PIs: Dr Mark Scott, Mr Charles Knowles, Professor Gareth Sanger, Mr Peter Lunniss, Professor Norman Williams

Colorectal disorders, characterised by symptoms of constipation and faecal incontinence (FI) are common in the general population (~5% and 15% respectively), and constitute an enormous healthcare burden, as well as individual suffering. Despite considerable research, the pathophysiological mechanisms underlying these disorders are still not fully understood. Our group is using a translational approach to study the factors that lead to disorders of gut neuromuscular function. Such an approach has led to directed, rather than empirical therapies. For example, we have demonstrated that colorectal sensorimotor function plays a significant role in evacuatory disorders and FI, and that therapy directed solely at the anal sphincters is naïve.

• Mechanisms
  There is a research focus on three main areas: (1) to investigate the clinical impact and neurophysiological basis of impaired visceral sensation (hyposensitivity) in both constipation and FI; (2) using complementary in vivo and in vitro studies (including development of a novel peristaltic preparation), to enhance our understanding of colonic dysmotility in constipation; (3) to better define rectal evacuatory disorders using an integrated diagnostic approach (simultaneous assessment of morphology / anatomy and function).
• Diagnosis
  Originating in a fundamental philosophy of first understanding ranges of normality in healthy, asymptomatic volunteers, to carefully phenotype patients through comprehensive evaluation, using conventional (e.g. endo-anal ultrasound, radio- opaque marker studies, proctography), advanced (e.g. scintigraphy, barostat), and novel tests (e.g. pan-colonic manometry, high resolution manometry, ingestible wireless capsule technology, multimodal sensory testing, integrated MR proctography) of GI function and morphology. Over the last ten years, the GI Physiology Unit has grown to the extent that it investigates more patients with benign colorectal disorders than any other in the UK.
• Treatment
  (1) to provide evidence based on definitive national trials for evolving treatments, especially neuromodulation and novel pharmacological agents; (2) to rationalise the use of certain techniques (e.g. sacral nerve stimulation) for FI and constipation by appropriate randomised comparison trials, mechanism of action studies (currently unknown), and proof of principle studies in small groups of patients with specific pathophysiological phenotypes; (3) to target sensory dysfunction, as a biomarker of disease, using behavioural / biofeedback techniques and also novel pharmaceutical agents and surgical approaches.
• Expected outcomes
  within five years, it is expected that we will be better able to stratify patients into more homogenous cohorts, based on comprehensive physiological investigation, and that this will translate to improved clinical outcomes using phenotype-driven therapeutic strategies.

STRENGTHS

1. Recognised as opinion leaders in the field of chronic constipation
2. Collaboration with other acknowledged experts
3. State-of-the-art GI physiological investigations available, for which large normative data sets exist
4. Access to healthy volunteers and large cohorts of carefully phenotyped patients for clinical pharmacological trials
5. Database containing clinical information and test results on 8500 patients available
6. Access to human large bowel tissue for use in pre-clinical studies
7. Development of the first UK colorectal research network (18 centres)

REFERENCES

1. Lunniss PJ, Gladman MA, Hetzer FH, Williams NS, Scott SM. Risk factors in acquired faecal incontinence. J R Soc Med 2004; 97: 111-6.
2. Chan CLH, Scott SM, Williams NS, Lunniss PJ. Rectal hypersensitivity worsens stool frequency, urgency, and lifestyle in patients with urge fecal incontinence. Dis Colon Rectum 2005; 48: 134-40.
3. Dvorkin LS, Gladman MA, Scott SM, Williams NS, Lunniss PJ. Rectal intussusception: a study of rectal biomechanics and visceroperception. Am J Gastroenterol 2005; 100: 1578-85.
4. Zarate N, Knowles CH, Newell M, Garvie NW, Gladman MA, Lunniss PJ, Scott SM. In patients with slow transit constipation, the pattern of colonic transit delay does not differentiate between those with or without impaired rectal evacuation. Am J Gastroenterol 2008; 103: 427-34.
5. Gooneratne ML, Facer P, Knowles CH, Chan CL, Lunniss PJ, Scott SM, Anand P, Williams NS. Normalization of substance P levels in rectal mucosa of patients with faecal incontinence treated successfully by sacral nerve stimulation. Br J Surg 2008; 95: 477-83.
6. Murphy J, Chan CL, Scott SM, Vasudevan SP, Lunniss PJ, Williams NS. Rectal augmentation: short- and mid-term evaluation of a novel procedure for severe fecal urgency with associated incontinence. Ann Surg 2008; 247: 421-7.
7. Gladman MA, Aziz Q, Scott SM, Williams NS, Lunniss PJ. Rectal hyposensitivity: pathophysiological mechanisms. Neurogastroenterol Motil 2009; 21: 508-16.
8. Mohammed SD, Lunniss PJ, Zarate N, Farmer AD, Grahame R, Aziz Q, Scott SM. Joint hypermobility and rectal evacuatory dysfunction: an aetiological link in abnormal connective tissue? Neurogastroenterol Motil 2010: 22: 1085-e283.
9. Dinning PG, Zarate N, Hunt L Fuentealba S, Mohammed SD, Szczesniak MM, Lubowski DZ, Preston S, Fairclough PD, Lunniss PJ, Scott SM, Cook IJ. Pancolonic spatiotemporal mapping reveals regional deficiencies in, and disorganization of colonic propagating pressure waves in severe constipation. Neurogastroenterol Motil 2010: 22: e340-9.
10. Zarate N, Mohammed SD, O’Shaughnessy E, Newell M, Yazaki E, Williams NS, Lunniss PJ, Semler JR, Scott SM. Accurate localisation of a fall in pH within the ileo-caecal region: validation using a dual scintigraphic technique. Am J Physiol Gastrointest Liver Physiol 2010: 299: G1276-86.