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The Gut, our largest sensory organ: the 1st immune organ Pr. John B. Furness, ● September 2014 The Gut, our largest sensory The Gut, our largest sensory organ: the 1st immune organ Breizh Algae Tour - Sept. 15th, 2014 87 The gut as a sensory organ The small intestine presents a surface membrane area of about 60 m2, making it the largest vulnerable surface of the body. The total surface of the gastrointestinal tract that faces the external environment is 100 m2, compared to 2 m2 of skin. The external milieu (the luminal content of the gut) is continually modified by ingestion of food, drink and contaminants they may bring with them, by microorganisms, by microbial products, by enzymatic and chemical breakdown of complex molecules and by pharmaceuticals. The intestine has no advance knowledge of the materials that arrive at this surface – it requires sophisticated sensory and tissue defence systems. Breizh Algae Tour - Sept. 15th, 2014 88 Gut contents signal via hormones, neurons, immune responses and receptors for innate defence Breizh Algae Tour - Sept. 15th, 2014 Furness et al 2013 91 How extensive is the system? •12 major types of entero-endocrine cells. The gut is the largest endocrine organ in the body •The largest peripheral nervous system, about 500,000,000 neurons (human). About 50,000 vagal afferents, 6,000 spinal afferents, 2,000 pelvic afferents •Millions of immune cells •Innate Anti-microbial and Detoxifying defence throughout the gut •Fifty or more luminal receptors Breizh Algae Tour - Sept. 15th, 2014 92 Luminal Receptors • The taste receptors: Sweet: T1R2–T1R3; amino acids, the umami (savoury) receptor, T1R1–T1R3; the undimerised T1R3 receptor • The bitter receptor family, T2Rs • The sour (acid) receptor, PKD2L1 • Receptors for protein breakdown product receptors: CaSR, LPAR5 (also known as GPR92/ GPR93), GPRC6A, T1R1–T1R3 • Free fatty acid receptors: FFAR 1–3, GPR119, GPR120 • Phytochemical Receptors, including TRPV1, TRPV2, TRPV5, TRPV6, TRPA1, TRPP2 (PKD2L1); the bitter receptor (T2R) • Olfactory receptors • Mechanosensitive channels of nerve endings and enteroendocrine cells • Receptors for physicochemical attributes, including Temp, osmolarity, pH • Bile acid receptors, TGR5 • Pattern recognition receptors: Toll-like receptors 1–9, NOD1, NOD2 • T-cell receptors: peptides, lipopolysaccharides, vitamin B metabolites, cytokines • Receptors for emetogenic toxins • Receptors for advanced glycation end products (RAGE receptors) Breizh Algae Tour - Sept. 15th, 2014 Furness et al 2013 93 Enteroendocrine Cells: The primary source of feed-back signalling for physiological regulation Nerve fibres GLP-1 cell PYY cell Breizh Algae Tour - Sept. 15th, 2014 94 Signaling by the Major Gastrointestinal Hormones Ghrelin, A cell Promotes appetite, growth hormone release Gastrin, G cell Stimulates acid secretion Somatostatin, D cell Inhibits acid secretion Secretin, S Cell Stimulates HCO3 production CCK, I cell Stimulates gallbladder and pancreas, inhibits appetite GIP, K cell Promotes insulin secretion (incretin) GLP-1, L cell Increases insulin secretion (incretin), reduces appetite, slows gastric emptying GLP-2, L cell Stimulates mucosal growth, enhances nutrient absorption Peptide YY, L cell Slows small intestine transit , reduces appetite Motilin, M cell Triggers migrating complexes (differs between species) 5-HT (serotonin) , EC cell Low release: stimulates contractile activity and water and electrolyte secretion. High release: toxin expulsion (nausea, vomiting, diarrhea) (vomiting/ pica differs between species) Breizh Algae Tour - Sept. 15th, 2014 Furness et al 2013 95 Luminal sensors: modification of feeding Bitter taste stimulation in stomach In Wild-type, a-gustucin KO and ghrelin receptor KO Food Intake g/hr/mouse Intra-gastric gavage with bitter mix Plasma Ghrelin pg/mL Breizh Algae Tour - Sept. 15th, 2014 Janssen 2011 96 Luminal sensors: modification of nutrient handling Sweet receptor stimulant, sucralose, induces SGLT1 and glucose uptake SGLT1 protein SGLT1 mRNA Different sweeteners SGLT1 function Other sweeteners, aspartame, acesulfame, saccharine Breizh Algae Tour - Sept. 15th, 2014 Margolskee, Shirazi-Beechey 2007 97 Luminal sensors - hormone release - neural activation - transporter induction Breizh Algae Tour - Sept. 15th, 2014 Shirazi-Beechey 2011 98 The Enteric Nervous System: Notre cerveau originel (as explained by Michel Neunlist) There are two ganglionated plexuses: Myenteric, primarily motility control, Submucosal, primarily secretion/ blood flow control/ immune modulation Breizh Algae Tour - Sept. 15th, 2014 Furness, 2012 99 Enteric sensory neurons Enteric sensory neurons: modification of motility secretion, blood flow, digestion, appetite etc. Breizh Algae Tour - Sept. 15th, 2014 100 The complexity of integration of enteric sensory information: Exemplified by the L cell Inputs: Luminal nutrients Outputs: regulation of transit, secretion, blood flow, mucosal growth, gut defence, insulin secretion, immune function, appetite Breizh Algae Tour - Sept. 15th, 2014 Furness et al 2013 101 Gut Defences - overview he mucosa: large, highly permeable, especially in the small intestine, vulnerable, but nevertheless a barrier Mucus layer Toxin elimination: vomiting, pica, diarrhea Detoxification: In rumen (cattle etc); small intestine and liver enzymes Destruction: defensins etc Innate immunity: macrophages, neutrophils, T cell cytokines Adaptive immunity: B cell reservoir, CD4-CD8 T cells, NK T cells, MAIT cells, entry of antibodies into the lumen: Always vigilant, always active Two way modification: BacteriaImmune cell- Breizh Algae Tour - Sept. 15th, 2014 -Immune cell; -Bacteria 102 The mucosal barrier Breizh Algae Tour - Sept. 15th, 2014 Hooper et al, 2010 103 Compromised Gut Barrier Function: heat stress Thermo Neutral Heat Stress P- value Ileum TER (Ω × cm2) 182 ± 17 88 ± 18 <0.01 Colon TER (Ω × cm2) 133 ± 7 102 ± 8 <0.01 Ileum FITC Dextran (μg/mL/min/cm2) 3.6 ± 0.9 7.9 ± 1.1 <0.01 Colon FITC Dextran (μg/mL/min/cm2) 2.7 ± 3.6 15.7 ± 3.6 <0.01 Thermoneutral: 21°C; 35–50% humidity (n= 8) for 24 h Heat Stress: 35°C; 24–43% humidity (n = 8) for 24 h Breizh Algae Tour - Sept. 15th, 2014 104 Protecting the Gut Barrier against heat stress Heat Stress: 40°C; 21% humidity for 1.5 h Thermoneutral: 21°C; 21% humidity Breizh Algae Tour - Sept. 15th, 2014 Maseko et al, 2014 105 Innate Immunity: The mucosal barrier and Pattern Recognition Receptors Breizh Algae Tour - Sept. 15th, 2014 Mills, 2011 106 Paneth Cells and PRRS A major source of anti-microbial peptides The major PRR – Toll Like Receptors MAMP, PAMP – microbe associated molecular patterns, pathogen associated molecular patterns Breizh Algae Tour - Sept. 15th, 2014 Bevins & Salzman 2011 107 Modulation of adaptive immune responses in the gut by the Microbiota: Barrier protection and tolerance Breizh Algae Tour - Sept. 15th, 2014 Cerf-Bensussan 2010 108 Antigen sensing: follicular, mesenteric and lamina propria T cells Breizh Algae Tour - Sept. 15th, 2014 Mowat et al., 2003 109 Chemical selectivity of T cells in gut CD4+ and CD8+ T cells - peptide Breizh Algae Tour - Sept. 15th, 2014 CD1d NKT cells – lipid Chua et al., 2012 MAIT cells – B vitamins 110 Symbionts and Pathobionts Breizh Algae Tour - Sept. 15th, 2014 Cerf-Bensussan et al., 2011 111 Anti-inflammatory effect of an L. Delbrueckii strain in a human epithelial cell line Breizh Algae Tour - Sept. 15th, 2014 Santos Rocha, Blottière et al., 2012 112 Microbial – immune homeostasis he gastrointestinal tract is constantly exposed to variable luminal contents, and is thus always in a state of mild inflammation: the gut immune system is primed The gut immune system and gut bacteria have co-evolved. Thus in a healthy gut they are in equilibrium, and bacterial symbionts keep pathogenic bacteria under control Dysbiosis occurs when dysequilibrium occurs, and pathobionts mediate mucosal barrier disruption, tissue damage and systemic disease Enhancing gut health for animal production Utilising macro- and micro-nutrients that promote effective nutrient assimilation, maximise growth, production (milk, eggs) and carcass weight Utilising additives that are protective (e.g. anti-oxidants) or digestive enhancers (e.g. some phyochemicals) Application of probiotics We need research that provides a stronger evidence base Breizh Algae Tour - Sept. 15th, 2014 113 A Challenge: Understanding how the different sensors and their effectors work in harmony Breizh Algae Tour - Sept. 15th, 2014 Furness et al 2013 114 Merci - Thank you! All the nutritional benefits of regular worms, without the torture of having to be awake early Breizh Algae Tour - Sept. 15th, 2014 115 Thanks for your attention!