Gut-Brain Axis: An Exploration Tony Jelsma, Ph.D. Professor of - PowerPoint PPT Presentation

Gut-Brain Axis: An Exploration Tony Jelsma, Ph.D. Professor of Biology Dordt College

Initial Comments  I am not a practicing clinician  This field is large and rapidly expanding  Difficult to summarize concisely  Interdependence of multiple factors  People are different and so are their guts  I will describe some mechanisms and examples  I don’t know about its applicability to your practice  I believe there is promise but beware the hype

Overview  Anatomy of gut, brain, other relevant structures  Communication between gut and brain  Gut flora:  Types  Effects  Physiological changes involving gut flora  Psychological conditions affected by gut microbes  Feedback, review

Anatomy of the Digestive System

Organs of the Digestive System

Drainage of Blood from the Gut  Most blood drains into the hepatic portal vein and is processed by the liver  Rectal area drains into normal venous circulation  Bypasses the liver  More direct access to brain https://thoracickey.com/colon-and-rectum/

Four Layers of the Gut  Mucosa: digestion and absorption  Submucosa: blood & lymphatic vessels, nerves  Muscularis externa: peristalsis  Serosa: thin covering  Mucosa varies with location/function:  Esophagus  Stomach  Small intestine  Large intestine

Cells of the Mucosa  Vary with location:  Stomach (St)  Small intestine (SI)  Large intestine (LI)  Cell types:  Secretory cells (St)  Absorptive cells (SI, LI)  Mucous cells (St, SI, LI)  Enteroendocrine cells (St, SI, LI)  Stem cells (St, SI, LI)

Mucosa of Small Intestine  Function primarily in nutrient absorption  Organized in villi  Surface is mostly absorptive cells  Goblet cells produce mucus  Enteroendocrine cells at base secrete hormones  Capillaries, lacteals underlay the epithelium  Many immune cells monitor intestinal contents  Few bacteria https://library.med.utah.edu/WebPath/GIHTML/GI162.html

Mucosa of Large Intestine  No villi, just crypts  Primarily absorptive cells and mucous cells  Recovery of water and electrolytes  Many bacteria (10 12 /g) in colon  How are we protected from its contents?  How do they benefit us? http://www.histology-world.com/factsheets/largeintestine.htm

Protection from Intestinal Contents  Mucus layer secreted by cells  Antimicrobial substances (in small intestine)  Antibodies secreted into intestine  Tight junctions prevent leaking between cells  Many immune cells in submucosa  M cells allow immune cells to monitor intestinal contents

Peyer’s Patches contain immune cells  Function in immune response  Found in small and large intestine  Cells proliferate to fight infections  Intestinal epithelia are tightly joined to prevent leaking  How do immune cells monitor and attack intestinal contents?

Microfold (M) Cells Monitor Gut Contents  Intestinal cells are linked by tight junctions  Prevents leaking between cells  M Cells are cup-shaped cells covering Peyer’s patches  Intestinal samples are presented to immune cells underneath  Dendritic cells pick up foreign antigens and activate immune system

Summary of Gut Functions  Digestion and absorption of nutrients  Production of hormones to regulate digestion and overall physiology, including neural physiology  Interactions with gut bacteria:  Monitor gut contents  Induce inflammation when necessary  Attack potential pathogens  Absorb nutrients produced by bacteria  Respond to metabolites produced by bacteria

Anatomy of the Nervous System

Brain Anatomy - Cerebrum  Carries out conscious brain functions:  Receives conscious sensory information  Interprets sensory information  Decides on response  Sends out response signals

Brain Anatomy - Hypothalamus  Cerebrum, conscious brain functions  Hypothalamus, subconscious controls  Regulates autonomic nervous system  Mediates hormonal stress response  Regulates many hormone systems via pituitary  Regulates body temperature, hunger, thirst, …

Brain Anatomy – Limbic System  Cerebrum, conscious brain functions  Hypothalamus, subconscious controls  Limbic system, emotions  Motivated behaviors  Fear  Long term memory  Blood-brain barrier usually protects brain but is absent in some locations

Hypothalamus-Pituitary- Adrenal (HPA) Axis  Mediates stress response  Regulated by negative feedback  Glucocorticoid (cortisol) mediate stress response:  Suppresses inflammation  Alters energy metabolism http://goldfunctionalwellness.com/the-connection-between-oral-health-gut-health-and-overall-health/

Communication between Gut and Brain

How does the Gut Communicate with the Brain?  Endocrine:  Hormones are secreted by enteroendocrine cells, travel through the blood to the brain  Neural:  Sensory neurons in the gut signal to the brain  Metabolic:  Gut microbes produce metabolites that cross the intestinal wall and enter the bloodstream  Immune:  Gut inflammatory signals travel to the brain

Enteroendocrine Signaling to the Brain Intestinal hormone production is altered in response to food At least 18 hormones, including:  Cholecystokinin (CCK) induces satiety, increases anxiety  Ghrelin stimulates appetite  Peptide YY suppresses appetite  Glucagon-like peptide 1 promotes satiety  Hormones act on prefrontal cortex, amygdala, insula, and hypothalamus to regulate appetite/satiety  These actions are affected by bacterial metabolites

Enteric Nervous System  500 million neurons, from esophagus to anus  Afferent and efferent  Many neurotransmitters, 90% of serotonin, 50% of dopamine in the body is enteric  Receives sympathetic and parasympathetic inputs  Parasympathetic (vagus nerve) stimulates digestion  Motility  Secretion https://www.nature.com/articles/nrgastro.2016.107.pdf  Sympathetic inhibits digestion

Enteric Nervous System  Many afferent (sensory) projections to CNS  80% of vagus nerve is afferent  Can operate independently of the CNS  Sensory neurons and interneurons reflexively respond to stimuli in gut (food), inducing:  Secretion to stimulate digestion  Vasodilation for nutrient uptake  Peristalsis for movement https://www.nature.com/articles/nrgastro.2016.107.pdf

Enterochromaffin Cells Activate Neurons  Subset (majority) of enteroendocrine cells  In small intestine (duodenum)  Sense contents of intestine by odorant receptors  Respond by secreting 5-HT (serotonin)  Serotonin stimulates gut motility  Affects weight gain and satiety  This activity is altered by spore-forming bacteria and high fat diet (Besnard, 2012; Primeaux et al., 2013)

Enteroendocrine cells also directly connect to brainstem  Enteroendocrine cells also form synapses with vagal afferent neurons  Faster communication than via hormones  Kaelberer 2018

Is there a Gut-Feet Axis?

Summary of Neural/Hormonal Activity  Enteroendocrine cells respond to gut contents, secrete hormones to regulate physiology  Enterochromaffin cells respond to gut contents, activate enteric nervous system  Enteric nervous system also regulates gut activity

Gut Microbiome Effects on the body Regulation of microbiome

Tools (Rodents and Humans)  Germ-free mice  Fecal microbiota transplantation  Antibiotic treatment  Probiotics (bacteria in food)  Prebiotics (food favorable to particular bacteria)  Cutting vagus nerve blocks afferent and efferent neural communication with brain  Genome sequencing to characterize bacteria  Other molecular analytical methods

Microbes in the Gut  Outnumber total human cells 2:1  Composition is reasonably stable but affected by diet  Bacteroidetes  Firmicutes, related to diabetes, obesity  Increased in high fat diet  Produce short-chain fatty acids to supply calories to host  Increases gut permeability and inflammation  Other minor phyla  Some yeast

How do gut microbes affect our physiology?

Proportions change with BMI a: BMI < 18.5 b: BMI 18.5-24.9 c: BMI 25-29.9 d: BMI > 30  Bacteroidetes decrease  Firmicutes increase  Correlation or causation?

Effects of Bacterial Metabolites  Digestion of dietary fiber produces short chain fatty acids (SCFAs) and other metabolites  These can enter the bloodstream and provide energy  SCFAs promote obesity by activating parasympathetic activity via gut hormones  Gut microbes affect tryptophan metabolism

Gut Permeability, or “Leaky” Gut  Bacterial and viral pathogens compromise tight junctions  Intestinal contents pass between cells  Associated with inflammatory diseases  Other factors also affect gut leakiness By BallenaBlanca - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48122216

Psychological Effects of Gut Dysfunction  Stress  Depression  Cognition  Autism  Parkinson’s Disease  We will look at animal and human studies