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Gut Microbiome, Bile Acids and Butyric Acid

As previously discussed, Machine Learning and Network Analysis have suggested the possible role of Bile Acids in ME/CFS and several other syndromes such as Post-Finasteride Syndrome, Post-Accutane Syndrome and Gulf War Ilness Syndrome .

It is time to look at one more reason on why Bile Acid metabolism and Liver pathology (e.g Hemochromatosis, WIlson's Disease, Gilbert's Syndrome) should be further investigated :

The reason is the association of Bile Acids (BAs) with the Gut Microbiome.

As discussed in [1] :

"the gut microbiota closely interact and modulate each other; BAs exert direct control on the intestinal microbiota. By binding to FXR, they induce production of antimicrobial peptides (AMPs) such as angiogenin 1 and RNase family member 4, which are directly involved in inhibiting gut microbial overgrowth and subsequent gut barrier dysfunction"

Professors Derya Unutmaz (Jackson laboratories) and W. Ian Lipkin (Columbia University) are investigating the importance of Gut Microbiome to the pathology of ME/CFS. Machine Learning also identifies "Gut" as being an important piece of the puzzle of ME/CFS as shown below :



As shown, the "Gut" is being ranked at the fourth position in this specific Feature-selection run.


I also present an example of a Classification Analysis below, where we see entries of  Sepsis, Gut, Liver Disease and Milk Fat Globule Membrane (which is associated with MFGE8) :




In [1] it is further discussed that Liver pathology such as NAFLD (Non-Alcoholic Fatty Liver Disease) NASH (Non-alcoholic Steatohepatitis) and Liver Fibrosis / Damage are associated with Gut Microbiome. Interestingly, Endoplasmic Reticulum and Oxidative Stress -which have been previously discussed in this Blog-  are also being mentioned  :

"An imbalance in BAs and gut bacteria elicits a cascade of host immune responses relevant to the progression of liver diseases"

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"Additionally, TLR4 signalling also promotes fibrosis by downregulating BMP and activin membrane-bound inhibitor homologue (BAMBI) (a decoy receptor for transforming growth factor-β (TGFβ)) in hepatic stellate cells. These steps lead to expression of inflammatory cytokines, oxidative and endoplasmic reticulum (ER) stress and subsequent liver damage"
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"All experimental models of liver fibrosis result in gut microbial dysbiosis and increased intestinal permeability, and treatment of the gastrointestinal tract with nonabsorbable antibiotics (such as rifaximin and neomycin) improved survival by immuno-modulation, reducing translocation and incidence of infection. Mice with genetic ablations of the receptors for bacterial product ligands (TLR2, TLR4, TLR9 and NLP3) are protected from experimental liver fibrosis"

A potentially interesting acid can be Butyric Acid and its association with MFGE8 which has been also identified as important by Machine Learning.

As discussed in [2] :

"In this study, we intrarectally injected butyric acid into mice that received DSS treatment, and found that the robust induction of MPO activity and proinflammatory cytokines during the acute phase of DSS-induced colitis was significantly downregulated by those injections. On the other hand, a less protective effect was seen in MFG-E8 KO mice, with no significant differences found regarding bacterial composition and concentration changes of butyrate acid between WT and MFG-E8 KO mice with DSS treatment. Therefore, these results support the concept of an anti-inflammatory effect of butyric acid via modulation of MFG-E8 and indicate a therapeutic benefit from intrarectal administration for intestinal inflammation."

In other words, Butyric acid significantly attenuates proinflammatory cytokines through regulation of MFGE8 (in mice). Butyric acid has many other interesting qualities as also discussed in [2], including the maintenance of integrity of intestinal barrier  :

"Butyric acid, a short-chain fatty acid and one of the main metabolites of intestinal microbial fermentation of dietary fiber, has been shown to have an important role in maintaining the integrity of the intestinal mucosa, while it also has been shown to exert potent anti-inflammatory effects both in vitro and in vivo"

Putting this all together in a form of a Hypothesis :

Impaired Bile Acid Metabolism -which can be a result of existing Liver pathology such as Hemochromatosis, Wilson's Disease or any kind of Liver Stressor - affects the composition of Gut Microbiota which in turn may be responsible for the pathology of ME/CFS and several other syndromes discussed. On the other hand, Gut Dysbiosis may be responsible for initiating Liver pathology such as Liver Disease, Liver Fibrosis, NAFLD, NASH. These pathologies may then further affect Gut Microbiota, ultimately ending up in a vicious cycle.

A reasonable argument here is that not all people having Liver Disease and/or Gut Dysbiosis end up with ME/CFS. I hypothesize that the reason for some individuals getting the Syndromes discussed is any combination of impaired functioning of Endoplasmic Reticulum Stress, Reverse Cholesterol Transport, Inflammatory Response, Phagocytosis, Proteolysis and Bile Acid Metabolism. Other interesting targets are LXR Receptor, Peroxisome Proliferators (PPARs) and MFGE8.



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