Is dysbiosis of the upper-GI tract to blame for esophageal gastroesophageal reflux disease (GERD) and it’s related conditions, Barrett’s esophagus and adenocarcinoma? For the past four years we’ve known that individuals with GERD have imbalances in the microbial ecology of the distal esophagus. One consequence of this microbial shift is increased levels of Gram-negative bacteria, which harbor on their cell surface an inflammatory membrane component known as lipopolysaccharides (LPS) or endotoxin (1). It’s through this combination microbial imbalances allowing for an increase in both opportunistic pathogens that synthesize carcinogenic metabolites and endotoxin from Gram-negative bacterial cells that create a perfect storm, manifesting as reflux disorders like GERD, and if left untreated Barrett’s esophagus and upper GI cancers (2).
However, this recently published review in the American Association for Cancer Research‘s (AACR) Clinical Cancer Research Journal expanded our mechanistic understanding by which the dysbiosis mentioned above leads to inflammation-mediated tissue abnormalities and esophagial cancer (2). Yang et al discsuss how increased levels of the bacterial endotoxin causes an upregulation of many pro-inflammatory cytokines which cause activation of immune pathways through their stimulation of the innate immune system toll-like receptor 4 (TLR4) and subsequent activation of the master inflammatory-gene trascription factor, NF-kB.
So how does microbial activation of inflammatory pathways cause GERD and Barrett’s esophagus?
NF-kB stimulation leads to increased iNOS activity leading to the relaxation of the lower esophageal shincter, increasing the esophageal mucosa to gastric contents, including imbalanced bacteria and their inflammatory membrane componenets. Moverover, microbial activation of NF-kB is thought to indirectly delay gastric emptying through the NF-kB’s increased synthesis of COX-2. Thus over time, elevated activity of iNOS and COX-2 from dysbiotic microbes may have a 2-fold effect on increasing the inflammatory damage to the squamous epithelium leading to GERD, and if prolonged, Barrett’s esophagus.
Given the above, can we really ameliorate GERD by simply turning off the cellular switch responsible for producing hydrochloric acid (HCl) with proton-pump inhibitor (PPIs) medications? While low HCl production may be an “initial” contributing factor leading to the development of dysbiosis, it appears that HCl’s collateral damage to the esophageal epithelium is sustained from inflammatory mediators synthesized as a result of imbalanced gut microbiota-particularly of the Gram-negative, endotoxin harboring variety.
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