Archaebiotics
see the origin of the concept archaebiotics here
Next generation probiotics - Prophylactic pharmabiotics in order to prevent diseases like atherosclerosis or trimethylaminuria?
Intestinal microbiota and food, an union that can turn morbid...
Since the works of Stan Hazen (Cleveland, Ohio, 2011), components of our diet are known to give rise to a compound found in the blood and very deleterious, under the action of certain bacteria of the intestinal microbiota.
These compounds / nutrients are more particularly phosphatidylcholine (or lecithin) / choline, L-carnitine, TMAO (or trimethylamine oxide) and glycyl-betaine.
Most of these compounds are also necessary / mandatory in certain quantities. They are then absorbed and used by our body.
However, some of them can be used by some gut microbiota bacteria, most of them still unknown in 2016-2017. Some of these bacteria have enzymes that can metabolize (anaerobically) these compounds.
This results in the formation of trimethylamine or TMA in the intestine. This TMA is absorbed by the intestinal epithelium and will join the liver by the portal vein.
In the liver, this molecule can have 2 different fates depending on the activity of a liver enzyme, Flavin Monoxygenase 3 or FMO3.
- For the majority of people, this enzyme is functional (left arrow on the figure). TMA of intestinal origin then undergoes oxidation and leads to the formation of trimethylamine oxide (TMAO), a molecule that Stan Hazen and collaborators have revealed to be an important cardiovascular risk factor, which actively participates in various mechanisms involved in atherosclerosis. See here for more details.
- For some people, the liver enzyme FMO3 is not functional or absent, for genetic reasons (rare, autosomal recessive disease, with a carrier heterozygote rate in the UK of 0.5 to 1% (see here). In that case, TMA will diffuse in different body fluids. However, this molecule is very volatile and especially ... very smelly: it is indeed the one which gives its characteristic smell to rotten fishes, to which we are extremely sensitive. People with this pathology therefore present a trimethylaminuria (presence of trimethylamine TMA, in the urine) where it is detected to diagnose this pathology. Also called "Fish-odor syndrome", this pathology is psycho-socially very disabling.
Which way to prevent these diseases?
The two previous pathologies are ultimately induced by the genesis of trimethylamine TMA by the human intestinal microbiota, from several nutrients. This makes it difficult to prevent, because these nutrients are also essential for the proper functioning of the body, and deficiencies can cause significant and severe disorders.
Therefore, intervention on the diet could be a possible but very delicate task, because foods that provide these nutrients are very various and we must guarantee a minimum intake of these N-methyl compounds to avoid deficiencies.
Another approach would be to intervene on the human intestinal microbiota, so as to prevent the conversion of these N-methylated compounds into TMA: For the moment, the involved bacteria remain unknown and probiotic trials have proved to be ineffective until now . Acting more violently using antibiotics can not be considered a long-term or generalizable solution, although it is occasionally used in case of trimethylaminuria. A promising avenue could be the use of inhibitors of bacterial enzymes involved in TMA synthesis. It could nevertheless lead to changes in the intestinal microbiota, in its overall composition, whose consequences are not predictable, and it seems difficult to have a single inhibitor for the various enzymes involved. Nevertheless, applied in a personalized way, depending on the bacteria of the individual involved, this may be an interesting solution. One could also imagine a replacement of the hosted microbiota which is responsible by a "safe" microbiota that does not have these bacterial enzyme activities: carried out by Fecal Microbiota Transfer (or FMT), this solution is very attractive but remains unusable quickly and on a large scale, raising ethical and health issues. Finally, one could imagine intervening on the activity of the human liver enzyme FMO3, the one responsible for the transformation of the intestinal TMA into circulating TMAO, to prevent cardiac pathologies or chronic renal diseases. However, if it is successful, it will create trimethylaminuria / trigger a rotten fish smell syndrome.
Another potential prophylactic way, the use of archaea?
Another possible solution is to act after the formation of TMA by the intestinal microbiota, but before it is absorbed and transformed by the liver into TMAO. This consists of a remediation of synthesized TMA into a molecule that is safe for humans. This also requires micro-organisms capable of living in the human intestinal microbiota, and capable of transforming this molecule in this environment which is anaerobic (human intestine).
Archaebiotics
However, this type of metabolism seems effective in non-bacterial microorganisms found naturally in the microbiota: certain methanogenic archaea of the order Methanomassiliicoccales. These can convert TMA into methane, a gas considered "inert" for human health. Are other microorganisms able to do this? The answer is difficult to provide but the recognition of trimethylamine TMA for its enzymatic transformation into anaerobic requires the use of a particular amino acid, Pyrrolysine. This amino acid ("Pyl" in 3-letter international code , "O" in 1-letter code) is in fact the 22nd amino acid encoded by the genetic code, and was very recently discovered (2002) However, Pyl is present only in very rare organisms, and for most of them, they are methanogenic archaea:
Methanosarcinales (absent from human intestinal microbiomes) and Methanomassiliicoccales (and not all).
This approach is described (originally) in the scientific article available here , and in a more simple way in a book chapter here.
Titre du paragraphe
The need for the amino acid Pyl / Pyrrolysine in this metabolism makes the phenomenon more complex. First, you need an organism capable of producing this amino acid, which is achieved by 3 enzymes from a "typical" amino acid, Lysine. In a very original way, these organisms use a modification of the genetic code, by reassigning an encoding function to the amber codon (usually a "Stop" codon), using a dedicated tRNA (transfer RNA, encoded by the pylT gene in the figure), ensuring the "orthogonality of the genetic code", ie the correspondence between a codon (3 nucleic bases) and one amino acid. This requires an enzyme capable of recognizing both the good tRNA and binding the good amino acid, Pyl-tRNA amino acyl transferase PylS. In the case of the Pyl system of Methanomassiliicoccales, tRNA and the enzyme linking Pyl to tRNA are very original in their structures.
For a more advanced description of the Pyl system (figure representing a 3D modeling of the structure of the amber codon suppressor tRNA-Pyl, in Methanomethylophilus alvus), you can consult some of our scientific articles, especially this one. Also, see the dedicated page on this site.
A conceivable approach?
Some of the important benefits of this approach include:
- that there are no known pathogens in archaea (or for humans, animals or even plants!), which makes the idea promising, knowing that some Methanomassiliicoccales are naturally present in the human intestinal microbiota
- that this metabolism of methanogenesis is an obligatory metabolism for these species, which can only be realized with substrates other than TMA: this allows to consider an efficiency in the conversion of thisTMA.
- Important technological developments will have to be made before reaching this end, especially in the capacity to produce and keep active these strains supposedly extremely sensitive to oxygen.