Tocotrienols, Probiotics and PhosphoGlycolipids: A Perfect Prescription for the Liver?

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By Michael Ash, BSc, DO, ND, F.DipIOn

One of my primary areas of research and expertise is the gut microbiota and its diverse impact on our health. Your liver receives nearly 70% of its blood supply from the intestine, and represents a first line of defence against gut-derived antigens. Intestinal bacteria—and the antigens they produce—play a key role in the maintenance of gut-liver axis health. Modulation of the gut microbiota to achieve and maintain symbiosis represents a new way to treat or prevent non-alcoholic fatty liver disease (NAFLD). Along with the concomitant use of tocotrienols and glycophospholipids, we may be starting to see the emergence of a truly profound intervention for a complex metabolic disease, using safe,natural compounds.

Here is how I see the three approaches merging. First, membrane consistent glycophospholipids are used to repair the bi-layer of the mitochondrial membrane. In the (prior Issue) of FOCUS, Garth Nicholson, PhD, and I wrote about the emerging role of the mitochondria—and damage to the mitochondrial lipid membrane—in integrative medicine. We explored how glycophospholipid replacement could reduce adverse spillage of reactive oxygen species (ROS), the energy-carrying enzyme ATP and oxidized DNA. The latter two are  known as Damage Associated Molecular Patterns (DAMPS).

We also wrote about gastrointestinal bacterial dysbiosis, and the consequential increase in pathogen-associated microbial patterns (PAMPS) .  Together, DAMPS and PAMPS drive inflammation and heighten receptor sensitivity in both tissues – with adverse outcomes in human health and physiology.[i]

Mitochondria and gastrointestinal bacteria share a common ancestry—bacterial cells called prokaryotes. This historical genetic lineage means bacterial antigens and mitochondrial DNA are recognised by the same immune receptors on and in cells. The intracellular receptors, when activated, release two potent cytokines – IL-1β & IL-18. Research shows these cytokines are intimately linked to liver diseases including NAFLD and are instrumental in its progression to non-alcoholic steatohepatitis (NASH) .[ii]

A “two hit” mitochondrial mechanism may drive NAFLD/NASH pathogenesis.[iii] The first hit, hepatic steatosis, is closely associated with lipotoxicity-induced mitochondrial abnormalities that sensitise the liver to additional pro-inflammatory insults. The second hits include enhanced mitochondrial lipid peroxidation and increased generation of reactive oxygen species (ROS) and increased release of oxidised mitochondrial DNA.[iv]

Next, intracellular protein complexes called inflammasomes are activated. Inflammasomes trigger the maturation of the highly inflammatory IL-1β & IL-18. When inflammasomes which are also sensors and regulators of the colonic microbiota are activated, the gut microbiota is also altered. Could this altered composition influence events in the liver?[v] I believe so. Changes in the composition of the microbiota as a result of inflammasome activation or dysbiosis trigger the cytokine cascade with initiation and progression of inflammatory liver disease.

A cautiously optimistic idea is now taking hold that invokes using mitochondrial and bacterial induced symbiosis of the gut microbiota to track, target and treat a plethora of diseases, even ones beyond the confines of the gastrointestinal tract.[vi] Adding tocotrienols to this dual approach creates a therapeutic trinity of natural, safe agents.

References


[i]Bird L. Innate immunity: Linking mitochondria and microbes to inflammasomes.Nat Rev Immunol. 2012 Mar 9;12(4):229View Abstract

[ii]Kubes P, Mehal WZ. Sterile inflammation in the liver.Gastroenterology. 2012 Nov;143(5):1158-72. View Abstract

[iii] Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998 Apr;114(4):842-5 View Abstract

[iv]Sanyal, A. J.et al.Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology120, 1183–1192 (2001)View Abstract

[v]Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature482, 179–185 (2012)View Abstract

[vi]Korecka A, Arulampalam V. The gut microbiome: scourge, sentinel or spectator? J Oral Microbiol. 2012;4. doi: 10.3402/jom.v4i0.9367. Epub 2012 Feb 21. View Abstract

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