PIs: Professor Joanne Martin, Mr Charles Knowles, Dr Nikhil Thapar

The term GI neuromuscular disease (GINMD) describes a group of heterogeneous conditions characterized by impaired motility often with chronic visceral dilatation in which the problem is presumed or proven to be caused by an underlying abnormality of enteric neuromuscular function. This may manifest congenitally, in infancy or later in life; examples include Hirschsprung’s disease, intestinal pseudo-obstruction and slow transit constipation. Most have no uniformly effective treatment strategy. Patients are generally passed from one specialist to another, each attempting to address isolated aspects lying within their specific area of expertise instead of adopting a more holistic approach. Regrettably, with the passage of time such patients may undergo numerous invasive and unnecessary investigations or ill-advised and damaging surgeries that can lead to progression of problems such as chronic pain and malnutrition. Indeed, sequelae such as psychiatric disorders (acknowledged suicide rate), opiate dependence (for severe abdominal pain) and malnutrition with requirement for parenteral nutrition with attendant morbidity and mortality, are well-recognised.

There is therefore an urgent unmet clinical need to identify cohorts of patients with similar pathophysiology so that specific treatment options can be explored. We will continue to (1) identify histopathological phenotypes of patients with gut neuromuscular disease using minimally-invasive approaches (and lead international efforts to rationalize techniques and classification); (2) progress studies of disease mechanism including the role of autoimmunity directed to enteric neuronal ion channels; (3) develop patient cohorts of with homogeneous disease phenotypes to enable stratification for therapeutic trials; (4) develop tailored medical and surgical therapies for patients on the basis of clinicopathological diagnosis.

Strengths

1. Charles Knowles is Chair of the International Working Group directed to the study of GI neuromuscular pathology. This group has produced the first guidelines on the study of GI neuromuscular histopathology techniques and also the first approved international classification system (The London Classification).
2. Professor Martin with Mr Knowles have identified several new phenotypes of GINMD. A new systemic Glycogen storage disease with a genetic basis and presenting as an adult GINMD is pending submission publication.
3. In association with the charity the Pseudo-obstruction Research Trust (PORT) and a commercial partner we have developed a bespoke international database for patients with GINMD thus addressing the rare nature of these disorders by the amalgamation of sufficient meaningful data. This will facilitate also telemedicine, research studies and trials of new therapy.
4. Mr Knowles is pioneering a novel method of GI neuromodulation for patients with severe midgut dysmotility syndromes (see also surgical innovation).
5. Dr Nikhil Thapar is continuing the development of enteric neuronal progenitor cells for human implantation. We are now attempting to bridge the gap between the extensive published rodent work and human disease by performing ‘first in human’ safety and proof of principle studies.

References

1. Knowles CH, Nickols CD, Scott SM, Bennett NI, de Oliveira RB, Chimelli L, Feakins R, Williams NS, Martin JE. Secondary smooth muscle degeneration with inclusion bodies in slow transit constipation. J Pathol 2001; 193: 390-7.
2. Knowles CH, Nickols CD, Feakins R, Martin JE. A systematic analysis of polyglucosan bodies in the human gastrointestinal tract in health and disease. Acta Neuropathol 2003; 105: 410-3.
3. Knowles CH, Silk DBA, Darzi A, Feakins R, Raimundo AH, Veress B, Crompton T, Lindberg G, Martin JE. Deranged smooth muscle alpha-actin: a biomarker of intestinal pseudo-obstruction. A controlled multinational case series. Gut 2004; 53: 1583-9.
4. Knowles CH, Veress B, Tornblom H, Wallace S, Paraskevas P, Darzi A, Martin JE, Nyborg B, Lindberg G. Safety and diagnostic yield of laparoscopically assisted full-thickness bowel biospy. Neurogastroenterol Motil 2008; 20: 774-9.
5. Hubball A, Lang B, De Giorgio R, Martin JE, Knowles CH. The role of humoral autoimmunity in Gastrointestinal neuromuscular disease. Prog Neurobiol 2008; 87: 10-20.
6. Barlow AJ, Wallace AS, Thapar N, Burns AJ. Critical numbers of neural crest cells are required in the pathways from the neural tube to the foregut to ensure complete enteric nervous system formation. Development 2008; 135: 1681-91.
7. Knowles CH, De Giorgio R, Kapur RP, Bruder E, Farrugia G, Geboes K, Gershon MD, Hutson J, Lindberg G, Martin JE, Meier-Ruge WA, Milla PJ, Smith VV, Vandervinden JM, Veress B, Wedel T. Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol 2009; 118: 271-301.
8. Martin JE, Hester TW, Aslam H, Sinha S, Knowles CH. Discordant practice and limited histopathological assessment in gastrointestinal neuromuscular disease. Gut 2009; 58: 1703-5.
9. Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar N. Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 2009; 136: 2214-25.
10. Knowles CH, De Giorgio R, Kapur RP, Bruder E, Farrugia G, Geboes K, Gershon MD, Hutson J, Lindberg G, Martin JE, Meier-Ruge WA, Milla PJ, Smith VV, Vandervinden JM, Veress B, Wedel T. The London Classification of GI Neuromuscular disease. Gut 2010; 59: 882-887.