Everyone in the digestive health sphere writes about leaky gut, myself included. I am guilty myself of fixating on the health and microbiome of the lower abdomen, most people that contact me suffer from either general dysbiosis and SIBO (small intestine bacterial overgrowth). Many people, however, are approaching me with upper gut overgrowth issues. There is less available information on these matters, so I am compelled to write about it more. Different reflux mechanisms are believed to stem from gastrointestinal problems and most of the time when you improve one’s digestive health, reflux alleviates. Acid reflux (GERD), pepsin reflux (LERD), and bile reflux are some of the different proposed causes of reflux. However, there is a fourth cause of reflux, endotoxins, which may contribute to causing all of the other forms of reflux in the first place. Correcting microbiome dysbiosis, especially from Gram-negative overgrowth in the digestive system is what relieves reflux for most people. However, why do some people get reflux symptoms and others have no symptoms whatsoever, even when they are both suffering from digestive issues? I was mistaken in my research; I should have looked directly at the esophagus itself instead of the lower gut to determine why we develop reflux symptoms and what can be done to relieve it. The difference is excessive upper gut inflammation from microbial dysbiosis; the solution is to improve the diversity and health of your microbiome and repair the injured tissue.

So What is the Lesser Known Fourth Type of Reflux?

Like I mentioned in the above paragraph many people know or have suffered from GERD (heartburn). Fewer people have heard of LERD and even less bile reflux. Nevertheless, who has heard of endotoxin reflux?

The average person refluxes stomach chyme (acid, partially digested food, pepsin, organisms) multiple times throughout the day. When we burp, we reflux. When we sneeze, we reflux. When we swallow food, we might reflux. Our esophagus has mechanisms to handle these components and the average person without upper gut issues, has little to no inflammation in the esophagus. However, when you are suffering from upper digestive dysbiosis (Gram-negative dysbiosis mainly) endotoxins that the make up the bacterial cell wall can create inflammation when over-targeted by our immune system triggering symptoms.^{1 2}

How Does Our Esophagus Protect Us From Reflux?

Our esophagus has antireflux defense mechanisms in place to help protect itself from most components of stomach reflux that occurs throughout the day. When we reflux, stomach contents attach themselves to the esophagus. One of our many reflux defense mechanisms is the esophagus’s ability to clear the components mechanically. When we swallow, we swallow a mixture of saliva and salivary bicarbonate to help normalize the pH of the esophagus and inactivate both stomach acid and pepsin. If we reflux into the oral cavity, less saliva and salivary bicarbonate are produced and what is produced is used within our oral cavity to protect the oral mucosa, leading to a poorer esophageal defense. Also, we have cells in our esophageal lining that produce carbonic anhydrase which forms bicarbonate to help further buffer refluxed contents as well. Cells that produce the carbonic anhydrase are found in the basal layer of the esophagus (one of the outermost layers), which is easily damaged by endotoxins and bile reflux. When these cells are damaged less carbonic anhydrase is produced reducing the ability of the esophagus to protect itself from even ordinary daily acidic reflux events leading to symptoms. Finally, the sphincters (upper esophageal and lower esophageal sphincter) themselves are a form of mechanical protection in that when they have proper muscle tone they close properly to prevent contents from leaving the stomach (lower esophageal sphincter) or reaching the larynx and oral cavity (upper esophageal sphincter) and contributing to symptoms.^{3 4 5 6 7 8 9}

Sadly, our esophagus does not have proper mechanisms in place to protect itself from bile or endotoxin reflux as much as it does pepsin and acidic reflux.

So What is Endotoxin Reflux?

Most people are unaware that your stomach has a microbiome. Our stomach is not sterile. Either is our oral cavity or our esophagus. Nowhere in the body is sterile, not even our brain. Our microbiome is composed of both probiotic and opportunistic Gram-negative bacteria. Endotoxins are a significant component of the outer membrane of Gram-negative bacteria and protect the bacteria from other microorganisms and our immune system. Endotoxins increase the negative charge of the bacterial cell membrane and stabilize the structure of the membrane. Since Gram-negative bacteria are everywhere within our body as a part of our microbiome (some places more than others, for example, our digestive tract is where they primarily reside), our immune system and microbiome try their best to prevent them from becoming dysbiotic. Since Gram-negative bacteria are ubiquitous within our microbiome, when they are in proper balance with our microbiome and immune system, their endotoxins can cause a hormetic effect and actually not harm us or may be good for our health (for example, “probiotic” H. pylori strains becoming normal flora in childhood in a healthy microbiome and immune system might protect against asthma). For instance, endotoxins trigger an immune response inside of the digestive tract when overabundant and can lead to symptoms like gastritis and reflux (H. pylori, for example). Endotoxins especially trigger a robust immune response if they leak out of the digestive tract into our bloodstream and have been implicated as a main cause of cerebrovascular and cardiovascular disease. Endotoxins bind to the CD14/TLR4/MD2 receptor complex in many immune cell types, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids leading to increased inflammation. Endotoxins also decrease mitochondrial health by triggering generation of the oxidant superoxide within the mitochondrial electron transport chain from increased biological cellular stress in dealing with an overactive immune system from improper endotoxin exposure. Finally, endotoxins are known pyrogens, meaning they induce fever.

So what is the difference between the microbiome of someone that has reflux and someone who does not? We do have a few clues in trying to determine the difference. It appears in people that have reflux have a reduction in the probiotic mucus maintaining Gram-negative bacteria Akkermansia muciniphila. Akkermansia muciniphila helps preserve the mucosal lining of the esophagus and the stomach, reducing inflammation and symptoms of reflux. Akkermansia muciniphila’s cell wall does contain and shed endotoxins, so an overgrowth of it may cause issues. However, it does appear to be a probiotic Gram-negative bacteria that does not cause the immune system to overreact unless it is dysbiotic ( very high concentration). Gram-negative bacterial dysbiosis of the stomach (H. pylori for example) causes elevated amounts of endotoxins in refluxed material causing inflammation in the esophagus and reflux symptoms. Finally, most people that have reflux symptoms are shown through studies to have an upper gut dysbiosis of the stomach and the esophagus of Gram-negative bacteria. An abundance of Gram-negative bacteria causes an increased production of endotoxins which creates inflammation and immune reactions that irritate and degraded the esophagus mucosa and damage the lining.^{10 11 12 13 14 15 16}

The tissue structure of the esophagus also changes in people with reflux symptoms. The mucosa as mentioned earlier thins from microbiome changes (reduction of Akkermansia muciniphila for example) and epithelial cells in the esophagus become damaged. The tight cellular junctions in the esophagus open up allowing acid and pepsin to degrade the integrity of the esophagus further, creating more inflammation. Endotoxins have been shown in studies to open up tight cellular junctions in the digestion tract from improper immune reactions and inflammation. The front layer of the esophagus epithelial cells can protect itself from acid and pepsin, but the back layer of cells have no defense mechanisms and are vulnerable to reflux. The esophageal cells become weakened to the refluxed material over time causing inflammation and the typical symptoms of reflux (throat burning, sore throat, dysphagia, and chest pain). The lower esophageal sphincter can also become weakened by excessive immune responses and inflammation from repeated exposure to endotoxins from Gram-negative dysbiosis. Excessive gas production from the dysbiosis forces the stomach contents upward further weakening the lower esophageal sphincter increasing the number of esophagus reflux occurrences. Excessive endotoxin exposure in the upper gut clinically manifests itself as gastritis, reflux symptoms, esophageal erosion, ulcers, and eventually Barrett’s esophagus. Finally, excessive inflammation caused from an overactive immune response by Gram-negative bacterial endotoxins being in the esophagus further contributes to the reflux pathology.^{17 18 19 20 21}

Conventional treatments for reflux like the use of proton pump inhibitors may help the symptoms for a short period of time because the stomach chyme refluxed from the medication will be a higher pH (two to five) which will not cause as much inflammation. That being said, a low stomach pH is proper for the healthy and the microbiome of our upper gut, dysbiosis will increase when the pH is lowered over time and for most people their reflux symptoms eventually return. Antibiotics may help if you do not want to use a natural herbal protocol to tackle your upper gut dysbiosis, but it depends on the strain of the upper gut bacteria that is causing the dysbiosis. Proton pump inhibitors also possibly have a mild antimicrobial effect at first when combined with antibiotics by increasing the stomach pH further and allowing more of the dysbiotic flora to come out from biofilm or the mucosa. Finally, though antibiotics may be needed to reduce dysbiotic flora when used correctly, it will also further reduce the microbiome diversity of your upper gut possibly causing further issues. Probiotic upper gut bacterial colonies that antibiotics would harm include Lactobacillus and Akkermansia.²²

So what can be done to improve the microbiome of the upper gut naturally? Well, currently there is no Akkermansia muciniphila probiotic on the market. However, we do know what the bacteria like to ingest to increase its colony forming units. Akkermansia muciniphila enjoys polyphenol-rich fruits including cranberries and pomegranate. These fruits and their juices might be too harsh on an injured esophagus because of their low pH, but polyphenol extracts of these fruits in capsule form are beneficial as well. Akkermansia muciniphila also enjoys omega 3 fatty acids, which a diet that contains sufficient servings (three to four times weekly) of wild seafood might both increase the population of the bacteria and decrease inflammation as well. Proper sunlight exposure might increase endogenous vitamin D production, improve the cellular integrity of the esophagus, increase microbial diversity in the esophagus, reduce inflammation, and calm an overactive immune system. If you are suffering from low stomach acid production (hypochlorhydria) or elevated stomach pH, supplementing with betaine HCL for a short period of time may improve your symptoms since many Gram-negative opportunistic bacteria (like H. pylori) cannot survive in the proper low pH environment of a healthy stomach. Supplements like DGL, slippery elm, zinc carnosine, and D-limonene might help protect the upper gut tissue and reduce reflux symptoms. Finally, relieving upper gut dysbiosis might be vital in conquering endotoxin reflux and stopping reflux symptoms for good!²³

Conclusion

Why people have symptoms of reflux is very complicated since there are many different causes. The main issue that needs to be resolved for most people is to fix their upper gut dysbiosis and reduce inflammation so that over time their sphincters and tissue may heal. Immune reactions to excessive endotoxins (from having dysbiosis) can trigger unnecessary inflammation leading to major health problems like cardiovascular and cerebrovascular disease. For everything there is a balance and even though Gram-negative bacteria are essential for our health. Having an imbalance of opportunistic bacteria of any type or strain can cause significant health issues ranging from reflux, to Crohn’s disease, to even rheumatoid arthritis. Hopefully, “leaky esophagus” and the esophageal microbiome will continue to be studied so we can learn more about the mechanisms behind reflux symptoms and how to deal with them so that conditions like GERD, LERD, endotoxin reflux, and bile reflux can be conditions of the past.