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Part 1: https://ccnm.ca.panopto.com/Panopto/Pages/Vi ewer.aspx?id=4acc4014-903a-4459-805e- afcb00098066 Part 2: https://ccnm.ca.panopto.com/Panopto/Pages/Vi ewer.aspx?id=4fd36ff9-4519-4639-816e- afcb0017200b PHL & PAT Esophagus BMS 150 Week 11  GI: Esophagus Junquiera...

Part 1: https://ccnm.ca.panopto.com/Panopto/Pages/Vi ewer.aspx?id=4acc4014-903a-4459-805e- afcb00098066 Part 2: https://ccnm.ca.panopto.com/Panopto/Pages/Vi ewer.aspx?id=4fd36ff9-4519-4639-816e- afcb0017200b PHL & PAT Esophagus BMS 150 Week 11  GI: Esophagus Junquiera 13th p 299-301 Guyton p 763-766 Boron Chapter 41  Esophagus Collapsible muscular tube about 25cm long Lies posterior to trachea Begins at inferior end of laryngopharynx Passes through inferior aspect of neck to enter mediastinum Pierces diaphragm through esophageal hiatus Ends in superior portion of stomach Esophagus: Histology Mucosa - Epithelium Nonkeratinized stratified squamous epithelium Langerhans cells present - Lamina propria Esophageal cardiac glands in 2 clusters (near pharynx and stomach) - secrete mucous Lymphoid nodules - Muscularis Only a single layer of longitudinally smooth muscle mucosae Submucosa Dense, irregular fibroelastic CT Esophageal glands proper: mucous and serous cells Muscularis externa Outer and inner layers, with variable amounts of skeletal muscle upper 1/3 mostly skeletal, middle 1/3 mixed, lower 1/3 mostly smooth muscle Serosa / adventitia Adventitia until it pierces the diaphragm, then serosa  ç Esophagus: Anatomy Major arteries include thoracic branches of the aorta superiorly Branches of the left ç gastric artery inferiorly Major venous drainage (next slide) via the azygous vein and the portal venous system via the left gastric veins ç ç Esophagus – Anatomy At the lower esophagus, the portal circulation (branches of the left gastric vein) “overlaps” or drains the same area as the systemic venous circulation (esophageal branches à azygous vein) This interface is a pathologically important site of bleeding if the veins rupture Discussed later in liver pathology Muscular anatomy The larynx compresses the esophagus superiorly to some extent Muscles that move the larynx and hyoid upwards and anteriorly to allow swallowing (don’t need to memorize them here) The cricopharyngeus muscle and the rest of the inferior pharyngeal constrictor muscle are the major players in “pushing food down” There’s a “weak spot” just above the cricopharyngeus ç muscle (circled) ç Sometimes an outpouching develops and food “gets stuck” – known as a Zencker Diverticulum  ç Esophagus: Anatomy FYI diagram – note the rich nerve ç plexuses around the esophagus, including ç the vagi and thoracic ç ç sympathetic nerves ç  Esophageal Movements Deglutition (swallowing) § Complex process involving mouth, pharynx and esophagus § Can be divided into: Voluntary stage Pharyngeal stage Esophageal stage  Esophageal Movements Voluntary Stage of swallowing: § After chewing, food is voluntarily squeezed or rolled posteriorly into the pharynx § By pressure of the tongue upward and backward against the palate § From here on, swallowing becomes almost entirely automatic Esophageal Movements Pharyngeal Stage of swallowing: § Reflex controlled by brain stem (medulla) 1.Food in pharynx – tactile stimulation 2.Soft palate pulled upward Good idea – blocks the nasal cavity so food doesn’t get shoved out your nose 3.Palatopharyngeal folds pulled together creates “sagittal slit” for selective action Esophageal Movements 4. Trachea is closed (respiration inhibited) Vocal cords approximated Larynx raises and epiglottis covers vocal cords 5. Relaxation of UES 6. Peristaltic contraction of pharynx  Nervous control of Pharyngeal Stage Swallowing Center - medulla - Sensory input from pharnyx and esophagus - Coordinates activity from vagal nuclei with other centers (e.g., inhibits respiratory center) Pharyngeal Phase - - Food in pharynx ® afferent sensory input via vagus N. / glossopharyngeal N. ® swallowing center ® brain stem nuclei ® efferent input to pharynx Coordination of Swallowing Entire pharyngeal swallowing stage occurs in less than 2 seconds § Only interrupts respiration for a fraction of a usual respiratory cycle Swallowing center inhibits respiratory center of the medulla, halting respiration at any point in its cycle to allow swallowing to proceed Peristaltic waves “push” food down into the stomach (takes more than one) Esophageal Movements Secondary peristalsis § Result from distention of the esophagus by retained food, or by reflux of gastric contents into the esophagus Continue until all the food has emptied into stomach § Initiated by intrinsic neural circuits in myenteric nervous plexus and vagal afferent fibers from esophagus to medulla and back to esophagus through vagal efferent fibers Lower Esophageal Sphincter (LES) 1-2 cm below diaphragm and 2-5cm above juncture with stomach where esophageal circular muscle functions as LES (aka GES) § Normally remains tonic and constricted When a peristaltic wave passes down esophagus, receptive relaxation relaxes the LES ahead of the peristaltic wave to allow easy propulsion of food into stomach § Prevents reflux Esophageal manometry: -Note the high resting pressures of the UES, and the low resting pressures of the LES -Note the higher pressures in the LES after food has passed into the stomach -Relaxation of the LES mainly due to activity of NO- and VIP-secreting branches of the vagus nerve Esophageal Pathology The Esophagus A wide range of common pathologies that run the gamut from benign to deadly § Not to mention the rare stuff… Basic “groups” of pathologies: § Dysphagic/motility diseases Dysphagia = difficulty swallowing § Inflammatory diseases § Metaplastic/neoplastic diseases Done in future lectures § Vascular diseases Done in future lectures Motility/obstructive disorders Nutcracker esophagus § Visceral pain from the esophagus is well-localized, and excess distention cause relatively intense, brief chest pain High-amplitude esophageal contractions Outer longitudinal layer of smooth muscle contracts before the inner circular layer Cause periodic short-lived esophageal obstruction Other motor disorders of esophagus include diffuse esophageal spasm (very common) § result in minor obstruction or chest pain as well § Due to dysfunction of inhibitory nerves Patchy neural degeneration localized to nerve processes noted on histology Motility/obstructive disorders Achalasia § Increased tone of the LES can be due to impaired smooth muscle relaxation If inhibitory neurons do not release VIP or NO after swallowing, the LES won’t relax properly § Achalasia = incomplete LES relaxation, increased LES tone, and aperistalsis of the esophagus § Primary achalasia is idiopathic, caused by failure of distal esophageal inhibitory neurons Degenerative changes in neural innervation, either intrinsic to the esophagus or within the extraesophageal vagus nerve or the dorsal motor nucleus of the vagus, may also occur § Secondary achalasia: diabetic autonomic neuropathy, malignancy Infections (tropical countries) - Trypanosoma cruzi infection causes destruction of the myenteric plexus, failure of peristalsis, and esophageal dilatation, partial or absent lower esophageal sphincter relaxation Motility/obstructive disorders Achalasia § Clinical features: Dysphagia, chest pain, regurgitation Incidence of 1/100,000/year Does not affect mortality – unless malignancy is involved § Treatment: Botox Myotomy Esophageal imaging – barium swallow Diffuse esophageal spasm Achalasia Manometry studies  Motility/obstructive disorders Other causes of dysphagia: Iron-deficiency anemia or chronic reflux disease sometimes causes fibrosis or non-malignant growths that obstruct the esophagus Worsening dysphagia and reflux symptoms in many populations needs to be investigated to ensure that the patient has not developed esophageal cancer § We will cover esophageal malignancies later this semester  Esophagitis Infectious esophagitis § Usually a sign of immunosuppression HSV (small “punched-out” lesions), cytomegalovirus (CMV), or fungal organisms Among fungi, candidiasis is most common, although mucormycosis and aspergillosis may occur § Typically grayish-white pseudomembrane on a tender, erythematous base Autoimmune esophagitis § Crohn’s disease (rare) § Scleroderma – mostly obstructive & regurgitation vs. inflammatory findings, since LES and distal esophagus becomes atrophic and loses functionality § Eosinophilic esophagitis – emerging disease Eosinophilic Esophagitis Esophagitis that is usually distributed throughout the length of the esophagus, with primarily esosinophilic inflammation § > 15 eosinophils/high-power field, much fewer neutrophils and lymphocytes § Marked basal cell hyperplasia and elongation of the submucosal papillae Increasing in incidence and is a disease of both children and adults § Not uncommon – prevalence of ~ 50/100,000  Normal and Eosinphilic esophagitis Brief pathophysiology: Th2 response with an abundance of IL-4, IL-5, and IL-13 in serum and in affected tissue Often a history of atopic illness during or before the GI symptoms No candidate genes identified as of yet – food intolerance/allergies are thought to be major inciting factors  Eosinophilic esophagitis Clinical features: § Kids – nausea and vomiting, small for age, weight loss if severe Heartburn/reflux less prominent in small children, more common in older § Adults – main symptom is dysphagia and food impaction – chest pain can occur as well Heartburn can be present, and is usually resistant to PPIs, though occasionally does respond to PPIs Diagnosis: § Endoscopy § Often IgE levels are elevated Reflux esophagitis Normal histology = stratified squamous epithelium § Resistant to abrasion from foods but is sensitive to acid § Submucosal glands, more abundant in the proximal and distal esophagus, secrete mucin and bicarbonate § Constant lower esophageal sphincter tone prevents reflux of acidic gastric contents Though most people have physiologic occurrence of reflux that is asymptomatic or mildly symptomatic Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis § Most common outpatient GI diagnosis in the United States  Reflux esophagitis Caused by reflux of bile and gastric acid into the esophagus § Decreased LES tone or increased abdominal pressure likely contribute to GERD § Aggravating factors include alcohol and tobacco use, obesity, central nervous system depressants, pregnancy, hiatal hernia, delayed gastric emptying, and increased gastric volume  Reflux esophagitis Findings include: § Hyperemia, mild eosinophilic infiltration in less severe cases § Basal zone hyperplasia exceeding 20% of the total epithelial thickness and elongation of lamina propria papillae may be present in more severe cases § Barrett’s esophagus = patches of red, velvety mucosa extending upward from the gastroesophageal junction that alternate with the smooth, pale normal esophageal mucosa Metaplasia looks similar to intestinal glandular epithelium – goblet cells are present – with time many will progress to dysplasia More common with more significant reflux Can be a pre-malignant change, but most do not progress to esophageal cancer – Barrett’s needs to be followed via endoscopy over time Esophagitis images  Reflux esophagitis Clinical features § Dysphagia, heartburn, and, less frequently, regurgitation § Rarely, chronic GERD is punctuated by attacks of severe chest pain that may be mistaken for heart disease Treatment with proton pump inhibitors or H2 histamine receptor antagonists, which reduce gastric acidity, typically provides symptomatic relief § Severity of symptoms is not closely related to the degree of histologic damage but disease duration is § Heartburn that increases in severity and is accompanied by dysphagia is a red flag for esophageal carcinoma More later this semester Food Triggers Coffee and tea Chocolate Spicy food Beer, wine, and other forms of alcohol Fried or greasy foods Mint Tomatoes and tomato-based foods Sweets and high-glycemic index foods Physiology 5.01 Physiology of the Gastrointestinal Tract and Introduction to Gut Microbiome Dr. Maria Shapoval BMS 150 Week 10 Overview Overview of Gastrointestinal Tract Gut Physiology Motility Digestion Absorption Regulation Microbiome Amounts per GI Typical families Value/ function/ role of microbiome in health Bidirectional relationship between microbiome and human physiology and health Learning Objectives Describe the different types of movements specific to the digestive tract Discuss the role of ICC, smooth muscle cells, enteric and central nervous systems in regulating gut motility Briefly explore additional hormones that can influence GI motility Summarize the function and mechanism of digestion Compare and contrast the absorption of carbohydrates, amino acids and fats Describe the gut microbiome, including the different bacterial families and their locations within the GI tract Discuss the role of the gut microbiome in digestive function and intestinal health Consider pathological implication of gut dysbiosis Learning Objectives Discuss the relationship between dietary factors and microbiome Describe the role that antibiotics play in influencing the gut microbiome Big Picture – Gut Function Gastrointestinal Tract (GI) is involved in transporting food by- products at appropriate times to areas that are functionally designed to break them down and others that are designed for absorption 60 tonnes of food pass through GI tract through average life time It is also involved in some degree of decontamination of the food by-products as well as facilitating and maintaining appropriate relationships with live non-human cells (bacteria, viruses, fungi, etc) with the help of the immune system Largest interface between host, environmental factors and antigens Overview of the GI Tract Here are the different structures that contribute to the function of the gastrointestinal tract. We will cover some of these today and some we will be covering in future. Mouth, teeth, salivary glands Esophagus, lower esophageal sphincter (LES), stomach, pyloric sphincter Small Intestine (SI): duodenum, jejunum, ileum Large Intestine (LI) Ascending, transverse, descending, sigmoid colon Rectum, anus Supporting organs: liver, gallbladder, pancreas Future lectures will dive into anatomy and physiology of discrete components and organs Today we are talking about physiology overall and introduce role of microbiome Motility There are 3 basic movements that take place along the GI tract: Peristalsis Involves entire GI tract, starting with esophagus Waves of smooth muscle contractions that propel food bolus throughout GI tract Rhythm is believed to be produced by interstitial cells of Cajal (located with the myenteric plexuses; enteric nervous system) Involves contraction behind (proximal) the food bolus and relaxation in front (distal) of the food bolus May also be stimulated or promoted by distention of smooth muscle cells (aka stretch) Function: propel food further along GI tract Some problems: esophageal spasms, atonic colon (an example of cause of constipation), gastroparesis Motility There are 3 basic movements that take place along the GI tract: Segmentation Occurs within SI and LI Produced by the coordination of smooth muscle cells and interstitial cells of Cajal (ICC) Function: promote mixing the food particles to increase interaction between the villi of the enterocytes and various food particles to promote absorption Motility There are 3 basic movements that take place along the GI tract: Migrating motor complex (MMC) Occurs within stomach and SI (and a few other locations) Small movement, almost a vibration, that occurs predominantly during fasting 1.5-2 hr intervals Movement is promoted by motilin, secreted by Mo-cells located in the duodenum (upper SI) Function: suspected that it is a self-cleaning mechanism, as this movement causes small food particles and bacteria to be dislodged from the intestinal wall and prevents bacteria from traveling from LI into SI Some problems: lack of MMC has been implicated in pathogenesis of small intestinal bacterial overgrowth, reduced during pregnancy and may explain or contribute to constipation and heartburn  Interstitial Cells of Cajal (ICC) Pacemakers of the GI Form a network with each other and smooth muscle cells via gap junctions, as well as enteric motor neurons Found throughout the entire GI tract Generate slow waves - these do not typically lead to muscle contractions Can also cause spike potentials that do trigger smooth muscle contractions à contribute to all types of different movements Interstitial Cells of Cajal (ICC) Pacemakers of the GI Excitability of smooth muscle can be increased by additional factors such as: Muscle stretch (distention) Acetylcholine Other GI hormones Excitability can be decreased by: Norepinephrine (causes hyperpolarization) Enteric Nervous System (ENS) Composed of sensory, motor and interneurons Organized into: Submucosal Plexus Located between the layers of submucosa and circular muscle (only present in SI and LI) Function to regulate motility, local blood flow, regulate secretions and epithelial cell function Myenteric Plexus Located between longitudinal and circular muscles (entire GI) Function to regulate motility CNS and GI Motility While the enteric NS can function independently, the CNS does innervate the GI tract in several places and provides additional regulation and modification of the ENS Examples of nerves that connect CNS and ENS Vagus Nerve Pelvic Splanchnic Nerves Thoracic Sympathetic Trunk In general, sympathetic NS opposes GI motility (as well as digestive secretions) Parasympathetic role is not as straightforward as it can both stimulate and inhibit motility Transport Throughout GI Tract Timing is key! If the food is transported too quickly, may not have enough time to digest or absorb it For example, if the food is allowed to enter the duodenum before being properly digested in the stomach the digestive enzymes in the duodenum may not be able to complete digestion limiting what can be absorbed from the food …And then someone else might eat our food, like gut bacteria! If the food is transported too slowly, it may irritate the local or neighboring mucosa For example, if the food content stays in the stomach for too long this increases likelihood that stomach acid will enter the esophagus (i.e. heartburn) Regulating Timing of GI Motility Many different cells/tissues can influence motility Already discussed smooth muscle cells, ICC, ENS and CNS Some of these cells response to mechanical stimulation (i.e. distention) while others respond to chemical cues (i.e. presence of peptides or free fatty acids can trigger cholecystokinin to be released) Secretion promoting motility: I-cells – cholecystokinin Enterochromaffin cells – serotonin G-cells – gastrin Mo-cells – motilin Beta-pancreatic cells – insulin Regulating Timing of GI Motility Many different cells/tissues can influence motility Already discussed smooth muscle cells, ICC, ENS and CNS Some of these cells response to mechanical stimulation (i.e. distention) while others respond to chemical cues (i.e. presence of peptides or free fatty acids can trigger cholecystokinin to be released) Secretions reducing motility: S-cells – secretin D-cells – somatostatin Pancreatic cells - Pancreatic peptide YY Alpha-pancreatic cells – glucagon These hormones have multiple functions beyond regulating motility, such as regulating other endocrine cells, metabolism, appetite and much more  Digestion – Overview Digestion = breaking down macromolecules into smaller molecules to increase absorption Two major types: Mechanical digestion: physically cutting, crushing, and churning food so that the volume of each food particle decreases (and therefore SA:volume ratio favours chemical digestion) Mouth – chewing Stomach – the segmentation-like movements of the stomach (churning) “smashes” food against the firm bumps and ridges in the mucosa of the stomach (rugae) Food is broken down into smaller and smaller pieces as it is mixed with the fluid secretions of the stomach Digestion – Overview Digestion = breaking down macromolecules into smaller molecules to increase absorption Two major types: Chemical Digestion: chemical processes that allows absorption of food particles. Can be described as: Enzymatic digestion – enzymes Lipid solubilization – emulsifiers (bile break macronutrients down into salts, lecithin) secreted by the liver smaller and smaller particles emulsify ingested lipids so that through the process of hydrolysis enzymes can break them down to smaller, absorbable molecules  Digestion – Overview Carbohydrate digestion – begins in the mouth with salivary amylase (minority), further broken down by pancreatic amylase and brush border enzymes within SI (majority of CHO digestion) Protein digestion – begins in the stomach with HCL and pepsin, further digested by pancreatic enzymes and brush border enzymes Fat digestion – begins in the stomach with HCl and lipase (minority), further digested by pancreatic lipase and emulsified by bile acids released by the liver (majority of lipid digestion) The mechanics of digestion will be further explored in other lectures Thoughts to ponder: what complications would you expect to see if any of these digestive processes were struggling or incomplete? Digestion - Summary Location Enzymes/ Contributing What is being Secretion organs/ structures digested? Mouth Salivary amylase Salivary glands Carbohydrates, all Mucus, water Teeth else broken into Mastication smaller particles Stomach HCl, lipase, pepsin Vagus nerve Proteins, fats, carbs promotes HCl – limited digestion release other than protein Small Intestine Bile acids, Liver contributes Proteins – pancreatic bile, pancreas pancreatic enzymes, Most enzymes, brush release numerous brush border important site border enzymes enzymes including enzymes; of chemical lipase and amylase Carbs – brush digestion border enzyme and amylase Lipids – lipase and bile acids Large Intestine Gut microbiota some of what hasn’t been digested yet Absorption Absorption: movement of any substance across the mucosal epithelium of the alimentary tract and into the bloodstream (most substances) or lymphatics (lipids) Largely takes place in the small intestine and is dependent on the health of the villus and microvilli of enterocytes Effective absorption is dependent on a large surface area at the apex of the epithelial cell (brush border, villi) Supported by segmentation to increase food bolus contact with microvilli and villi Proper timing required (transit that is too quick won’t allow enough time for absorption) Chyme (“watery” product of gastric digestion) needs to be mechanically digested into small particles and chemically digested into small molecules for absorption to occur Carbohydrate Absorption Digestion breaks polysaccharides into monosaccharides Galactose, glucose, fructose Only monosaccharides can be transported across the epithelial cells of the small intestine – disaccharides and polysaccharides cannot be transported Na+/glucose (galactose) co-transporter (SGLT1) Transports glucose and galactose (hexoses) from lumen into enterocyte Depends on high concentration of Na+ within lumen to power the transport of the hexoses (Na+ moves down its concentration gradient) If defective, can’t absorb these into the body Na+/K+ pump needs to continue to maintain low intracellular [Na+] Carbohydrate Absorption GLUT-5 Passive transport (facilitated diffusion) of fructose from lumen into enterocyte GLUT-2 and GLUT-5 basolateral side Transport of monosaccharides from enterocyte into blood stream (hepatic portal vein) Protein Absorption Majority of protein is absorbed in the duodenum and jejunum (very little left for ileum) Only 2-3% of protein escapes digestion and absorption (under healthy conditions) Absorption of undigested protein (by adults) has been linked with allergic symptoms Na+ symporters (similar to SGLT1) for amino acids 5 different types PepT1 transporter Transports dipeptides and tripeptides into enterocyte Relies in H+ instead of Na+ concentration gradient These are hydrolyzed into amino acids by intracellular enzymes (cytosolic digestion) within the enterocyte Amino acids are released into blood stream; hepatic portal vein Nucleic Acid Absorption Nucleic acids are broken into nucleotides and further broken into nucleoside and phosphoric acid via digestion Split further into sugars and purines and pyrimidine bases Bases absorbed via nucleoside transporters (active transporters) Fat Absorption Passive diffusion (and possible carrier proteins) Free fatty acids 10-12 carbons long Pass through enterocyte unmodified and enter portal circulation Remain free and unesterified Chylomicron Free fatty acids >10-12 carbons long Re-esterified into triglyceride once inside enterocyte Cholesterol (also esterified), transported via NPC1L1 transporter FFA’s and cholesterol are coated with proteins, more cholesterol and phospholipids à chylomicron Enters lymphatics (too big to pass between endothelial cells into blood stream) Fat Absorption Majority of ingested fats are absorbed (95% in adults, 85- 90% in infant) Assuming moderate amount of fat in the diet Steatorrhea Impaired fat digestion and absorption resulting in high amount of fat in the stool What kind of problems or pathological processes would you expect to contribute to this finding? Vitamin and Nutrient Absorption Fat-soluble vitamins (A, D, E, K) Depend on incorporation into micelle for absorption (similar process as with other fats) Majority absorbed in duodenum (upper SI), however vitamin B12 is absorbed in the ileum Most of the B-vitamins and vitamin C require Na+ cotransporters for absorption Iron absorption: Occurs within duodenum via divalent metal transporter 1 (DMT1) – Fe2+ (ferrous) enters enterocytes Transported out of enterocyte by ferroportin 1 and hephaestin In plasma Fe2+ is converted into Fe3+ (ferric) and is transported by being bound to transferrin The Human Microbiome What is the microbiome? The collection of all organisms living on and in a given environment or habitat (i.e., the human body) Also known as microbiota or commensal organisms Human microbiome project - the catalog of the microbes in human and their genes (within entire organism) Composition: Recent estimates ~1014 cells (100 trillion) Bacteria, viruses, fungi, etc. Virus composition outnumbers bacterial composition ~ 5:1 Bacteria vs. fungi ~ 10:1 Distribution determined in part by environment (pH, O2 access, tropism, etc.) Composition varies from person to person Bacterial Amounts within GI Tract Oral Cavity (Mouth) 1011 /g: Spirochaetes Esophagus 102 – 104/ mL: Streptococci, Lactobacilli, gram negative bacilli Genus: Prevotella, Veillonella, Megasphaera, Granulicatella, Rothia, Fusobacterium, Gemella, TM7, etc Stomach 103/mL: Helicobacter pylori Small Intestine 104-106/mL: Lactobacilli, gram positive cocci Large Intestine 1012 /g: Bacteroides, Bifidobacteria, Clostridia, Peptostreptococci, Fusobacteria, Lactobacilli, Enterobacteria, Enterococci, Eubacteria, Methanogens, Sulphate reducers, etc Microbiome Impact on Humans All species live in symbiosis with other organisms, and this codependency has shaped our evolutionary development We share significant homology with many bacterial, viral, and fungal organisms at the genetic level The human body has evolved to develop in the context of a microbial presence The body relies on microorganisms to perform vital functions – prevent colonization by pathogens, improve digestion and metabolism, develop immune competency FYI illustration. Gut Microbiome: 93.5% of gut bacteria belong to the following phyla: Firmicutes (major composition) Bacteroidetes (major composition) Proteobacteria (minor composition) Actinobacteria (minor composition) Gut Microbiome: Firmicutes Genus: Lactobacillus, Clostridium, Enterococcus Examples: Lactobacillus reuteri, Enterococcus caecium Bacteroidetes Bacteroides, Prevotella Examples: Bacteroides fragilis, Prevotella spp. Proteobacteria –Helicobacter, E. coli, Shigella, Salmonella, Yersinia (some commensal and some pathological bacteria) Actinobacteria – Bifidobacterium longum, Bif. Bifidum Homework: Look at the composition of a probiotic – what phyla is it composed of? Which of these are producers of SCFA? Gut Microbiome: Functions of the gut microbiome: Harvesting energy (digesting and absorbing nutrients that we can’t utilize) Strengthen gut integrity Shape intestinal epithelium Regulation of immune function Regulate intestinal motility Protection against pathogenic microbes Production of some nutrients Vitamin K2 (menaquinone), short-chain fatty acids Considered an “endocrine organ” Gut Microbiome Development Birth process plays a role in determining the types of amounts of bacteria that will colonize the infant’s GI tract C-section: less Bacteroides and more Clostridium species Vaginal: more characteristic of mom’s microbiota Initial food: Breastfeed: Bifidobacterium high Formula fed: Bifidobacterium low, higher diversity and altered ratio of E. coli, Clostridium difficile, Bacteroides fragilis Under fed: increase in entero-pathogens like Enterobacteriaceae By 2.5 years of age the composition, diversity and functional capabilities of child’s gut flora is similar to that of an adult microbiota Remains fairly stable throughout life, meaning there are some fluctuations but the majority of the ratio’s of different phyla and families will remain consistent Diet and Gut Microbiome Many different factors can influence the composition of the gut microbiota, including genetics, diet, medications and other factors. Example of dietary impact: Starch, fiber and plant diet Infant microbiota is composed of Actinobacteria (10.1%) and Bacteroidetes (57.7%) Prevotella – present; produce short-chain fatty acids (SCFA’s) Diet high in sugar, starch and animal protein Infant microbiota Actinobacteria (6.7%) and Bacteroidetes (22.4%) Prevotella – largely absent Short-Chain Fatty Acid (SCFA): Microbiome metabolite Produced duration fermentation of indigestible carbohydrates (fibers) by gut microbiota Acetate, propionate, butyrate Promote intestinal integrity by: Regulating luminal pH Regulate mucus production Produce fuel for the epithelial cells Modify mucosal immune function Influence overall metabolism: Appetite regulation Energy expenditure Glucose homeostasis Immunomodulation FYI illustration. FYI illustration. Microbiome Metabolites SCFA – already discussed Trimethylamine (TMA) Choline, phosphatidylcholine and L-carnitine can be metabolized into TMA by microbiome. TMA can be further converted into trimethylamine oxide (TMAO) which has been linked to increasing risk factor for atherosclerosis and thrombosis Bile acids Produced by the liver and secreted into the intestines can be further modified by gut microbiome Bile acids have been correlated with changes in energy metabolism (i.e. high cholesterol, insulin insensitivity) Indoles Produced by metabolism of tryptophan Maintain intestinal barrier and influence immune response Gut Microbiome and Intestinal Integrity The presence of various bacterial species has been correlated with changes in epithelial cell function and structure Examples of healthy and beneficial changes: Non-pathogenic E. coli – increase epithelial mucus secretion and reduce epithelial permeability Lactobacillus rhamnossus – increase expression of occludin and ZO-1 proteins Review: what was the function of these proteins? L. rheuteri – increase epithelial cell proliferation Gut Microbiome and Intestinal Integrity The presence of various bacterial species has been correlated with changes in epithelial cell function and structure Examples of pathological changes: Salmonella entetica – reduced ZO-1 and occluding proteins and tight junction complexes What would be the impact on intestinal permeability? Clostridium difficile – reduced mucin production Enterovirus E11 – direct cytotoxicity Gut Microbiome and Intestinal Motility Observations: Giving probiotics (live bacteria) to adults with constipation improves gut motility and increases number of bowel movements per day Transplanting fecal flora from patients with constipation to germ-free mice results in constipation symptoms Mechanisms: SCFA’s promote serotonin production and thus increase motility SCFA’s (butyrate) increase ratio of intermuscular cholinergic neurons – speeds up transmission of ENS signals and increase motility Gut bacteria can modified bile composition which can also influence gut motility Methane gas released by some intestinal bacteria can slow down motility by influencing smooth muscle cell contractions Gut Microbiome and Intestinal Motility Bi-Directional Relationship: Changes in motility influence the survival of different bacterial groups Constipation (related to irritable bowel syndrome) causes changes to gut bacteria: Increased: Bacteroides and Enterobacter Decreased: Bifidobacterium and Prevotella Diarrhea: Increased: Prevotella Decreased: Bifidobacterium, Bacteroides and Lactobacillus Antibiotics Terms and Concepts Bacteriostatic Mechanism of action interferes with bacterial cell activity (including replication) without directly causing death Require host immune function to fully clear the overgrowth Example: macrolides and tetracyclines Bactericidal Mechanism of action directly kills the bacteria Increased risk of adverse events compared to bacteriostatic antibiotics Broad spectrum Antibiotic is able to effect different types of bacteria’s including gram positive, gram negative, and others (spirochetes, atypical) Antibiotics and Gut Microbiome Negative Effects on Gut Microbiome: Reduce species diversity Altered metabolic activity Select the antibiotic-resistant organisms May lead to development of Clostridium difficile overgrowth resulting in antibiotic-associated diarrhea However, in most cases, the gut bacteria will recover to their baseline state within a few weeks after antibiotic is discontinued However, several studies argue that long-term dysbiosis is also frequent Not all antibiotics have the same impact on gut microbiome Doxycycline (tetracycline class) – reduce Bifidobacterium diversity Clarithromycin – reduce Bifidobacterium spp and Lactobacillus sp Nitrofurantoin (used for UTI) and amoxicillin – little impact on gut bacteria Antibiotics and Gut Microbiome Antibiotic-associated diarrhea (AAD): Occurs in 5-30% initially during antibiotic treatment or within 2 months after discontinuation Host factors that increase likelihood: age >65, immunosuppression, ICU or prolonged hospitalization Caused by disruption in normal gut microbiome C. difficile accounts for 10-25% of AAD cases Symptoms: mild diarrhea ranging to acute pseudomembraneous colitis (100% due to C. difficile) Note yellowish Watery diarrhea, fever, leukocytosis pseudomembranes seen on (increased WBC in blood) colonoscopy. Antibiotics and Gut Microbiome Antibiotics in childhood Association with development of asthma, juvenile arthritis, type 1 diabetes, Crohn’s disease (IBD) and mental illness Thought to be due to dysbiosis: Reduced richness of microbiome; diversity and abundance Reduction of Bifidobacteria and Lactobacillus Increase in E. coli Study Guiding Questions Compare and contrast the different types of movement; location? purpose? Cells/ chemicals involved? Compare and contrast the absorption mechanism of proteins, nucleic acids, carbohydrates and fats Summarize the impact of gut microbiome on intestinal function and overall health Summarize the impact of the environment on the different populations of gut microbiome References Zhou M, Zhao J. A review on the health effects of pesticides based on host gut microbiome and metabolomics. Front Mol Biosci. 2021; 8. Ganong’s Review of Medical Physiology – 25th edition – Chapters 25, 26 and 27 Gierynska M, et al. Integrity of the intestinal barrier: the involvement of epithelial cells and microbiota- a mutual relationship. Animals (Basel). 2022; 12(2): 154 Liu Q, et al. Interaction between the gut microbiota and intestinal motility. Evid Based Complement Alternat Med. 2022 Rinninella E, et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet and disease. Microorganisms. 2019; 7(1): 14 Silva YP, et al. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol. 2020; 11  Visceral Anatomy and Histology The Gastrointestinal Tract References: Moore’s Clinically- Oriented Anatomy, Chapter 2 BMS 150 Junqueira’s Basic Histology Text and Week 10 Atlas, Chapter 15 General Anatomy of the Abdomen Part of the trunk bounded by: ▪ diaphragm superiorly ▪ Musculo-aponeurotic walls anterolaterally ▪ A virtual boundary inferiorly – the pelvic inlet The pelvic and abdominal cavities are continuous – any “boundary” is purely conceptual ▪ Vertebrae posteriorly  General contents of the abdominal cavity: Alimentary canal: Lower esophageal sphincter, stomach Duodenum, jejunum, ileum ▪ Parts of the small intestine will “dip into” the pelvic cavity Cecum, ascending colon, transverse colon, descending colon ▪ Note – the sigmoid, rectum, and anus extend into the pelvic cavity, but will be discussed in BMS 150 Accessory organs, other structures Liver, gall bladder, pancreas, and their ducts Spleen, kidneys Peritoneal folds and many vessels and nerves General contents of the abdominal cavity: Peritoneal reflections have been removed for clarity Peritoneum & Peritoneal Cavity Characteristics of the peritoneum: Transparent, thin membrane that lines the abdominopelvic cavity and is continuous with the serosa of the abdominopelvic organs Parietal peritoneum – lines the interior of the body wall ▪ Pain here is well-localized to the overlying dermatome Exception – peritoneum overlying the diaphragm is referred to C3 – C5 Can sense pressure, cutting, heat, cold, laceration, inflammatory irritation Visceral peritoneum – lines the visceral organs and is continuous with the serosa ▪ Also forms major folds known as mesenteries , omenta, or ligaments ▪ Pain is poorly-localized but can be understood somewhat by knowledge of the embryologic derivatives of some abdominal contents (GI embryology later this semester) Can sense ischemia, inflammation, stretch, chemical irritation Peritoneal Cavity Frontal view – greater omentum sectioned to show underlying structures ▪ Omentum – double-layered peritoneal membrane continuous with serosal surfaces, connected to the stomach Greater and lesser omenta shown here ▪ Mesentery/mesocolon – double-layered peritoneal membrane that surrounds the small intestine (mesentery) and large intestine (mesocolon) at particular sites A clearer view – peritoneal folds Make reference to this slide for the peritoneal content See notes for details  Basics of the major peritoneal folds Greater omentum ▪ One of the largest folds ▪ Extends from the greater (inferior) curvature of the stomach → over the anterior aspect of the abdominal cavity (right next to the abdominal wall) → folds “back up” to join with the transverse colon ▪ Stores a lot of visceral fat (fatty apron) ▪ Contains many lymph nodes and is somewhat mobile – can “wrap around” inflamed or perforated viscus  Basics of the major peritoneal folds Lesser omentum ▪ Extends from the lesser (superior) curvature of the stomach and proximal duodenum → to the inferior aspect of the liver ▪ Clinically-important structures lie within the lesser omentum: Hepatic artery, common bile duct, hepatic portal vein See bottom picture  Basics of the major peritoneal folds The mesenteries Mesentery = double-fold of small intestinal peritoneal lining continuous with the serosa ▪ Lines the jejunum and ileum, binds them to the posterior abdominal wall ▪ Houses many important vessels and nerves ▪ Helps keep the small intestine from being “tangled” Mesocolon – 2 separate double-folds that connect the transverse and sigmoid colon to the posterior abdominal wall ▪ Also lots of blood and lymphatic vessels as well as nerves Basics of the major peritoneal folds The falciform ligament Divides the liver into left and right lobes Attaches to the anterior abdominal wall ▪ Embryologically interesting – the distal edge that connects to the anterior abdominal wall (round ligament) There are many more anatomically- is the remnant of the interesting but “too in-depth” anatomical umbilical vein… so it terms for these peritoneal structures connects to the All are important surgical landmarks umbilicus  Navigating the peritoneal cavity Many structures are not fully “surrounded” by peritoneum ▪ Either the entire surface does not really contact the peritoneum or the surface of the structure is not completely surrounded by the peritoneal lining ▪ Lots of terms for this, but we’ll just call them all “retroperitoneal” (this isn’t strictly anatomically correct): Most of the duodenum, parts of the ascending and descending colon, anal canal Pancreas Kidneys, adrenal glands, ureters Aorta and inferior vena cavae  Navigating the peritoneal cavity There are certain “sacs” or bursa that are present within the peritoneal cavity that are clinically-relevant (and very surgically-relevant) The omental bursa is behind the stomach and lesser omentum ▪ Can enter it via the omental foramen – just to the right and posterior to the border of the lesser omentum The greater sac includes all compartments (see next slide)  Navigating the peritoneal cavity FYI compartments: ▪ The supracolic (above the transverse colon and mesocolon) ▪ The infracolic (below the transverse colon and mesocolon) Abdominal Arterial Vasculature - Overview Also known as the splanchnic circulation (see next slide) Arteries branch off the abdominal aorta at 3 major sites: ▪ Celiac trunk – gives rise to: Left gastric artery, common hepatic artery, splenic artery Pancreas, liver, gallbladder, stomach, duodenum, spleen Supplies the structures of the embryologic foregut (more later) ▪ Superior mesenteric artery – gives rise to arteries that supply: pancreas, stomach, small intestine, as well as the large intestine up to the point of the transverse colon Supplies the structures of the embryologic foregut and midgut ▪ Inferior mesenteric artery – gives rise to arteries that supply the rest of the large intestine and superior anus (embryologic hindgut) Circulation of the GI tract Hepatic artery Abdominal Venous Vasculature - Overview The venous circulation is a portal circulation ▪ Portal circulation = capillary networks that are in series with each other ▪ i.e.: artery → capillary → portal vein → capillary → vein → right atrium Celiac trunk Inf. mes. Inf. vena Hepatic artery cava portal vein Sup. mes. artery Sup. mes. Splenic Hepatic vein vein vein Abdominal Venous Vasculature - Overview Inferior mesenteric vein joins with the splenic vein The splenic vein and the superior mesenteric vein come together to form the hepatic portal vein The hepatic portal vein carries poorly-oxygenated but nutrient- rich blood to the liver from most of the organs within the abdominal cavity artery → capillary → portal vein → capillary → vein → right atrium Celiac trunk Inf. mes. Inf. vena Hepatic artery cava portal vein Sup. mes. artery Sup. mes. Splenic Hepatic vein vein vein Circulation of the GI tract  General GI tract histology Although each organ is different, the tract follows a common theme (the accessory organs are unique) ▪ From lumen → outer wall, the layers are: Mucosa – absorption, secretion, chemical digestion, many endocrine functions, some immune functions Submucosa – secretion, lots of blood vessels, contains a large plexus of neurons (submucosal or Meissner’s plexus), some immune functions Muscularis – two to three layers of smooth muscle, main function is propulsion, another large neuronal plexus exists here (muscular or Auerbach’s plexus) Serosa/adventitia – connective tissue that anchors the GI tract and at the same time allows mobility – forms the peritoneum General GI tract histology Mucosa: epithelial lining, lamina propria, & muscularis mucosa Epithelial lining consists of: ▪ Epithelium: simple columnar with apical microvilli in high-absorption areas (small intestine) stratified squamous or cuboidal in other areas Apical microvilli in many parts of the tract greatly increase SA, and often the mucosa and sometimes the submucosa are also folded to further increase SA ▪ Goblet cells are often present (secrete mucous) Mucous protects/lubricates the GI tract, forms a water layer for diffusion of nutrients, and helps “store” IgA ▪ Enteroendocrine cells are often present General GI tract histology Mucosa cont... ▪ Lamina propria has MALT, blood + lymphatic vessels, some glands – loose connective tissue A lot of mast cells present, not necessarily associated with lymphatic nodules ▪ Muscularis mucosa forms the border between the mucosa and submucosa Increases folding of the mucosa layer As it moves, ensures all absorptive cells have access to the contents of the lumen Enteroendocrine cells (DNES) Part of the epithelial lining – lots in the stomach and small intestine Can be open or closed ▪ Open - contact the lumen and can sense luminal contents ▪ As they are activated they secrete their granules along the basal surface, towards the blood and other cells Thus can have paracrine (most common) and endocrine function ▪ Closed - do not contact the lumen, thus they are dependent on other sources of input to regulate secretion i.e. hormones or nervous system input  Important Enteroendocrine Cells Cell Location Hormone (Stimulus) Main Hormonal Functions Somatostatin Generally “turns down” the Stomach, duodenum, D pancreas (many different stimuli cause release) release of hormones from nearby cells ECL – stomach ECL – histamine (stimulated by vagus) ECL – stimulates acid EC, ECL EC – stomach, small and EC – serotonin, substance P production large intestines (mechanical, neural, endocrine) EC – increased motility Gastrin (amino acids in the stomach, Increases secretion of G* Stomach vagal stimulation, gastrin-releasing stomach acid peptide) CCK (fats and proteins in the Pancreatic enzyme secretion, duodenum) gallbladder contraction, I* Small Intestine satiety Inhibits gastric acid secretion Glucagon-like peptide (amino acids & Insulin secretion, satiety L Small intestine carbs) Inhibits gastric acid secretion Motilin (fasting) Migrating motor complex Mo* Small intestine Secretin (acid in small intestine, Bicarbonate and water especially duodenum) secretion from pancreas S* Small intestine Inhibits gastric acid secretion and gastric emptying Enteroendocrine cells (DNES) What should we know from that chart at this point? Know the “bold & underlined” information ▪ The cells highlighted are key regulators of GI physiology that impact: Motility in the GI tract Acid secretion Secretion of pancreatic enzymes and bicarbonate Secretion of bile ▪ We’ll go through the rest as we learn more small intestinal physiology General GI tract histology Submucosa: ▪ Large blood vessels and lymphatics ▪ Submucosal plexus Meissner’s plexus is thought to regulate the secretory activity of the tract, and also convey sensory information from the lumen to other parts of the gut or the CNS ▪ The lymphatic nodules may also be found here ~ 80% of the antibodies made in the body are in the GI tract – epithelial cells can take up antibodies produced in the nodules and translocate them into the lumen High concentration of lymphocytes and macrophages in these nodules Histology of the GI Immune System GALT: ▪ MALT – smaller nodules rich in macrophages and lymphocytes, found in the mucosa (lamina propria) ▪ Peyer’s patches – very large (extends right through to the submucosa) nodules that may be cm in length found mostly throughout the distal small intestine (jejunum, ileum) In the epithelium overlying Peyer’s patches are M (microfold) cells ▪ M-cells selectively endocytose antigens and present them to dendritic cells and lymphocytes – important in regulating the immune response to intraluminal antigens Peyer’s Patches General GI tract histology Muscularis: ▪ Most parts have an inner circular and outer longitudinal layer of smooth muscle Stomach has an additional oblique layer ▪ Muscular nervous plexus (Auerbach’s plexus) is found between the two layers, and is thought to mainly regulate the muscular movements of the GI tract Serosa/Adventitia: ▪ Esophagus has an adventitia (no mesothelium, dense connective tissue) ▪ Serosa forms the outer layer of the rest of the tract – loose connective tissue covered by a simple squamous mesothelium Mesothelium is continuous with the fluid-secreting peritoneum in the abdominal cavity Many large blood and lymphatic vessels are found within the mesentery/serosal layer Enteric Nervous System A basic schematic of the enteric nervous system is shown in the next slide Much of the activity of the GI tract is autonomous, though input from the autonomic nervous system is essential for normal function ▪ Autonomic nervous system efferents can impact muscular movements (Auerbach’s plexus interactions) or secretions from glands in the mucosa and submucosa (Meissner’s plexus interactions) Auerbach’s (myenteric) plexus is located between circular and longitudinal muscle layers, Meissner’s (submucosal) plexus is found diffusely within the submucosa ▪ Local reflexes can also regulate coordinated muscular movements and secretions  Enteric Nervous System Note the nerves that travel with the vessels within the mesentery Efferents from the ANS Afferent sensory information as well Anatomy and Physiology, 2nd ed. Fig. 23.3 Peritoneal membrane – a closer look Peritoneal membranes have a similar surface area (~ 1.7 m2 ) to the total skin surface area Although the entire surface is covered in secretory squamous mesothelium, only 50 – 75 mL (4 – 5 tablespoons) of peritoneal fluid is present ▪ Due to the constant circulation and absorption of peritoneal fluid ▪ Small particles are absorbed by venous pores and enter the portal circulation ▪ Larger particles are absorbed by lymphatic capillaries and enter the thoracic duct Lymphatic absorption is responsible for draining extra fluid that is produced during inflammatory processes Excess accumulation of peritoneal fluid = ascites  General Histologic Features - Esophagus Mucosa – non-keratinized stratified squamous epithelium with some glands near the LES Submucosa – some mucous-secreting glands Muscularis – upper part is striated muscle, lower part is smooth muscle, middle part is a transition between the two Outer layer is adventitia, SSE – stratified squamous epithelium; D – not serosa duct from submucosal glands; MM - ▪ Does not secrete fluid muscularis mucosa; GL – glands in submucosa  General Histologic Features - Stomach Mucosa – simple columnar epithelium arranged into pits and glands that run deep into the lamina propria ▪ Glands are deep to the pits ▪ Function of the glands varies depending on region of the stomach (acid secretion in fundus and body) ▪ Mucous neck cells are found throughout – secrete alkaline mucous that protects the stomach from secreted acid Muscularis – three layers instead of two ▪ Inner layer is oblique Serosa is continuous with the greater and lesser omentum  General Histologic Features – Small Intestine Mucosa: ▪ 3 levels of “folding” to optimize surface area: Plicae circulares, villi, and microvilli (on the surface of enterocytes) The submucosa also occupies the plicae circulares ▪ Peyer’s patches found in the ileum ▪ Crypts are depressions in between villi Submucosa: ▪ Large Brunner glands can be found in the duodenum (protective against stomach acid ▪ Peyer’s patches in the ileum extend from lamina propria all the way to submucosa Muscularis and serosa: ▪ Typical muscular layer, serosa  General Histologic Features – Large Intestine Mucosa – arranged into tubular intestinal glands that penetrate deep into the lamina propria ▪ simple columnar epithelium, fewer microvilli than in the small intestine ▪ Many goblet cells that secrete mucous ▪ Lots of MALT nodules in lamina propria Muscular layer is unique ▪ Circular layer is continuous, like other areas of the alimentary canal ▪ Longitudinal layer is arranged into 3 separate bands known as the teniae coli  Gross Anatomy of Large Intestine Note the teniae coli Longitudinal muscle layer is discontinuous and therefore somewhat weak Will review when we discuss diverticulosis