured using the Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome, GSRS-IBS and depressive symptoms (measured using the Montgomery-Åsberg Depression Rating Scale – Self-Assessment, MADRS-S. Personality traits were assessed using the Swedish Universities Scales of Personality (SSP), in which three anxiety-related personality traits (stress susceptibility, psychic trait anxiety somatic trait anxiety) were assessed.

Results: Patients, both on psychotropic medication and those not currently on psychotropic medication reported more GI symptoms than controls (median 30 vs. 22, p<0.001). GI symptom burden was higher in women than men (median 32 vs. 28, p<0.001). A principal component analysis produced a six-factor structure explaining 63% of the total variance in the data set. A cluster analysis was performed that allowed the identification of six cluster groups, characterised by the varying levels of these factors. The total GSRS-IBS score significantly correlated with depressive symptom severity (r=0.391, p<0.001), a relationship that remained after adjusting for possible confounders (sex, body mass index, bulimia). The total GSRS-IBS score correlated with the three SSP subscales: somatic trait anxiety (r=0.313, p<0.001), psychic trait anxiety (r=0.147, p=0.001) and stress susceptibility (r=0.233, p<0.001).

Conclusion: GI symptoms are highly prevalent in young adult psychiatric outpatients compared with controls, regardless of whether the patient is currently on psychotropic medication or not. Depressive symptom severity and degree of trait anxiety are independently related to the total IBS symptoms score.

Keywords
IBS, human, mood disorder, depression, anxiety, personality
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
urn:nbn:se:uu:diva-397086 (URN)
Funder
Stiftelsen Söderström - Königska sjukhemmetSwedish Society of MedicineErik, Karin och Gösta Selanders Foundation
Available from: 2019-11-18 Created: 2019-11-18 Last updated: 2019-11-20Bibliographically approved
4. Daytime Salivary Melatonin Related to Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care
Open this publication in new window or tab >>Daytime Salivary Melatonin Related to Gastrointestinal Symptoms in Young Adults Seeking Psychiatric Care
Show others...
2018 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 83, no 9, p. S185-S186Article in journal, Meeting abstract (Other academic) Published
Keywords
Melatonin, Irritable Bowel Syndrome, Depression
National Category
Psychiatry Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-361431 (URN)000432466300462 ()
Conference
73rd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), 2018, New York, NY
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2019-11-18Bibliographically approved

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