Archaea, specific genetic traits, and development of improved bacterial live biotherapeutic products: another face of next-generation probiotics

Abstract

Trimethylamine (TMA) and its oxide TMAO are important biomolecules involved in disease-associated processes in humans (e.g., trimethylaminuria and cardiovascular diseases). TMAO in plasma (pTMAO) stems from intestinal TMA, which is formed from various components of the diet in a complex interplay between diet, gut microbiota, and the human host. Most approaches to prevent the occurrence of such deleterious molecules focus on actions to interfere with gut microbiota metabolism to limit the synthesis of TMA. Some human gut archaea however use TMA as terminal electron acceptor for producing methane, thus indicating that intestinal TMA does not accumulate in some human subjects. Therefore, a rational alternative approach is to eliminate neo-synthesized intestinal TMA. This can be achieved through bioremediation of TMA by these peculiar methanogenic archaea, either by stimulating or providing them, leading to a novel kind of next-generation probiotics referred to as archaebiotics. Finally, specific components which are involved in this archaeal metabolism could also be used as intestinal TMA sequesters, facilitating TMA excretion along with stool. Referring to a standard pharmacological approach, these TMA traps could be synthesized ex vivo and then delivered into the human gut. Another approach is the engineering of known probiotic strain in order to metabolize TMA, i.e., live engineered biotherapeutic products. These alternatives would require, however, to take into account the necessity of synthesizing the 22nd amino acid pyrrolysine, i.e., some specificities of the genetics of TMA-consuming archaea. Here, we present an overview of these different strategies and recent advances in the field that will sustain such biotechnological developments. Key points• Some autochthonous human archaea can use TMA for their essential metabolism, a methyl-dependent hydrogenotrophic methanogenesis. • They could therefore be used as next-generation probiotics for preventing some human diseases, especially cardiovascular diseases and trimethylaminuria. • Their genetic capacities can also be used to design live recombinant biotherapeutic products.• Encoding of the 22nd amino acid pyrrolysine is necessary for such alternative developments.

The host-associated archaeome

“…Therefore, the prevention of these diseases could rely on the supplementation of TMA-consuming Methanomassiliicoccales (so-called 'archaebiotics' 14 ). As a proof-ofconcept, a single inoculation of M. luminyensis B10 (the so-far unique isolate of Methanomassiliicoccales 150 ) significantly lowered the concentration of plasma TMAO in standard C57BL/6 laboratory mice through a 30days experiment, despite a very poor colonization 151,152 . M. smithii and two TMA-using methanogenic archaea (non-human and environmental) also showed a protective effect on a mouse model prone to atherosclerosis 151 .…”

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases

“…It is worth noting that some bacteria from the phylum Proteobacteria may also be able to metabolize the TMAO ingested via the diet into TMA via TMAO reductase using metabolic retroconversion [ 54 ]. Finally, it has recently been found that intestinal archaea such as some members of the order Methanomassiliicoccales are able to reduce TMAO to methane [ 55 ]. Therefore, a current area of research relies on the use of such microorganisms as potential probiotics, in order to reduce the circulating levels of TMAO, which have been associated with an increased cardiovascular disease risk.…”

Colon-Specific Delivery of Bioactive Agents Using Genipin-Cross-Linked Chitosan Coated Microcontainers

“…However, the delivery systems designed for this purpose face many challenges such as early release of bacteria while passing through the stomach and the small intestine, which may reduce viability of bacteria that are sensitive to the conditions in the upper part of the digestive tract . Research into next-generation probiotics is focused on putative applications on a number of alternative microorganisms, many of which are more vulnerable to the environment of the upper gastrointestinal (GI) tract and can benefit from direct delivery to the colon. − …”