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Final Report Summary - NEUROGUT (European Training in Neural Regulation of Intestinal Function)

Functional disorders of the gastrointestinal tract are thought to be due to disorganised "gut-brain interaction" of either afferent or efferent or both pathways in control of intestinal functions. Research is needed to establish the links between the various components of the "gut - brain - gut axis" that would allow a better differentiation of these conditions. This is the aim of the ITN "European Training in Neural Regulation of Intestinal Function" (NeuroGut). The subprojects of NeuroGut are arranged along the process of digestion. This process ("digestive circle") illustrates the interconnectivity of all functions along the gut-brain axis.
The subprojects (SP) of NeuroGut represent the various aspects of neural control of gut functions, especially in functional bowel disorders of "irritable bowel syndrome" type (IBS). Included is the luminal and mucosal challenge of the gut immune system through food intake, processes of inflammation involving the enteric nervous system (ENS), thereby affecting gut motility, secretion and absorption, leading to visceral sensations, that may impress as symptoms in functional bowel disorder (FBD) (pain, hypersensitivity, dyspepsia, diarrhea, constipation). These symptoms are transmitted via the spinal and vagal afferent branches of the autonomic nervous system (ANS) to the brain - thereby affecting food intake, the psychological state of patients, and chronification of the disease state.

Following recruitment of 14 young researchers, the work started in mid-2014 with training of the ESRs and ERs in the respective technologies of the laboratories involved, and with basic training across the settings, e.g. trainings schools in business management (Entrepreneurship Academy), genetics, and microbiota analysis etc. All ESRs and ERs presented their data not only at the various NeuroGut meetings, but also at national and international conferences, e.g. the European Neurogastroenterology and Motility Meetings, held in Istanbul in June 2015 and in Cork in August 2017. Some ESRs attended prestigious Young Investigator Meetings, e.g. LBBB (of the international Federation of Neurogastroenterology and Motlity Societies, FNM) and TANDEM (of the European Neurogastroenterology and Motility Society, ESNM).

Work package 1
WP1 investigated the mechanisms by which regular and disordered gut functions are transmitted via the autonomic nervous system (ANS) to the brain and how they are processed in the brain. At the peripheral level (subproject (SP) 8) a large IBS patient cohort was screened for clusters of functions that are disorders either at the peripheral (microbiota, motility, secretion) or at the central level (perception, pain, psychological symptoms). SP10 explored how the ANS responds to both central (pain, perception, emotion) as well as peripheral stimuli (food, acid, visually-induced nausea) in healthy volunteers and patients with functional bowel disorders, and identified important response clusters. SP1 used an established technology (functional magnetic resonance imaging, fMRI) in patients with functional dyspepsia and in healthy controls, while SP 11 installed a novel technology (magnetoencephalography, MEG) to record central nervous system (CNS) activity following visualization and/or ingestion of food of different caloric load (SP1) or the brain processing of social stress after experimental manipulation of the intestinal microbiota by probiotics and antibiotics.
WP1 contributed to a better understanding and differentiation of patients with functional bowel disorders, as is evident from two major publications (see below: Nature Reviews Disease Primers on Functional Dyspepsia (2017) and Irritable Bowel Syndrome (2016)). The Early Stage Researchers (ESRs) working on WP1 completed and published 10 papers, with some more under review or in preparation. The PIs of SP11 succeeded in registering two European patents (in Ireland) related to the effects of a novel "psychobiotic" on stress-related CNS functions.

Work package 2
WP2 included basic science projects of the NeuroGut network dealing with physiological, immunological and genetic contributions to gut function and dysfunction. While most studies in the past were based on animal models of inflammation and hypersensitivity that lack relevance for human diseases, the subprojects of WP2 used in vitro tests of biological tissue (biopsies, supernatant from biopsies) from patients with irritable bowel syndrome, inflammatory bowel disorders and healthy controls: SP2 explored the role of the mucus layer and its organization and proposed a novel model of understanding, how mucus is organized in the colon: covering the feces rather than covering the bowel wall. SP3 - in collaboration with SP7 - used supernatants from biopsies of IBS and IBD patients to test pharmacology (SP7) and physiology (SP3), e.g. activation of enteric neurons, a new technology for pre-clinical drug screening, e.g. of bacterial mediators. SP5 clustered phenotype and genotype data from patients with very severe functional bowel disorders (chronic intestinal pseudo-obstruction, CIPO) (in collaboration with project partner 9) and found a dissociation between severity of symptoms and abnormal histopathology. The ESRs of WP2 completed and published 2 papers, more and in progress, as basic science papers are more time consuming and difficult to publish.

Work package 3
WP3 is a clinical cluster focusing on recording different gastrointestinal functions in vivo (motility, transit, absorption, secretion, sensitivity) in patients with functional bowel disorders (and in healthy controls) to relate them to their symptoms (pain, diarrhea, constipation, bloating, vomiting, reflux, dyspepsia, etc.). Many of these tests are clinical routine tools in highly specialized setting (e.g. manometry, transit studies, impedance, pH-monitoring, etc.), but may also include development of novel diagnostic methods (image analysis) but occasional additional data may include biopsy or fecal material assessed for potential biomarkers of the disease.
SP4 focused on esophageal function in patients with swallowing disorders and non-cardiac chest pain, and contributed to new standards in its clinical diagnosis. SP6 links clinics of functional gastrointestinal disorders (FGD) back to basic science (WP2) and provides a first animal model that closely mimics post-infectious irritable bowel syndrome patients. In contrast, SP9 links to WP1 (central processing) by investigating a contribution of sensory processing (taste and smell) towards intestinal functions, and investigated these peripherally (motility) as well as on the central level (fMRI) - an entirely new and so far widely neglected topic in (neuro-)gastroenterology, but a focus in psychology. The ESRs of WP3 have been very successfully publishing 17 papers altogether.

Work package 4
WP4 comprises 3 subprojects that were conducted by one academic partner and by two industrial partners in collaboration with one or more of the academic partners. All three subprojects were equipped with one Experienced Researcher (ER) for two years and dispersed across WP 1 to 3, hence their main outcome was thought to be less academic (e.g. publication) in nature than relevant for the participating industry. SP13 yielded and succeeded in identifying a new target for drug testing in FGD and designing a "proof-of-principle" study design. SP14 broadened our view of the (lack of) efficacy of probiotic therapy in IBS, and succeeded in establishing a novel information tool (Microbiota Newsletter) for clinicians on microbiota knowledge, continuing ever since.

A total of 31 publications were accepted for publication from ESRs and ERs, among which is one with all young researchers together providing a new vision on irritable bowel syndrome after collectively attending the "IBS Days" in Bologna, May 2016:
Albusoda A, Barki N, Herregods T, Kamphuis JB, Karunaratne TB, Lazarou M, Lee I, Mazurak N, Perna E, Polster A, Pribic T, Uhlig F, Wang H, Enck P. A fresh look at IBS - opportunities for systems medicine approaches. Neurogastroenterol Motil. 2017 Mar;29(3).

The Principal Investigators of the NeuroGut network continued their traditional collaboration - that is mirrored in more than 100 papers in PUBMED with two or more of the NeuroGut PIs as authors - they collectively established some standards of understanding and managing functional bowel disorders, that is reflected in two outstanding common publications:
Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, Niesler B, Quigley E, Rajilić-Stojanović M, Schemann M, Schwille-Kiuntke J, Simren M, Zipfel S, Spiller RC. Irritable Bowel Syndrome. Nature Reviews Diseases Primers 2016 Mar 24;2:16014.
Enck P, Azpiroz F, Boeckxstaens G, Elsenbruch S, Feinle-Bisset C, Holtmann G, Lackner JM, Ronkainen J, Schemann M, Stengel A, Tack J, Zipfel S, Talley NJ. Functional dyspepsia. Nature Reviews Disease Primers. 2017 Nov 3;3:17081.


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