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 (1012/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

Sympathetic inhibits digestion

https://www.nature.com/articles/nrgastro.2016.107.pdf

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 MicrobiomeEffects 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

Tryptophan metabolism

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)

Gut Microbiome and Stress

Gut Microbiome and Stress in Mice

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

Gut Microbiome and Stress

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)

Gut Microbiome and Stress in Humans

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)

Gut Microbiome and

Depression

Effects of Gut Microbiome on

Depression - Mouse

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

obesity

Effects of Gut Microbiome on

Depression - Human

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)

Gut Microbiome and Cognition

Cognition – Mice

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

Cognition - Human

Western diet impairs hippocampal-dependent learning

and memory (Noble 2017)

Altered gut permeability

Altered blood-brain barrier integrity

Autism and the Gut

Autism and the Gut

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?

Mouse model of inducible autism

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

Mouse model of inducible autism

Probiotic treatment

(Bacteroides fragilis) reverses

the process

Hsiao et al., 2013, Cell 155:1451

Autism and the Gut – Human

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)

Autism and the Gut - Human

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

Parkinson’s Disease and the Gut

Parkinson’s Disease

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%)

Now for something different…

Ketogenic diet (KD, low carbs)

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

Summary of Effects of Gut Microbes

“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

Summary

There is an Interplay of Multiple Factors

Diet, probiotics

Gut microbiome composition

Gut permeability

Inflammation

Stress, HPA axis, cortisol

Vagus nerve

Caveats to all of this

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

Two Recent Studies Urge Caution

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

Are Probiotics Ready for Treatments?

Not yet

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

Thank you for your attentionAny questions?