Intestinal Physiology Three Stories Dr Vivien Rolfe BSc
Intestinal Physiology Three Stories Dr Vivien Rolfe BSc Ph. D Intestinal Physiologist and Open Educator This is an open educational resource in recognition of Open Education Week 2016 (7=12 th March) Breaking down the barriers to education CC BY (unless assets otherwise indicated)
Learning Outcomes • By the end of this session you will: – Understand the basic structure and function of the enteric nervous system (ENS). – Gain insight into global diarrhoeal disease and cellular physiology. – Gain insight into gut motility and research commercialisation. – Debate – “Is the gut the site of origin of Parkinson’s disease”?
Quiz 1. How long is the (deceased) adult gut? 2. Where is the largest accumulation of immune cells in the body? 3. Where is the largest accumulation of micro‐ organisms? 4. What part of the body has the highest rate of cell turnover (3‐ 4 days)? 5. What part of the body has a nervous system with as many neurones and neurotransmitters as the CNS?
Gross Structure • Adult gut is around 10 m when deceased (muscle relaxes). • It has the largest accumulation of immune cells – oral tolerance and defence. • The colonic microflora ferment and create energy. • The small intestinal epithelium has a high turnover (2‐ 5 days) and impressive stem cell activity. • The ENS is called the “little brain”.
Internal Structure By Goran tek‐en [CC BY‐SA 3. 0], via Wikimedia Commons, Available: https: //commons. wikimedia. org/wiki/File: Layers_of_the_GI_Tract_english. svg
ENS INTRINSIC INNERVATION 1 Mucosa – Epithelium lining 2 Submucosa – Submucosal plexus 3 Muscularis – Circular – Myenteric plexus – Longitudinal 4 Serosa EXTRINSIC Autonomic (PS + and S ‐)
ENS “Little Brain” • As many neurones as the CNS mainly arranged in two main plexi. • Neurone types: – Primary afferent neurones (sensory) – Glial cells – Interstitial cells of Cajal stomach “pacemaker” cells • Neurotransmitters: – Contains most neurotransmitters known in the central nervous system – ACh, 5 HT, dopamine plus NO. • Can largely act independently following severance of vagus nerve due to intrinsic reflexes in the wall.
Control of Gut Functions • ENS controls: – Splanchnic (gut) circulation and blood flow is responsive to local activity, e. g. dilation during digestive processes. – Mucosal transport (secretion and absorption). – Mucus secretion from goblet cells triggered by food to lubricate and protect. – Muscle activity – from swallowing to defecation reflexes; peristalsis and mixing. – Activity declines with aging as do many gut functions.
Learning Outcomes • By the end of this session you will: – Understand the basic structure and function of the enteric nervous system (ENS). – Gain insight into global diarrhoeal disease and cellular physiology. – Gain insight into gut motility and research commercialisation. – Debate – “Is the gut the site of origin of Parkinson’s disease”?
Diarrhoeal Disease: Global Killer. Little girl with kwashiorkor By Dr. Lyle Conrad [Public domain], via Wikimedia Commons, Available: https: //en. wikipedia. org/wiki/Kwashiorkor#/media/File: Starved_girl. jpg
Physiology • ENS and endocrine messengers control the tone of absorption and secretion in small intestine (SI) and colon. • SI absorbs water, salts and digested nutrients. • Colon absorbs to dehydrate contents and form stools. • Under fine control through epithelium receptors: – Secretory – ACh and 5‐HT. – Absorptive – Nor adrenaline. • Pathogens can override these processes as part of innate defenses.
Pathophysiology • Diarrhoea – 2 nd most common cause of death of children under 5 years of age. (1 st – neonatal mortality). • Toxigenic Escherichia coli (E. coli) major culprit – releases heat stable and heat labile toxins. • The statistic hasn’t changed in 20 years. • Diarrhoea exacerbated by malnutrition as gut becomes hypersecretory. • Measurement? In vitro electrophysiology, in vivo fluid movement. By Credit: Rocky Mountain Laboratories, [Public Domain], Available: https: //commons. wikimedia. org/w/index. php? curid=104228
Cellular Mechanisms STa GC CFTR Epithelial barrier c. GMP CFTR - Cystic fibrosis transmembrane conductance regulator STa – stable toxin A GC – guanylate cyclase
Chloride efflux STa GC c. GMP Cl. CFTR
Cl- STa GC CFTR c. GMP Transporter 2 Cl- Na+ K+ ATPase co‐transport
Osmosis Water Cl- STa GC CFTR c. GMP Transporter 2 Cl- Na+ K+
Aqueporin channels Water STa GC ? Nitrinergic Myenteric secretory reflex NO Synthesis Remote secretion Lin et al (2010). Available: http: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 3153287/
NOS – neuronal, endothelial NO Synthase (enzyme) NO + citrulline L‐arginine Oxygen Tetrahydrobiopterin BH 4 (plus other cofactors)
Where There’s Muck, There’s Brass?
Motility Functions • During fasting, interstitial cells of Cajal initiate waves of peristalsis – migrating motor complex (MMC) to sweep the bowel clean “housekeeping function” = tummy rumble. • ENS controls peristalsis (propulsion) and segmentation (mixing). • Colon movement is slow for the dehydration of contents and nutrient recycling by microflora. • Research has well established that dietary fibre is vital for human colonic health.
Pet Nutrition Industry Translation of human science Develop non‐invasive methods Go to market with health claims Identify parameters of gut health Secure intellectual property Test out functional foods Spike by Viv Rolfe [CC BY]
Pet Nutrition Industry Translation of human science Develop non‐invasive methods Go to market with health claims Identify parameters of gut health Secure intellectual property Test out functional foods Spike by Viv Rolfe [CC BY]
Image links to: https: //www. waltham. com/dyn/_dmp_assets/images/dogsensitivitywdc 14. jpg By Cabot Health, Bristol Stool Chart [CC BY‐SA 3. 0], via Wikimedia Commons, Available: (http: //cdn. intechopen. com/pdfs‐wm/46082. pdf)
Physiological findings • We found a relationship between gut transit time (time for food to travel through bowel) and stool quality – slow transit = better stool quality. • Different fibres had different effects. • The physico‐chemical properties of fibre are still being investigated – particle size, viscocity, fermentation index? Rolfe V et al (2006). Available: http: //onlinelibrary. wiley. com/doi/10. 1111/j. 1748‐ 5827. 2002. tb 00075. x/abstract; jsessionid=F 916 F 5789 FA 239460 C 120394 BCA 6 BF 55. f 03 t 03
Where there’s muck…. • NHS budget: 2015/16 £ 116. 4 billion (NHS 2016) • Global pet care industry by 2017 US$74. 8 billion. • UK pet owners spend about $7 billion a year (about £ 5 billion) (TMR 2015) NHS (2016). Available: http: //www. nhs. uk/NHSEngland/thenhs/about/Pages/overview. aspx TMR (2015). Available: http: //www. transparencymarketresearch. com/pressrelease/pet‐food‐ market. htm
From Somatic to the Psychologic? • The gut‐brain axis (GBA) is two‐way communication between the CNS and ENS – links emotional centres of the brain with peripheral intestinal functions. • Importance of psychotherapies in irritable bowel syndrome being explored (Read 1999). Read NW (1999). Available: http: //www. ncbi. nlm. nih. gov/pubmed/10580923
Is the Gut is the Site of Origin of Neurodegeneration? EMSL [CC BY‐NC‐SA 2. 0], Flickr, Available: https: //www. flickr. com/photos/emsl/4704802544
Emerging Theory. Are We Looking in the Wrong Place? • Parkinson’s Disease is mainly age‐related neurodegeneration secondary in number to Alzheimer’s Disease. • Epidemiological predictions are based on the assumption that population longevity is set to increase. • Approximately 127, 000 people in the UK (Parkinson’s. org. uk). Around 300, 000 people (often children) live with inflammatory bowel diseases (C&C Org UK). Parkinson’s Org UK (n. d. ). Availiable: http: //www. parkinsons. org. uk/content/what‐parkinsons Crohn’s and Colitis Org UK (n. d. ). Available: http: //www. crohnsandcolitis. org. uk/about‐ inflammatory‐bowel‐disease
Research Synthesis Citation Study type Experiment Svennson 2015 Population study on Truncal vagotomy Parkinson’s Disease (PD) reduced incidence of PD patients compared control Vagal nerve may be critically involved in pathogenesis of PD. Haehner 2013 Clinical intervention study Olfactory training may increase smell in PD patients. Chung 2015 Diagnostic development Alpha‐synuclein immunoreactivity similar in PD versus healthy control gastric and colonic biopsies Alpha‐synuclein has limited role as a biomarker for pre‐ motor PD Kelly 2014 Validation of animal model (lipopolysaccharide model LPS) Model may be relevant for further investigation into pathophysiology and therapeutic development Olfactory decline in PD patients – partially ‘retrained’ using sniffing sticks LPS caused Alpha‐ synuclein accumulation in colon similar to observed in PD. Prior to nigrostriatal degeneration and motor dysfunction. Key result
Research Synthesis Citation Study type Experiment Key result Rahne 2013 Clinical study Absorption and soeffectiveness of drug levadopa was compared in PD patients infected with H. pylori or not. H. Pylori reduces levadopa effectiveness. What is the significance of interplay of bacteria and drug actions?
Last Word? • Brain‐gut axis interactions are significantly modulated by the gut microbiota. • This might account for gut manifestations in pre‐motor stage of PD. (Mulak 2015). • So what are some of the key questions now?
Last Word? • Cause or consequence? • Does the pathological process spread from the gut to the brain? • How does this relate to gut bacterial dysbiosis? • What is role of ENS? • What are the future prospects for early diagnosis and/or treatment?
References • • • Chung, S. J. , Kim, J. , Lee, H. J. , Ryu, H. S. , Kim, K. , Lee, J. H. , Jung, K. W. , Kim, M. J. , Kim, Y. J. and Yun, S. C. (2015). Alpha‐synuclein in gastric and colonic mucosa in Parkinson's disease: Limited role as a biomarker. Movement Disorders. Haehner, A. , Tosch, C. , Wolz, M. , Klingelhoefer, L. , Fauser, M. , Storch, A. , Reichmann, H. and Hummel, T. (2013). Olfactory training in patients with Parkinson's disease. Plo. S one, 8(4), p. e 61680. Kelly, L. P. , Carvey, P. M. , Keshavarzian, A. , Shannon, K. M. , Shaikh, M. , Bakay, R. A. and Kordower, J. H. (2014). Progression of intestinal permeability changes and alpha‐synuclein expression in a mouse model of Parkinson's disease. Movement Disorders, 29(8), pp. 999‐ 1009. Mulak, A. and Bonaz, B. (2015). Brain‐gut‐microbiota axis in Parkinson's disease. World journal of gastroenterology: WJG, 21(37), p. 10609. Rahne, K. E. , Tagesson, C. and Nyholm, D. (2013). Motor fluctuations and Helicobacter pylori in Parkinson’s disease. Journal of neurology, 260(12), pp. 2974‐ 2980. Svensson, E. , Horváth‐Puhó, E. , Thomsen, R. W. , Djurhuus, J. C. , Pedersen, L. , Borghammer, P. and Sørensen, H. T. (2015). Vagotomy and subsequent risk of Parkinson's disease. Annals of neurology, 78(4), pp. 522‐ 529.
We have discussed: • By the end of this short session you will: – Understand the basic structure and function of the enteric nervous system (ENS). – Gain insight into global diarrhoeal disease and importance of intestinal research. – Gain insight into gut motility and how research outputs can be commercialised. – Is the gut the site of origin of Parkinson’s disease?
Do discuss more @vivienrolfe or vivien. rolfe@uwe. ac. uk Frenchay 1 A 07
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