THE PATH AHEAD
Toxins From the Gut
Joseph Pizzorno, ND, Editor in Chief
W
hen I was a third-year naturopathic medical
student in 1973, one of my professors (Bob
Carroll, DC, ND) started the first class of the year
with the provocative statement, “Death begins in the
colon!” I was skeptical. Having just finished basic sciences,
the textbooks were very clear that the gut was a perfect
protective membrane only allowing in nutrients the body
needed. He then went on to lecture about how patients with
digestive problems were more “toxic” and that by restoring
proper digestive function and healthy flora, many
experienced improved health. While I could see during
clinic rotations that improving digestion and recommending
eating natural yogurt helped patients with diverse diseases,
I remained skeptical until I graduated in 1975.
During the first year of practice, I subscribed to several
journals to read during those slow times building patient
flow. I was quite diverse in my reading, ranging from the
Lancet (which, though conventional medicine, had a
surprising number of articles on nutrition and environmental
medicine), the American Journal of Clinical Nutrition (back
then, very conservative and dismissive of nutritional
supplements), and a half dozen others. To my great surprise,
I read a startling and controversial study reporting that in
healthy animals, up to 1% of ingested proteins are absorbed
intact and absorption increases to as much as 10% during
severe gastrointestinal infection. My immediate thought
was that “old” doctor Carroll might be right!
I have since followed with considerable interest our
growing understanding of the role of the gut in health and
disease. Integrative medicine clinicians are now well aware
of how maldigestion, malabsorption, leaky gut, small
bowel overgrowth of bacteria, inappropriate bacteria in
the gut, and others contribute to and may even cause
disease. When Michael Friedman, ND, asked me what
topic I would like to present at the October 2014 Restorative
Medicine in Santa Fe, New Mexico, I suggested I could
dive into the research to see if this old idea about toxins
from the gut was clinically relevant. Happily, he
enthusiastically agreed. Following is what I found—and I
think only the tip of the iceberg.
Gut Dysfunction
When thinking about toxins from the gut, many gut
dysfunctions, as shown in Table 1, would appear to
contribute to the problem.
8 Integrative Medicine • Vol. 13, No. 6 • December 2014
Table 1. Gut Dysfunctions That Contribute to/Cause
Gut Toxins
• Maldigestion
• Loss of Permeability Control
• Food Constituents
o Improper digestion/metabolism of food
constituents
o Food additives
• Bacterial Problems
o Wrong bacteria
o Bacteria in the wrong place
o Endotoxins from “normal” bacteria
• Loss of liver cleaning of undesirable constituents
from the portal vein
• Gut inflammation
Maldigestion, loss of liver detoxification function, and gut
inflammation are all important topics, and for space
considerations, they are topics for future editorials.
Basically, what appears to be happening is that most
patients have the wrong bacteria in their gut and/or gut
permeability control has been lost. This results in
unhealthy metabolites (“toxins”) from gut bacteria
entering into circulation. In fact, research has shown that
up to one-third of the small molecules in the blood come
from bacteria in the gut. Worse, however, is when a patient
has overgrowth of particularly unhealthy bacteria,
especially Gram-negative, the absorbed lipo-
polysaccharides (LPS) are highly toxic with blood levels
correlating with many chronic diseases.
Aggravating these problems are many food
constituents that, when improperly digested and absorbed
and/or not detoxified by the liver, cause diverse metabolic
abnormalities—diamines in migraine being a typical
example. Unfortunately, space limitations require moving
this fascinating topic to another editorial as well.
Endotoxins
According to Wikipedia, endotoxin is defined as “any
toxin secreted by a microorganism and released into the
surrounding environment only when it dies.” Technically
in the research literature, only bacterial LPS are considered
“endotoxins.” LPS are the most studied and considered
prototypic activators of innate immunity by gut bacterial
Pizzorno—The Path Ahead
 Figure 1. Metabolic Effects of Endotoxins2

Interleukin-1 and Tumor necrosis factor

interleukin-2
Histamine
Activation of coagulation
system
Myocardial
depressant
factor
Prostaglandin,
thromboxane,
Anaphylatoxins C5a and Endotoxin leukotriene, and
C3a
prostacyclin release

Platelet-activating factor Beta-endorphins

Oxygen-derived free
radicals Bradykinin

products. These LPS represent 80% of the cell-wall mass of
Gram-negative gut bacteria.
Here we use the more clinically relevant broader
definition of endotoxin as “any metabolite or cell wall
constituent released by gut bacteria that damages human
physiology,” because a surprising 25% to 33% of the small
molecules in human blood can be derived from gut
bacteria.1 As can be seen in Figure 1, the effects of LPS and
the many other endotoxins from gut bacteria cause
substantive and diverse physiological dysfunctions.
When endotoxins reach a high enough level in the
blood, a threshold is reached called metabolic endotoxemia.
Once this threshold is reached, several strong, dose-
dependent disease associations become apparent, a few of
which are shown in Table 2.
Table 2. Diseases Associated With Metabolic
Endotoxemia3,4,5,6
Cardiovascular disease
Chronic inflammation
Diabetes (type 2)
Dyslipidemia
Insulin resistance
Nonalcoholic fatty liver disease
Obesity
Stroke
There are many reasons for the increased levels of
endotoxins seen in modern civilizations. Obvious causes are
the overuse of antibiotics, increased incidence of Cesarean
births, and lack of breast-feeding. Less obvious, perhaps, is
stomach acid secretion suppression by proton-pump
inhibitors and H2 blockers. The research is very clear that
the use of these agents results in increased colonization of
the gut by Clostridium difficile, thus substantially increasing
the release and absorption of LPS.8
Loss of Gut Permeability Control
Even when the gut flora is unhealthy, releasing LPS
and toxic metabolites, the properly functioning gastric
mucosa is normally effective at discrimination and
protection. Unfortunately, many factors have resulted in
loss of control over gut permeability. Readers will recall
my August, 2013 IMCJ editorial, “Zonulin! The Wheat
Conundrum Solved (Well, Mostly …).”9 Basically,
according to haptoglobin (Hp) type, eating foods with
gluten grains (wheat, rye, and barley) results in the
release of zonulin, which opens up the tight junctions
allowing free entry of gut constituents. As can be seen
from Table 3, 79.4% of the US population is homo- or
heterozygous for Hp 2, the precursor of zonulin.
Table 3. Incidence of Haptoglobin Type in US
Population

Hp Phenotype % in Healthy US Population

Interestingly, high levels of endotoxins also cause Hp 1-1 20.6%
epigenetic changes similar to those seen in obesity, Hp 1-2 43.5%
suggesting another mechanism for the known association Hp 2-2 35.9%
between various gut flora and risk for obesity.7

Pizzorno—The Path Ahead Integrative Medicine • Vol. 13, No. 6 • December 2014 9
 Table 4. Occurrence of Adverse Effects of NSAIDs in
the Lower Gastrointestinal Tract12
Adverse Effect Frequency (%)
Increased gut permeability 44-70
Gut inflammation 60-70
Blood loss and anemia 30
Malabsorption 40-70
Mucosal ulceration 30-40
Many other factors cause loss of gut permeability
control, including both type 1 and 2 diabetes, excessive
alcohol consumption, nonsteroidal anti-inflammatory
drugs (NSAIDs)—the list is long.10,11 The later is
particularly important, as can be seen in Table 4.
There is also emerging research showing that those
with some genetic variations have increased risk of
excessive gut permeability. For example, patients with
inflammatory bowel disease with mutation in NOD2i are
found to have a 75% increased risk of excessive gut
permeability. In apparently healthy first-degree relatives,
the risk of leaky gut is a significant 40%.13
Not only does excessive gut permeability increase
absorption of endotoxins, so does a high-fat diet. This may
be part of the reason for upregulation of inflammation
after even a single high-fat meal.14
Bottom line, loss of gut permeability control is
surprisingly common in our modern age, emphasizing the
critical importance of optimal gut flora for health as well
as optimizing digestion and healing the gut mucosa.
Conclusion
After spending approximately 100 hours looking at the
research, I am convinced the idea of toxins from the gut has
substantial clinical relevance. In fact, the more I look at the
research, the more I find, suggesting we are only seeing the
tip of the iceberg. Once again, the old timers were right.
When speaking to new naturopathic students, I
typically start with the admonition, “Read the old timers!”
They had remarkable clinical insights. But I warn them to
realize that their explanation of what they were seeing was
probably wrong, as their understanding was impaired by
the very limited physiological research of the time. My
other caution is to realize that once a clinician developed
an insight that helped a lot of patients, he/she would then
go on to inappropriately assert that his/her theory was the
cure for all disease. Sadly, as we all know, there is no such
thing as one cure for all disease. I have now had the
opportunity to delve deeply into the current science that
evaluates many of these old concepts. I continue to be
amazed by their remarkable clinical acumen. While often
the explanation was not validated, their observations and
interventions were right on.
10 Integrative Medicine • Vol. 13, No. 6 • December 2014
One more thought, please: For the past 14 years I have
written more than 70 editorials, many on the foundational
concepts of natural/integrative/functional medicine. The
more research I study (and the more patients I treat), the
more clearly I am seeing that all of the fundamentals of
health are now so undermined that only treating disease is
no longer a viable strategy. In fact, I would assert that the
foundations of health must first be reestablished before we
can know if a patient’s apparent disease is real or simply
the body’s best adaptation to their distorted environment.
In This Issue
As John Weeks so eloquently states, the partnership
between the Institute for Functional Medicine and the
Cleveland Clinic could indeed be a tipping point. This is
a remarkable opportunity to demonstrate in a bastion of
conventional medicine that fundamentally changing the
way we think about patients is the only real solution to
the health care crisis. The leadership of Senator Tom
Harkin (D-IA) was pivotal for advancing integrative
medicine at the federal level. His retirement, while much
deserved, is cause for concern. At the events organized
by the integrative medicine community to honor Senator
Harkin, I interviewed the many integrative medicine
leaders in attendance and recorded the evening ceremony.
These will be the basis of my next editorial.
Providing further substance for my editorial,
Matthew J. Bull, BSc, PhD, and Nigel T. Plummer, PhD,
provide us a 2-part series (Part 2 forthcoming) on the
human gut microbiome. The first sentence of their
abstract says it all: “The bacterial cells harbored within
the human gastrointestinal tract (GIT) outnumber the
host’s cells by a factor of 10 and the genes encoded by the
bacteria resident within the GIT outnumber their host’s
genes by more than 100 times.”
One of the problems with the US Department of
Agriculture’s GRAS List (Generally Recognized as Safe)
is that food manufacturers appear to have used this as
justification/cover for indiscriminately adding large
amounts of various chemicals to the food we eat. This
has in some cases resulted in unexpected and significant
physiological dysfunction. Associate Editor Lara Pizzorno,
MDiv, MA, LMT, provides us an in-depth look at how our
modern, processed food diet has resulted in excessive
intake of phosphorous causing distorted metabolism and
increased risk for several diseases.
Managing Editor Craig Gustafson provides us an
intriguing interview of one of my heroes, Bruce Ames,
PhD, and his colleague Rhonda Patrick, PhD. They discuss
Ames’s triage concept, an extremely important
understanding of how the body prioritizes nutrient
utilization. The first time I heard him lecture on this
i. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2),
also known as caspase recruitment domain-containing protein 15 (CARD15)
or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans
is encoded by the NOD2 gene located on chromosome 16 (Wikipedia).
Pizzorno—The Path Ahead
concept, I was struck by how well it explained disparate
research findings.
I suggest you empty your bladder before reading
BackTalk by associate editor Bill Benda, MD.
Joseph Pizzorno, ND, Editor in Chief
drpizzorno@innovisionhm.com
http://twitter.com/drpizzorno
References
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effects of gut microflora on mammalian blood metabolites.  Proc Natl Acad
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2. The Free Dictionary by Farlex. Endotoxin. http://medical-dictionary.
thefreedictionary.com/endotoxin. Accessed October 31, 2014.
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