Michael Schemann

• Technical University of Munich

Background Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are disorders of gut–brain interaction (DGBIs). Patients with these disorders experience abdominal symptoms, frequently in relation to meal intake, and often are treated using pharmacological approaches that offer limited symptom relief. In addition to various pharmacotherapies...

Introduction We previously showed enteric nerve activation after application of colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS). The question remains whether this is a region-specific or a generalized sensitization. We tested the nerve-activating properties of supernatants from large and small intestinal region...

Introduction The herbal preparation STW 5 ameliorates functional dyspepsia partly by relaxing smooth muscle of the proximal stomach, thus improving gastric accommodation. We explored the unknown pathways responsible for this effect by testing targets known to modulate gastric smooth muscle relaxation. Methods STW 5‐induced relaxation of smooth mus...

It was suggested that intestinal mucosal secretion is enhanced during muscle relaxation and contraction. Mechanisms of mechanically induced secretion have been studied in rodent species. We used voltage clamp Ussing technique to investigate, in human and porcine colonic tissue, secretion evoked by serosal (Pser) or mucosal (Pmuc) pressure applicati...

Background Non‐allergenic, low molecular weight components of pollen grains are suspected to trigger changes in gut functions, sometimes leading to inflammatory conditions. Based on extensive neuroimmune communication in the gut wall, we investigated the effects of aqueous pollen extracts (APE) on enteric and spinal sensory neurons. Methods Using...

Background Gastrointestinal (GI) functions are controlled by the enteric nervous system (ENS) in vertebrates, but data on snakes are scarce, as most studies were done in mammals. However, the feeding of many snakes, including Crotalus atrox, is in strong contrast with mammals, as it consumes an immense, intact prey that is forwarded, stored, and pr...

Blockade or deletion of the pro-inflammatory P2X7 receptor channel has been shown to reduce tissue damage and symptoms in models of inflammatory bowel disease (IBD) and P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. Here we used P2X7-specific antibodies and nanobodies as well as a BAC tra...

Anti-neuronal autoantibodies can lead to subacute gastrointestinal dysmotility, presenting with various symptoms typical of intestinal pseudoobstruction, achalasia, gastroparesis, or slow intestinal transit, among others. Such autoantibodies may be produced in response to a remote tumor and accelerate the diagnosis of malignancy, but in other cases...

Background Despite numerous studies on the enteric nervous system (ENS), we lack fundamental knowledge on neuronal densities or total neuron numbers in different species. There are more anecdotal than actual figures on nerve counts. Methods We used standardized preparation techniques and immunohistochemistry with validated panneuronal markers (hum...

P2X7 receptors play an important role in cytokine release and immune cell regulation. Their upregulation has been described in inflammatory and degenerative processes and P2X7 blockade or deletion has been shown to reduce tissue damage and severity of symptoms in animal models of inflammatory bowel disease (IBD). Several studies have found that P2X...

Background Serotonin (5‐HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5‐HT receptors. The ionotropic 5‐HT3 receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5‐HT1P, 5‐HT4, and 5‐HT7 receptors to activate human submucous neurons. Met...

This protocol is to investigate the presence and localization of neurochemical markers in the submucosal and myenteric plexus of the porcine colon using immunhistochemical staining techniques.

Blockade or deletion of the pro-inflammatory P2X7 receptor channel has been shown to reduce tissue damage and symptoms in models of inflammatory bowel disease (IBD) and P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. Here we used P2X7-specific antibodies and nanobodies as well as a BAC tra...

This protocol is to quantify the presence of both Piezo1 and 2 in enteric neurons throughout the gastrointestinal tract using immunohistochemistry on human samples that were obtained from patients undergoing surgery. The samples were taken from macroscopically unaffected areas. Using immunohistochemical techniques to determine the expression of Pie...

Background Acetylcholine is the main excitatory neurotransmitter in the enteric nervous system (ENS) in all animal models examined so far. However, data for the human ENS is scarce. Methods We used neuroimaging using voltage and calcium dyes, Ussing chamber, and immunohistochemistry to study fast synaptic neurotransmission in submucosal plexus neu...

Zusammenfassung Diagnostik allein auf der Basis von Symptomen und Symptombeschreibungen ist heute selten, war aber im 18. und 19. Jahrhundert eher die Regel. Methoden In diesem medizinhistorischen Projekt wurden die Todesursachen von 25 Vor- und Nachfahren des Berliner Arztes und Wissenschaftlers Dr. Carl Lüderitz (1854–1930) aus historischen Quell...

Background Papaya is a traditional remedy for gastrointestinal complaints in the folk medicine. On this basis, papain, a cysteine protease of the fruit, is sold as a nutritional supplement, although scientific data on its effects in the gastrointestinal tract are lacking. We aimed to explore the effect of papain on gastric motility in vitro. Metho...

Background Carl Lüderitz provided the first comprehensive description of peristalsis in vivo in his publication from 1889 before Bayliss and Starling described the peristaltic reflex in isolated intestinal segments ex vivo 10 years later. At that time, the peristaltic reflex, responsible for progression of intestinal content, was referred to as the...

Background: Neurological autoimmune disorders (NAD) are caused by autoimmune inflammation triggered by specific antibody subtypes. NAD may disturb the gut-brain axis at several levels including brain, spinal cord, peripheral, or enteric nervous system. Case report: We present a case with antinuclear neuronal Hu (ANNA-1)- and antiglial nuclear (S...

Key points Neurons of the enteric submucous plexus are challenged by osmolar fluctuations during digestion and absorption of nutrients. Central neurons are very sensitive to changes in osmolality but knowledge on that issue related to enteric neurons is sparse. The present study focuses on investigation of osmosensitivity of submucosal neurons incl...

Background STW 5 is a combination of nine medicinal herbal extracts and used to treat functional gastrointestinal disorders including functional dyspepsia. It has a region‐specific effect by relaxing the proximal and contracting the distal stomach. The research combination STW 5‐II (Iberogast® Advance) lacks three herbal extracts but seems clinical...

The pig is commonly believed to be a relevant model for human gut functions—however, there are only a few comparative studies and none on neural control mechanisms. To address this lack we identified as one central aspect mechanosensitive enteric neurons (MEN) in porcine and human colon. We used neuroimaging techniques to record responses to tensil...

The gut’s own autonomous nervous system, the enteric nervous system (ENS), has fascinated scientists for more than 100 years. It functions, in the true sense of the word, autonomously, by performing complex tasks and controlling vital functions independently of extrinsic inputs. At the same time, the ENS is bombarded with signals from other cells i...

This protocol is to quantify the presence of both Piezo1 and 2 in enteric neurons throughout the gastrointestinal tract using immunohistochemistry on human samples that were obtained from patients undergoing surgery. The samples were taken from macroscopically unaffected areas. Using immunohistochemical techniques to determine the expression of Pie...

Background Herbal medicinal products with a broad activity spectrum may be promising alternatives to treat functional gastrointestinal disorders (FGD). Menthacarin® is a drug with a fixed combination of peppermint and caraway oils, which is clinically used to treat FGD‐associated symptoms. Materials We studied the effects of peppermint and caraway...

The Authors regret forgetting in the original version of this article to mention that this work was also supported by the US National Institute of Health (NIH) (1OT2OD024899-01).

Background: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. Methods: We performed a systematic, quantitative analysis of...

The enteric nervous system (ENS) resides within the gut wall and autonomously controls gut functions through coordinated activation of sensory, inter and motor neurons. Its activity is modulated by the enteric immune and endocrine system as well as by afferent and efferent nerves of the parasympathetic and sympathetic nervous system. The ENS is oft...

Piezo channels play fundamental roles in many physiological processes. Their presence and functional role in the enteric nervous system is still not known. We hypothesize that they play a role in mechanotransduction in enteric neurons. Our aims are to quantify the presence of both Piezo1 and 2 in enteric neurons throughout the gastrointestinal trac...

Background: Functional dyspepsia (FD) is one of the more common functional disorders, with a prevalence of 10-20%. It affectsthe gastrointestinal tract. Methods: This article is based on publications retrieved by a selective search of PubMed, with special attention to controlled trials, guidelines, and reviews. Results: Typical dyspeptic sympt...

Background & aims The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatan...

Quantified proteins in mucosal biopsy supernatants. (XLSX)

Characteristics of patient samples for generation of supernatants. (DOCX)

Mast cells are a part of the innate immune system implicated in allergic reactions and the regulation of host-pathogen interactions. The distribution, morphology and biochemical composition of mast cells has been studied in detail in vitro and on tissue sections both at the light microscopic and ultrastructural level. More recently, the development...

Background: Stimulant laxatives are widely used to treat constipation. We investigated in human small and large intestinal preparations the effects of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), the active metabolite of the laxatives bisacodyl and sodium picosulfate on smooth muscle tone and epithelial secretion. Methods: Circular and longit...

Background: Antineuronal antibodies can be associated with both gastrointestinal (GI) and brain disorders. For example, antibodies against the potassium channel subunit dipeptidyl-peptidase-like protein-6 (DPPX) bind to neurons in the central nervous system (CNS) and myenteric plexus and cause encephalitis, commonly preceded by severe unspecific G...

Within the enteric nervous system, the neurons in charge to control motility of the gastrointestinal tract reside in a particular location nestled between two perpendicular muscle layers which contract and relax. We used primary cultured myenteric neurons of male guinea pigs to study mechanosensitivity of enteric neurons in isolation. Ultrafast Neu...

Introduction: It is suggested that an altered microenvironment in the gut wall alters communication along a mast cell nerve axis. We aimed to record for the first time signaling between mast cells and neurons in intact human submucous preparations. Methods: We used the Ca²⁺ sensitive dye Fluo-4 AM to simultaneously image changes in intracellular ca...

Functional dyspepsia is one of the most prevalent functional gastrointestinal disorders. Functional dyspepsia comprises three subtypes with presumed different pathophysiology and aetiology: postprandial distress syndrome (PDS), epigastric pain syndrome (EPS) and a subtype with overlapping PDS and EPS features. Functional dyspepsia symptoms can be c...

Zusammenfassung Die vergangenen 35 Jahre (seit etwa 1980) haben eine Vielzahl von wissenschaftlichen Publikationen zum Thema Reizdarmsyndrom (RDS) erbracht, aber keinen wirklichen Fortschritt: Nach wie vor ist dessen Ätiologie und Pathogenese ungeklärt, und Diagnostik und Therapie sind weitgehend dem individuellen Verständnis der behandelnden Ärzti...

Background: We previously showed that mucosal biopsy supernatants from irritable bowel syndrome patients activated neurons despite low concentrations of tryptase, histamine, and serotonin which individually would not cause spike discharge. We studied the potentiating responses between these mediators on excitability of enteric neurons. Methods:...

Funktionelle Magendarmerkrankungen, wie Reizdarm oder Reizmagen, gehören zu den häufigsten Gründen, warum Patienten den Arzt aufsuchen. Diagnose und gezielte Therapie bleiben bis heute eine große Herausforderung. Beide Syndrome werden bisher rein symptomenbasiert nach Ausschlussdiagnose diagnostiziert. Inzwischen ist aber klar, dass Reizdarm und Re...

IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spik...

If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi...

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS includ...

Background and Aims: Malfunctions of enteric neurons are believed to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Our aim was to investigate whether neuronal activity in biopsies from IBS patients is altered in comparison to healthy controls (HC). Methods: Activity of human submucous neurons in response to electr...

Aim The herbal preparation STW 5 contains fresh plant extracts from bitter candytuft whole plant, extracts from greater celandine herb, angelica root, lemon balm leaves, peppermint leaves, caraway fruit, liquorice root, chamomile flower and milk thistle fruit. We recently reported that STW 5 increased intestinal chloride secretion and proposed that...

Key points: We present the first systematic and, up to now, most comprehensive evaluation of the basic features of epithelial functions, such as basal and nerve-evoked secretion, as well as tissue resistance, in over 2200 surgical specimens of human small and large intestine. We found no evidence for impaired nerve-evoked epithelial secretion or t...

For long it was believed that a particular population of enteric neurons, referred to as intrinsic primary afferent neuron (IPAN)s, encodes mechanical stimulation. We recently proposed a new concept suggesting that there are in addition mechanosensitive enteric neurons (MEN) that are multifunctional. Based on firing pattern MEN behaved as rapidly,...

The enteric nervous system (ENS) autonomously controls gut muscle activity. Mechanosensitive enteric neurons (MEN) initiate reflex activity by responding to mechanical deformation of the gastrointestinal wall. MEN throughout the gut primarily respond to compression or stretch rather than to shear force. Some MEN are multimodal as they respond to co...

The particular location of myenteric neurons, sandwiched between the 2 muscle layers of the gut, implies that their somata and neurites undergo mechanical stress during gastrointestinal motility. Existence of mechanosensitive enteric neurons (MEN) is undoubted but many of their basic features remain to be studied. In this study, we used ultra-fast...

To characterize pathogenic effects of antibodies to dipeptidyl-peptidase-like protein 6 (DPPX), a subunit of Kv4.2 potassium channels, on gut and brain neurons. We identified a new patient with anti-DPPX encephalitis and analyzed the effects of the patient's serum and purified immunoglobulin G (IgG), and of serum of a previous patient with anti-DPP...

Regulation gastrointestinaler Funktionen ist das Ergebnis komplexer Interaktionen zwischen Nerven, Hormonen, parakrinen Mediatoren, Muskulatur und Epithel.

Innervation interacts with enteric immune responses. Chronic intestinal inflammation is associated with increased risk of colorectal cancer. We aimed to study potential extrinsic neuronal modulation of intestinal tumor development in a mouse model. Experiments were performed with male ApcMin/+ or wild type mice (4 weeks old, body weight approximate...

New Findings What is the central question of this study? Supernatants from colonic mucosal biopsies from patients with irritable bowel syndrome (IBS) activate enteric and dorsal root ganglion (DRG) neurons. Based on the discomfort/pain threshold during rectal distension, IBS patients may be subtyped as normo‐ or hypersensitive. However, the link be...

The enteric nervous system (ENS) integrates numerous sensory signals in order to control and maintain normal gut functions. Nutrients are one of the prominent factors which determine the chemical milieu in the lumen and, after absorption, also within the gut wall. This topical review summarizes current knowledge on the impact of key nutrients on EN...

Irritable bowel syndrome (IBS) is one of the most frequent reasons why patients seek medical care and therefore, causes a significant socioeconomic burden. Historically, IBS is primarily a symptom-based diagnosis but such a symptom clustering causes significant problems because it is not clear whether and how IBS differs from other diseases. Recent...

Although animal models of the irritable bowel syndrome (IBS) have provided important insights, there are no models that fully express the features of this complex condition. One alternative approach is the use of human intestinal biopsies obtained during endoscopic procedures to examine peripheral mechanisms in this disorder. These studies have ser...

Objectives: Abnormal pain perception or visceral hypersensitivity (VH) is considered to be an important mechanism underlying symptoms in a subgroup of irritable bowel syndrome (IBS) patients. Increased TRPV1 (transient receptor potential cation channel subfamily V member 1) expression in rectal biopsies of IBS patients suggests a potentially impor...

The cholinergic anti-inflammatory pathway is an endogenous mechanism by which the autonomic nervous system attenuates macrophage activation via nicotinic acetylcholine receptors (nAChR). This concept has however not been demonstrated at a cellular level in intact tissue. To this end, we have studied the effect of nicotine on the activation of resid...

Das Reizdarmsyndrom (RDS) ist einer der häufigsten Gründe, warum Patienten den Arzt aufsuchen, und stellt hierdurch eine erhebliche sozioökonomische Belastung dar. Das RDS wurde aufgrund der geschichtlichen Entwicklung bisher symptomenbasiert definiert. Diese symptomenbasierte Definition durch Symptomencluster als Krankheit ist problematisch, da si...

Interstitial cell of Cajal (ICC) form a cellular network that is embedded in the musculature of the gastrointestinal tract. Previous studies provided clear evidence that ICC generate a rhythmic pacemaker current which manifests itself as slow-waves in membrane potential of smooth muscle cells resulting in rhythmic bowel contractions. However, a rol...

Key points We investigated altered colonic functions in high fat diet‐induced obesity in pre‐diabetic mice. After feeding an adipogenic diet for 12 weeks, accelerated colonic transit was associated with upregulation and enhanced signalling of acetylcholine and serotonin, two key mediators in the enteric nervous system (ENS). Importantly, these chan...

The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagus nerve stimulation (VNS) reduces intestinal inflammation and improves postoperative ileus. We investigated the neural pathway involved and the cells mediating the anti-inf...

Background: Hyoscine butylbromide (HBB, Buscopan(®) ) is clinically used to treat intestinal cramps and visceral pain. Various studies, mainly on animal tissues, suggested that its antimuscarinic action is responsible for its spasmolytic effect. However, functional in vitro studies with human tissue have not been performed so far. Methods: We wa...

The enteric nervous system contains excitatory and inhibitory neurons, which control contraction and relaxation of smooth muscle cells as well as gastrointestinal motor activity. Little is known about the exact cellular mechanisms of neuronal signal transduction to smooth muscle cells in the gut. Here we generate a c-Kit(CreERT2) knock-in allele to...

Background: Beneficial effects of ginger in the treatment of gastrointestinal (GI) problems and chemotherapy-induced nausea and vomiting are well accepted. In rodents, the action of ginger seems to be mediated by the inhibition of 5-HT3 receptors, which are established targets to combat emesis and irritable bowel syndrome. Methods: Heterologousl...

Close association between nerves and mast cells in the gut wall provides the micro-anatomical basis for functional interactions between these elements, supporting the hypothesis that a mast cell-nerve axis influences gut functions in health and disease. Advanced morphology and imaging techniques are now available to assess structural and functional...

Proteases play a decisive role in health and disease. They fulfil diverse functions and have been associated with the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The current knowledge focuses on host-derived proteases including matrix metalloproteinases, various serine proteas...

Compound 48/80 is widely used in animal and tissue models as a "selective" mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. We used in vivo recordings from extrinsic intestinal afferents together with Ca(++) imaging from primary cultures of DRG and nodose neurons...

Objective: Obesity is associated with altered colonic transit suggesting underlying nerve plasticity that may be linked to obesity-associated chronic low-grade inflammation. Methods: We therefore investigated functional changes in the distal colon of mice that were made obese with a high fat diet (DIO) before showing signs of metabolic syndrome. W...

Activity of the four known protease-activated receptors (PARs) has been well studied in rodent enteric nervous system and results in animal models established an important role for neuronal PAR2. We recently demonstrated that, unlike in rodents, PAR1 is the dominant neuronal protease receptor in the human submucous plexus. With this study we invest...

Background: We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa-nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS...