Heiko De Schepper assistant professor

Research Heiko De Schepper

Research team

Expertise

1. During my medical training, I participated in several experiments focusing on the characterization of neurotransmitters in motility of the mouse small intestine. We found evidence for a role of ATP in inhibitory neurotransmission and of all three tachykinin receptor subtypes in excitatory neurotransmission. 2. During my PhD I performed both functional and electrophysiological experiments detailing the effects of acute TNBS colitis in rats on gastrointestinal motility and sensitivity. The main contribution of this work was to identify TRPV1 receptors as potential therapeutic targets in visceral pain. 3. During my fellowship at the motility department of the AMC Amsterdam, I performed 2 technical studies on the performance of high resolution esophageal manometry in detecting esophageal motility disorders. 4. As a senior resident in the University Hospital of Antwerp, I have established a gastrointestinal motility clinic with a florid multidisciplinary pelvic floor unit. Several clinical research projects are currently ongoing, of which the first has now been published, concentrating on the manometric characterization of patients with fecal incontinence. 5. As a promotor at LEMP there are currently two broad research lines in the domain of irritable bowel syndrome (IBS). In a translational project we investigate the role of mast cells in the pathophysiology of IBS (cell culture, flowcytometry). In a second more clinical line we focus on the development of biomarker tests in IBS (volatomics, metabolomics).

The prevalence and the pathophysiological role of non-Helicobacter pylori Helicobacters in well-defined gastric diseases and (pre-) malignancies. 01/10/2024 - 30/09/2028

Abstract

In a minority of patients with chronic stomach pain, long, spiral-shaped non-Helicobacter pylori helicobacters (NHPH) are found. These helicobacters colonize the stomach of humans and animals (such as dogs, cats and pigs) and are considered to have zoonotic potential. In the past, NHPH have been referred to as H. heilmannii sensu lato group, which includes several species: H. suis, H. felis, H. bizzozeronii, H. salomonis, H. heilmannii, H. cynogastricus and H. baculiformis. Previous work suggests a contributing factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. NHPH bacteria are considered to also play a role in premalignant lesions of gastric cancer such as chronic gastritis, intestinal metaplasia and dysplasia. The exact prevalence of NHPH in these conditions is not clear. According to a recent study of our group, the prevalence of NHPH can vary between 20% to 25% in high risk patients and eradication with antibiotics can induce clinical and histological benefit in some patients. However up till now, 1/ no large multicenter prospective epidemiological studies on NHPH in patients with unexplained gastric disease exist, 2/ nor placebo-controlled randomized eradication studies for gastric NHPHs 3/ nor the impact of NHPH on the structural/functional heterogeneity of the mucin expression have been studied in the past and are therefore subject of the current PhD project. We would therefore link our expertise in mucin research with the topic of NHPHs in gastric disease. First, we will conduct a descriptive observational cross-sectional study on the prevalence of NHPH in high risk gastric patients. Second, a multicenter placebo-controlled randomized trial with antibiotics (Tryplera®) in NHPH positive patients will be performed in which the success rate of eradication and clinical, endoscopic and histological remission will be evaluated by means of standard genomic sequencing on target gastric biopsies. However, also new non-invasive tools as volatile organic compounds (VOCS) and genomic testing on saliva of patients will be tested for their diagnostic performance. Finally, the dynamics in mucins expression, that drive the evolution to more progressive gastric disease by causing enhanced inflammation and barrier dysfunction, will be studied and linked to the gastric microbial diversity and function (i.e. microbial-mucin mRNA isoform signature) in these well-defined gastric diseases and (pre-) malignancies in NHPH positive patients. Elucidating the pathogenic role of the NHPH and mucins in these associated diseases, can potentially improve the diagnosis and treatment of NHPH, can be beneficial to halt the progression towards gastric malignancy and can help patients with unexplained gastric symptoms.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

The role of Mrgpr (Mas-related G protein-coupled receptor) signaling in the activation of mast cells in irritable bowel syndrome. 01/10/2022 - 30/09/2026

Abstract

Irritable bowel syndrome (IBS) is a highly prevalent chronic gastrointestinal disorder characterized by abdominal pain and an altered bowel habit in the absence of organic disease. While the exact pathophysiology underlying the abdominal pain in IBS patients is not fully established yet, mast cells have been put forward to play an important role, mainly in IBS-D (diarrhea-predominant IBS). Upon activation, mast cells release different mediators that subsequently sensitize afferent nerves, thereby leading to visceral hypersensitivity resulting in abdominal pain complaints. Mast cell activation can occur via an IgE-dependent or IgE-independent system. Recently, researchers demonstrated an important role for the Mas-related G-protein coupled receptor MRGPRX2/Mrgprb2 in the IgE-independent mast cell activation pathway in itch. Besides, Mrgprb2 was found to be expressed by connective tissue mast cells in mouse colon in close proximity to colonic nerves. Furthermore, the human ortholog MRGPRX2 is expressed in human colon mast cells and an increased MRGPRX2 mRNA expression has been reported in distinct subsets of IBS patients. Taken together, these preliminary data point towards a potential interesting role for MRGPRX2/Mrgprb2 in IBS-D. Therefore, the overall objective of this project is to strengthen our knowledge of MRGPRX2 expression and function in the colon of IBS-D patients and the therapeutic potential of MRGPRX2 by evaluating their role in mast cell activation and visceral pain in a fundamental mouse model. In Work Package 1, we intend to characterize the expression pattern and location of MRGPRX2 in human colon biopsies from controls and IBS-D patients, using qPCR, immunohistochemical techniques and in situ hybridization. In Work Package 2, we will investigate the functional role of MRGPRX2 in mast cell priming and activation using human mast cell cultures and a novel colon organoid model. In Work Package 3, we aim to explore the functional role of Mrgprb2 in visceral hypersensitivity in a fundamental set-up in mice. Sensitivity will be assessed both in vitro using afferent nerve measurements from colon segments, and separately in vivo by studying the visceromotor response to colorectal distension.

Researcher(s)

  • Promoter: De Schepper Heiko
  • Co-promoter: Ceuleers Hannah
  • Co-promoter: Van Remoortel Samuel
  • Fellow: Mertens Caro

Research team(s)

Project type(s)

  • Research Project

Functional characterization of human mast cells and basophils in the pathophysiology of diarrhea-predominant irritable bowel syndrome. 01/10/2020 - 30/09/2022

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Functional characterisation of gut mast cells in irritable bowel syndrome. 01/04/2019 - 30/03/2020

Abstract

Irritable bowel syndrome (IBS) is a common yet difficult to treat chronic disorder characterized by abdominal pain combined with diarrhea and/or constipation. Mast cells are tissue-resident immune cells which are involved In the pathophysiology of IBS by activating and sensitizing sensory nerves endings, but the mechanisms and mediators involved are unknown. We aim to study these mast cells using a novel culture model developed by the Laboratory of Immunology of the University of Antwerp. This human mast cell culture will be incubated with mediators which are important in IBS pathophysiology. Markers of inhibition / activation and histamine release will then be measured using flowcytometry to study whether mast cells are indeed overly sensitive to their immediate environment in IBS compared to health. The goal of this research project is to advance knowledge on IBS pathophysiology, and to develop biomarkers which will allow to personalize IBS treatment.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Functional characterization of human mast cells and basophils in the pathophysiology of diarrhea-predominant irritable bowel syndrome. 01/10/2018 - 30/09/2020

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders, affecting around 11% of the population. The underlying cause of IBS is still largely unknown. Recently the importance of the immune system and more specifically mast cells (MC) and basophils (BP) was highlighted. These immune cells are heavily influenced by their surroundings and release mediators affecting gut sensitivity in response. In this research project we would like to elucidate the involvement of both mast cells and basophils in the development of IBS, using novel but validated immunological methods, and to study the mediators involved in mast cell and basophil activation in IBS, focusing on the diarrhea-predominant subtype. We will further subdivide these patients according to the underlying cause, concentrating on postinfectious onset and central risk factors (depression and anxiety). First of all, we will study whether BP and cultured MC of IBS patients are immunologically different compared to healthy controls. Subsequently we will study cultured MC in the presence of a large intestinal biopsy extract of IBS patients and healthy controls, to determine whether the gut environment influences MC reactivity. Lastly, we will look at the role of mas-related G protein-coupled receptors (MRGPR), a class of receptors involved in MC activity and in processing of gut pain, as potential therapeutic targets in IBS.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Effect of modulation of the integrity of the intestinal barrier in irritable bowel syndrome: a translational approach. 01/10/2018 - 31/10/2019

Abstract

Irritable bowel syndrome (IBS) is a disease without a clear cause which is associated with abdominal pain and altered bowel habits. A disturbed intestinal permeability and an increased sensitivity of internal organs are causal factors of disease. An important pathological role lies in the 'gut-brain interaction' in which signals from the intestine are conveyed to the brain and vice versa. This interaction is essential for a healthy bowel function and involves signaling molecules such as histamine, proteases, bile and fatty acids. Also the microbial content (the 'microbiome') of the intestine plays an important role in the gut-brain interaction. In this respect, we are particularly interested in the intestinal barrier function. The mucous membranes in the intestine provide an active barrier that allows passage of nutrients but impedes non-nutrients and toxins. It is well known that certain chronic diseases are associated with a disturbed intestinal barrier, also called 'leaky gut'. Possibly, a 'leaky gut' is also involved in IBS and that is what we will investigate in this project. We will study the role of different mediators such as vasoactive intestinal polypeptide, intestinal alkaline posphatase, serine protease inhibitors and mucoprotectants in a preclinical rat model and directly translate the importance of these mediators to the human situation validating their occurence and activity in human colonic samples. -

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Study of neuroimmune modulation of afferent signalling during intestinal inflammation in the rat. 01/10/2006 - 30/09/2008

Abstract

Introduction: Inflammation of the gastrointestinal tract can lead to disturbed motility and symptoms such as nausea, dyspepsia and diarrhea. After the gastrointestinal inflammation subsides, these bowel problems persist in one third of patients. A role for the enteric nervous system and afferent nerves was suggested. Aims: To determine the role of afferent neurones in the pathogenesis of gastrointestinal motility disturbances caused by TNBS-induced colitis in the rat, using functional and histological techniques. Methods: In vitro contractility experiments on isolated muscle strips and peristalsis measurements on bowel segments will be combined with in vivo assessment of gastric emptying and intestinal transit. A new technique will be introduced for direct measurement of afferent nerve discharge. Histological evaluation will complement these functional studies using routine and c-fos staining). Planning: In a first period, the role of synaptic neurotransmission and of extrinsic afferent neurones will be determined in vivo and in vitro. A second period will concentrate on the role of inflammatory mediators. Finally, the inflammatory modulation of receptor expression on afferent neurones will be studied.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Study of neuroimmune modulation of afferent signalling during intestinal inflammation in the rat. 01/10/2004 - 30/09/2006

Abstract

Introduction: Inflammation of the gastrointestinal tract can lead to disturbed motility and symptoms such as nausea, dyspepsia and diarrhea. After the gastrointestinal inflammation subsides, these bowel problems persist in one third of patients. A role for the enteric nervous system and afferent nerves was suggested. Aims: To determine the role of afferent neurones in the pathogenesis of gastrointestinal motility disturbances caused by TNBS-induced colitis in the rat, using functional and histological techniques. Methods: In vitro contractility experiments on isolated muscle strips and peristalsis measurements on bowel segments will be combined with in vivo assessment of gastric emptying and intestinal transit. A new technique will be introduced for direct measurement of afferent nerve discharge. Histological evaluation will complement these functional studies using routine and c-fos staining). Planning: In a first period, the role of synaptic neurotransmission and of extrinsic afferent neurones will be determined in vivo and in vitro. A second period will concentrate on the role of inflammatory mediators. Finally, the inflammatory modulation of receptor expression on afferent neurones will be studied.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project