When I was a third-year naturopathic medical student in 1973, one of my professors, Bob Carroll, DC, ND, opened the first class of the year with the 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.
Scientific evidence continues to suggest that the metabolic activities in the gut microbiome are intertwined with human health and disease.
During the first year of practice, I subscribed to several journals to read during those slow times while building my patient base. 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 (which was very conservative and dismissive of nutritional supplements at the time), and a half dozen others. To my great surprise, I read a startling and controversial study reporting that in healthy animals, up to 1 percent of ingested proteins are absorbed intact, and absorption increases to as much as 10 percent during severe gastrointestinal infection. My immediate thought was that Dr. Carroll might be right!
I have since followed with considerable interest our growing understanding of the gut’s role in health and disease. Integrative medicine clinicians are aware of how maldigestion, malabsorption, leaky gut, small bowel overgrowth of bacteria, inappropriate bacteria in the gut, and other factors that contribute to and may even cause disease.
Most patients appear to have the wrong bacteria in their gut and their gut permeability control has been lost. This results in unhealthy metabolites, or 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 an overgrowth of harmful bacteria, especially Gram-negative (pathogenic) bacteria, the absorbed lipopolysaccharides (LPS) are highly toxic. Perceptible blood levels of these substances correlate with many chronic diseases.
Aggravating these problems are many food constituents that, when improperly digested or not detoxified by the liver, cause diverse metabolic abnormalities—diamines in migraine being a typical example.
According to Merriam-Webster, endotoxin is defined as “a toxin that is present inside a bacterial cell and is released when the cell disintegrates.” 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 products. These LPS represent 80 percent 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 percent of the small molecules in human blood can be derived from gut bacteria. 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 called metabolic endotoxemia is reached. Once metabolic endotoxemia is achieved, several strong, dose-dependent disease associations become apparent, including cardiovascular disease, chronic inflammation, type 2 diabetes, dyslipidemia, insulin resistance, nonalcoholic fatty liver disease, obesity, and stroke.
Interestingly, high levels of endotoxins also cause epigenetic changes like those seen in obesity, suggesting another mechanism for the association between various gut flora and the risk for obesity.
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 breastfeeding. 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.
Loss of Gut Permeability Control
Even when the unhealthy gut flora is releasing LPS and toxic metabolites, the properly functioning gastric mucosa is normally effective at discrimination and protection. Unfortunately, many factors have resulted in a loss of control over gut permeability. 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. In the US population, 79.4 percent are homo- or heterozygous for Hp 2, the precursor of zonulin.
Many other factors cause loss of gut permeability control, including both type 1 and 2 diabetes, excessive alcohol consumption, and nonsteroidal anti-inflammatory drugs (NSAIDs)—the list is long. The latter is particularly important.
There is also emerging research showing that those with some genetic variations have an increased risk of excessive gut permeability. For example, patients with inflammatory bowel disease with a mutation in the NOD2i gene are found to have a 75 percent increased risk of excessive gut permeability. In apparently healthy first-degree relatives, the risk of leaky gut is a significant 40 percent.
Not only does excessive gut permeability increase the absorption of endotoxins, but so does a high-fat diet. This may be part of the reason for the upregulation of inflammation after even a single high-fat meal. The bottom line is, 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.
After spending approximately 100 hours studying 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 evidence I find, suggesting we are only seeing the tip of the iceberg. Once again, the old-timers were right. I continue to be amazed by their remarkable clinical acumen. While often the explanation was not validated, their observations and interventions were spot-on.
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