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
Tony Jelsma, Ph.D. Professor of Biology Dordt College
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
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
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/
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
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)
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
No villi, just crypts Primarily absorptive cells and mucous cells Recovery of water and electrolytes Many bacteria (1012/g) in colon How are we protected from its contents? How do they benefit us?
http://www.histology-world.com/factsheets/largeintestine.htm
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
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?
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
Digestion and absorption of nutrients Production of hormones to regulate digestion and
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
Carries out conscious brain functions: Receives conscious sensory information Interprets sensory information Decides on response Sends out response signals
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, …
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
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/
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
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
500 million neurons, from esophagus to anus Afferent and efferent Many neurotransmitters, 90% of serotonin, 50%
Receives sympathetic and parasympathetic inputs Parasympathetic (vagus nerve) stimulates digestion Motility Secretion Sympathetic inhibits digestion
https://www.nature.com/articles/nrgastro.2016.107.pdf
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
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 form synapses with vagal afferent neurons Faster communication than via hormones Kaelberer 2018
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
Effects on the body Regulation of microbiome
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
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
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?
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
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
Stress Depression Cognition Autism Parkinson’s Disease We will look at animal and human studies
Tryptophan is an amino acid Dietary uptake is for proteins and a variety of metabolites 1-2% is converted to serotonin and melatonin Germ-free male mice have higher levels of serotonin in the hippocampus, along with an increased stress response (Clarke 2013) The opposite effect was seen in the colon (Yano 2015)
Chronic treatment with a Lactobacillus strain (Bravo et al., 2011). Reduced corticosterone and anxiety- and depression-related behavior i.e. involved the HPA axis Altered GABA receptor levels consistent with antidepressant effects Effects required the vagus nerve Effects were strain-dependent
Corticotropin-releasing factor (CRH) from hypothalamus activates ACTH release from pituitary in response to stress But – CRH also increases intestinal permeability and activates inflammation (Overman et al., 2012, pig study)
Acute stress (public speaking) increased CRH and intestinal permeability (Vanuytsel et al., 2014) Cold pain stress increases intestinal permeability (in women only, Alonso et al., 2012) Maternal prenatal stress altered the gut microbiome of infants and resulted in more GI symptoms (Zijlmans et al., 2015)
Diet-induced obesity in mice induces stress and anxiety This is associated with decreased insulin signaling and increased inflammation in brain Effects are dependent on gut microbiota, can be transferred to germ-free mice (Soto 2018) This suggests that the gut microbiome can contribute to
Increased co-morbidity of psychiatric disorders and irritable bowel syndrome (Singh et al., 2012) Marital distress and depression work in tandem to increase gut permeability and inflammation (Kiecolt- Glaser, 2018)
Long-term administration of a Lactobacillus strain reduced cognitive decline in a senescence- accelerated mouse model (Corpuz, 2018) Behavioral effects Gene expression changes in hippocampus and cortex
Western diet impairs hippocampal-dependent learning and memory (Noble 2017) Altered gut permeability Altered blood-brain barrier integrity
Autism is frequently associated with GI disturbances Some genetic variants are associated with both ASD and gut development/function Could a leaky gut cause or exacerbate ASD features?
Inject a viral mimetic around E12, induces inflammation Autism features: vocalizations, sociability, repetitive/stereotyped behavior Susceptibility regulated by gut microbiota of the mother Caused by segmental filamentous bacteria Reside in ileum, not colon Mediated by inflammatory signal IL-17a Could be neutralized Thus, prenatal inflammation may be associated with the development of autism (Hsiao 2013)
Ivanov et al., 2009 Cell 139:485
Probiotic treatment (Bacteroides fragilis) reverses the process
Hsiao et al., 2013, Cell 155:1451
Autism and prenatal conditions: Premature birth is associated with higher rates of autism In utero inflammation is a contributing factor Gut-blood-brain barrier is compromised Brain inflammation contributes to autism (Angelidou 2012)
Excessive production of bacterial metabolites (SCFAs) may be linked to autism (MacFabe 2012) Injection of SCFAs into rat ventricles induces autism-like behaviors and neurochemical changes Some humans are partial metabolizers of SCFAs, resulting in accumulation
Mulak and Bonaz, 2015 GI dysfunction in 80% of PD patients, including constipation, nausea, defecatory dysfunction Alpha-synucleinopathy affects all levels of the brain-gut axis Triggers inflammation in the colon, increases gut permeability Bacterial overgrowth in small intestine is common (>50%)
Used for rapid weight loss Extra fat breakdown leads to ketone body accumulation Also used to control refractory epilepsy Gut microbiota are necessary and sufficient for these effects in a mouse model (Olson et al., 2018) Ketogenic diet increases proportion of certain bacteria These bacteria mediate the effects of KD
“Good” and “bad” microbes in colon, affected by diet Good microbes provide beneficial metabolites Inflammation allows harmful substances to enter the blood, crosses blood-brain barrier Enteric nervous system effects
Vagus nerve
Too many microbes in small intestine can be harmful
Diet, probiotics Gut microbiome composition Gut permeability Inflammation Stress, HPA axis, cortisol Vagus nerve
Research is in its early stages Much research has been done in rodents, not humans Human studies are much more complex, effects may be more subtle Need to tease out generalized benefits vs. effects on specific deficits How important is a “normal” diet? Many different types of bacteria, hard to generalize Understanding mechanisms is difficult Be careful of publication bias
Microbiome regeneration after antibiotic use is delayed by probiotics in humans (Suez 2018)
Autologous fecal transplants may be more effective Gut microbiomes are individualized, one-size-fits-all probiotics may not be effective
Microbes in stool samples may not accurately reflect those acting on the gut (Zmora 2018) Mucus layer has a distinct microbiome Probiotics do not colonize this mucus layer very well
We are individuals and have individual gut microbiomes We don’t know the right microbes to use for a particular situation We don’t understand how the various microbes work What dosages and frequencies are effective and not harmful? More work needs to be done
Any questions?