The Gut-Brain Connection: An Inside Look at Depression

Todd R. LePine, MD
May, 2009

“What a strange machine
man is! You fill him with
bread, wine, fish, and
radishes, and out comes
sighs, laughter, and dreams.”
Nikos Kazantzakis

Psycho-Neuro-Immuno-Endo-Gut-Ologist

The Gut
The Inner Tube of Life

―Consider the lowly gut and its nervous
system. The bowel just is not the kind
of organ that makes the pulse race. No
poet would ever write an ode to the
intestine. To be frank, the popular
consensus is the colon is a repulsive
piece of anatomy. Its shape is
nauseating, its contents disgusting and
it smells bad. The bowel is a
primitive, slimy, snakelike thing. Its
body lies coiled within the belly and it
slithers when it moves. In brief, the gut
is despicable and reptilian, not unlike
the brain, from which wise thoughts
emerge. Clearly, the gut is an organ
only a scientist would love.‖

The enteric nervous system
functions as a Brain in the Gut

The Enteric Nervous System NEJM April 25, 1996

―The intestine is an extremely complex living
system that participates in the protection of the
host through a strong defense against
aggressions from the external environment.
This defensive task is based on 3 constituents
that are in permanent contact and dialog with
each other: the microflora, mucosal barrier, and
local immune system.‖

Think Differently

Photo by Migraine Chick

How do we see illness?

How do we see ourselves?
Photos by zedzap and SuperFantastic

The Intestines and the Gut Microflora

Microflora- Varies from person to person
• > 100,000 billion bacteria (~2 lbs)
• > 500 different species
• 99 % of the bacteria come from 30-40 species
• Intense metabolic activity, especially in the colon
• Equilibrium (qualitative and quantitative)
is Critically Important
• ―Quorum sensing‖ i.e. communication between
the bacteria

So…Who‘s really in charge?

http://www.microbeworld.org/

―The ―we‖ refers to the wild profusion of
bacteria, fungi and viruses that colonize the
human body. These unseen passengers
number in the trillions. According to one
common estimate, the human gut contains
at least a kilogram of bacteria alone. They
contribute so much to human biology that it
is difficult to say where the body ends and
the microbes begin.‖

Nature 449, 811-818 (18 October 2007) | doi:10.1038/nature06245; Published online 17 October 2007

―Most of the cells in your body are not your
own, nor are they even human…They are
bacterial. From the invisible strands of fungi
waiting to sprout between our toes, to the
kilogram of bacterial matter in our guts, we
are best viewed as walking "super-organisms”
highly complex conglomerations of human
cells, bacteria, fungi and viruses.‖

Photo: http://commons.wikimedia.org/wiki/File:Bobtail_squid.jpg

―Through Bassler's discoveries, we're
learning that those on the lowest rungs of the
Darwinian ladder share one of the traits that
has, until recently, been thought of as
distinctly human: the propensity to create a
continuous stream of commentary about the
world. As Bassler puts it, for microbial
communities, the advent of the cell-to-cell
network made "the difference between
subsistence farming and living in Manhattan.”

Quorum sensing—a bacterial
discussion about light. The
bacterium V. fischeri emits a
chemical signal, known as an acyl
HSL, to announce its presence to
others. In the open sea this signal
rapidly dissipates (A). Within the
confines of the squid light
organ, however, the concentration
of acyl HSL increases as the
number of bacteria increases (B).
When the concentration reaches a
threshold level, the signal triggers
the expression of genes encoding
the proteins responsible for the
light-generating chemical reaction
(C).

Quorum Sensing in Bacteria

• Bacteria Talk to Each Other
• Bacteria are Multi-Cellular
• Bacteria can distinguish self from others
• The role of Quorum Sensing in ―Dysbiosis?‖

―Given that eukaryotic
cell-to-cell signaling
typically occurs through
hormones, and that
bacterial cell-to-cell
signaling occurs through
QS, we speculate that
QS might be a ‗‗language‘‘
by which bacteria and host
cells communicate.‖

―More than just an accumulation of
bacteria, biofilms are complex structures
in which the bacteria are likely to use a
substantially different set of genes than
in their free-floating form‖
T.J. Silhavy from ScienceDaily

―The membrane is the physical structure that
interfaces internal ―self‖ and external ―not-self.‖ It is
an interface that dynamically reads and interprets
environmental cues and responds by generating
signals that enable the cell to function and survive.‖
Bruce Lipton, PhD

Increased epithelial permeability may be
important in the development of chronic gut
T cell–mediated inflammation….
Pro-inflammatory cytokines then further
increase epithelial permeability, setting up a
vicious cycle of chronic inflammation
SCIENCE 2005

Am J Physiol Gastrointest Liver Physiol
280: G7–G13, 2001.

Therefore, vitamin D deficiency may
compromise the mucosal
barrier, leading to increased
susceptibility to mucosal damage and
increased risk of Inflammatory Bowel
Disease

―these findings provide evidence that
astroglial-like cells in both brain and gut
contribute interchangeably to barrier
functions, suggesting a previously
unrecognized paradigm whereby cellular
interactions previously thought to be unique
to the blood–brain barrier, also regulate gut
epithelial permeability.‖

The cytokine network. Image of the global network of cytokine interactions between the 14 immune cells (red nodes) and the 15 non-immune
body cells (blue nodes). The black edges represent mutual connections; the grey edges represent one-way connections.
Frankenstein et al. Biology Direct 2006 1:32 doi:10.1186/1745-6150-1-32

During an immune response
the brain and the immune
system ―talk to each other‖
and this process is essential
for maintaining homeostasis.
Two major pathway systems
are involved in this cross-talk:
the hypothalamic pituitary-
adrenal (HPA) axis and the
sympathetic nervous system
(SNS).
Elenkov IJ, Wilder RL, Chrousos GP, Vizi
ES., Pharmacol Rev. 2000 Dec;52(4):595-638.

The results show that intestinal mucosal
dysfunction characterized by an increased
translocation of gram-negative bacteria
(leaky gut) plays a role in the inflammatory
pathophysiology of depression. It is suggested
that the increased LPS translocation may
mount an immune response and thus IRS
activation in some patients with MDD and may
induce specific ―sickness behaviour‖
symptoms.

Inflammatory and
oxidative and nitrosative
stress pathways
underpinning chronic
fatigue, somatization and
psychosomatic symptoms
Michael Maes
Current Opinion in Psychiatry
2008, 21:1–9

―Induction of indoleamine
2,3-dioxygenase, which
converts tryptophan into
kynurenine, may play a role
in the pathophysiology of
depression through its
induction of neurotoxic
kynurenine metabolites.
Therefore, we proposed a
shift in the serotonergic
hypothesis of depression
from tryptophan depletion
to neurotoxicity‖
(Maes et al. 1994-2006)

Lord RS, Bralley JA, eds. Laboratory Evaluations for Integrative and Functional Medicine. Duluth, GA: Metametrix Institute; 2008.

59 yo female with Scleroderma, silicon breast
implants, recurrent herpes to sacral
area, depression and insomnia secondary to pain

Nicholson focuses on these chemicals
both because little is known about them
and because they appear to be highly
relevant: recent research suggests that
gut microbes play a crucial role in human
health and disease. They help us absorb
nutrients and fight off viruses and ―bad‖
bacteria; disrupting intestinal
colonies, such as with a course of
antibiotics, often leads to digestive
sickness. In fact, Nicholson says, “almost
every sort of disease has a gut bug
connection somewhere.”

THE PROLIFERATION OF HUMAN MICROBIOME PROJECTS

MetaHIT (EU & China)

Canadian
$31 million
Human MetaGenome
Microbiome Initiative Consortium (Japan)
$10 million MicroObes (France)
$5 million
$3 million

Meta-GUT China)
Human Microbiome
Project (USA) $1.5 million

$115 million Human Gastric
Microbiome (Singapore) Austrailian Urogenital
Microbiome Consortium
$750,000
All figures are estimates of cost in US dollars $600,000
Photo by Kathryn

THE PROLIFERATION OF HUMAN MICROBIOME PROJECTS
The NIH‘s five-year Human Microbiome
Project will spend much of its money
identifying which bacteria are lodged where in
the body and compiling a reference set of
MetaHIT (EU & China)

their genetic sequences. Metagenomics of
Canadian
$31 million
Human MetaGenome
the Human Intestinal
Microbiome Initiative Tract (MetaHIT), will Consortium (Japan)
focus on microbial inhabitants (France) gut, the
$10 million MicroObes
of the $5 million
$3 million
main repository of the microbiota, and how
they contribute to obesity and inflammatory
Meta-GUT China)
bowel disease.
Human Microbiome
$1.5 million
Project (USA)
NATURE|Vol 453|29 May 2008
$115 million Human Gastric
Microbiome (Singapore) Austrailian Urogenital
Microbiome Consortium
$750,000
All figures are estimates of cost in US dollars $600,000
Photo by Kathryn

―The bacterial flora of the gut may also
have an important role; encephalopathy
develops in patients with cirrhosis after
meals rich in protein when the gut flora
produces amino compounds, which are
absorbed from the gut and, bypassing the
liver, act as false transmitters in the brain.
Specific food residues are broken down
by the colonic microflora with the
production of chemicals, which, in
susceptible individuals with low
concentrations of relevant hepatic
enzymes, pass into the systemic
circulation to produce distant symptoms.‖
Hunter, JO Lancet.
338:495-496 (1991)

The human gut might
best be described as a
“continuous-flow
microbial growth
chamber”

Dietary Precursors for
Bacterial Products in Urine


―And you can geographically map people
according to their metabolic patterns,‖
The patterns do not seem to follow
genetics, Nicholson said. ―It has to do
with their diet and lifestyle and also
gut microorganisms,‖ Nicholson said.

―In terms of relaxing blood
vessels, it looks like hydrogen
sulfide might be as important
as nitric oxide,‖ Snyder
says, referring to the first
gasotransmitter that two
decades ago was discovered
to regulate blood pressure.

Functional GI Tests
• Traditional Digestive Stool Analysis
• Intestinal permeability testing
• Hydrogen breath test for bacterial
overgrowth
• Food Antibody Testing
• Urinary Organic acids for dysbiosis
• GI Effects test using PCR technology

Characteristics of IgE and IgG-
Mediated Reactions to Food


Elevated IgG1 & 4 Food Antibodies
Functional Measure of Leaky Gut
Milk Protein

Antigen — IgG1 & 4
Complex

Insoluble Large Complex

If you don’t look inside…
How do you know what is really going on?

There‘s Gold hidden in there!!

What Patient Populations Benefit
from GIfx Stool Analysis?
• Inflammatory bowel issues
• Skin conditions
• Fatigue of unknown origin
• Depression
• Autoimmune Disorders
• Change in bowel habits
• Refractory Obesity

To the researchers'
surprise, after 2
months, the newly infected
mice were 42% fatter, even
though they had eaten
29% less than the bacteria-
free mice. And fast
metabolism wasn't the
answer, as the metabolism
of the bacteria-free mice
was 27% slower than that
of their microbe-carrying
counterparts.

Metametrix Tests to look inside for
contributing factors in depression
• IgG 4 Food Allergy • RBC Essential Fatty Acids
Profile • Comprehensive
• Amino Acid Profile Organix Profile:
• TRIAD Profile • Neurotransmitter
• GI Effects Test metabolites, Methylation
markers, functional B-vitamin
markers, dysbiosis markers

The road to health is paved with good intestines…

The Gut-Brain Connection: An Inside Look at Depression

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