Biopsy samples from patients with irritable bowel syndrome, but not from those with mastocytosis or unspecific gastrointestinal complaints reveal unique nerve activation in all gut regions independent of mast cell density, histamine content or specific gastrointestinal symptoms.

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 regions of IBS patients with diarrhea (IBS-D) in comparison to those from mastocytosis patients with diarrhea (MC-D) or non-IBS/non-MC patients with GI-complaints.

Mechanisms involved in the muscle relaxing effects of STW 5 in guinea pig stomach.

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 muscle strips from guinea pig gastric corpus before and after pharmacological interventions were recorded with force transducers in an organ bath.

Distension evoked mucosal secretion in human and porcine colon in vitro.

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 application (2-60 mmHg) to induce distension into the mucosal or serosal compartment, respectively.

Allergen-free extracts from birch, ragweed, and hazel pollen activate human and guinea-pig submucous and spinal sensory neurons.

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 Ca and fast potentiometric imaging, we recorded the responses of guinea-pig and human submucous and guinea-pig dorsal root ganglion (DRG) neurons to microejection of low (<3 kDa) and high (≥3 kDa) molecular weight APEs of birch, ragweed, and hazel.

Enteric neuroanatomy and smooth muscle activity in the western diamondback rattlesnake (Crotalus atrox).

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 processed by the GI tract. We performed immunohistochemistry in different regions of the GI tract to assess the neuronal density and to quantify cholinergic, nitrergic, and VIPergic enteric neurons.

Macrophages and glia are the dominant P2X7-expressing cell types in the gut nervous system-No evidence for the role of neuronal P2X7 receptors in colitis.

The 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, 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 bacterial artificial chromosome transgenic P2X7-EGFP reporter mouse model and P2rx7 controls to perform a detailed analysis of cell type-specific P2X7 expression and possible overexpression effects in the enteric nervous system of the distal colon. In contrast to previous studies, we did not detect P2X7 in neurons but found dominant expression in glia and macrophages, which closely interact with the neurons.

Contribution of the Enteric Nervous System to Autoimmune Diseases and Irritable Bowel Syndrome.

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 they appear without an identifiable underlying cause. One example is the type I anti-neuronal nuclear antibody (ANNA-1 otherwise known as anti-Hu), which is usually linked to small cell-lung carcinoma.

How big is the little brain in the gut? Neuronal numbers in the enteric nervous system of mice, Guinea pig, and human.

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 (human or mouse anti-HuD/C) to determine neuronal densities in specimen from the entire gastrointestinal tract of mice, guinea pig, and humans.

Immunofluorescence Staining of P2X7 Receptors in Whole-Mount Myenteric Plexus Preparations.

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 P2X7 receptors are present on enteric neurons and glia and it was proposed that they mediate neuronal death during IBD.

Metabotropic 5-HT receptor-mediated effects in the human submucous plexus.

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

Fast synaptic excitatory neurotransmission in the human submucosal plexus.

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 neurons of the human gut.

Region-specific effects of the cysteine protease papain on gastric motility.

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.

Translating the seminal findings of Carl Lüderitz: A description in English of his extraordinary studies of gastrointestinal motility accompanied by a historical view of peristalsis.

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 Lüderitz-Bayliss-Starling reflex. This shows that his peers around 1900 were very well aware of the significant impact of Lüderitz´s papers.

Autoimmune encephalitis and gastrointestinal dysmotility: achalasia, gastroparesis, and slow transit constipation.

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 (SOX-1) autoimmune antibody-positive limbic encephalitis and significant gastrointestinal dysmotility consisting of achalasia type II, gastroparesis, altered small intestinal interdigestive motility, and severe slow transit constipation.

Effects of the herbal preparation STW 5-II on in vitro muscle activity in the guinea pig stomach.

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 clinically as effective as STW 5.

Submucosal enteric neurons of the cavine distal colon are sensitive to hypoosmolar stimuli.

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 including potential molecular mediating mechanisms.

Compression and stretch sensitive submucosal neurons of the porcine and human colon.

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 tensile or compressive forces in submucous neurons.

Peppermint and caraway oils have muscle inhibitory and pro-secretory activity in the human intestine in vitro.

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 oils on contractile and secretory activity in 255 human small and large intestinal preparations derived from surgical resections (73 patients).

Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.

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 neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients.

Correction to: Piezo proteins: incidence and abundance in the enteric nervous system. Is there a link with mechanosensitivity?

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).

To learn, to remember, to forget-How smart is the gut?

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 often referred to as the second brain and hence is able to perform sophisticated tasks.

Piezo proteins: incidence and abundance in the enteric nervous system. Is there a link with mechanosensitivity?

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.