''Methanobrevibacter smithii'' is the predominant

archaeon Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebact ...

in the

microbiota Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found ...

of the human gut. ''M. smithii'' has a coccobacillus shape. It plays an important role in the efficient

digestion Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small intest ...

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with w ...

s (complex sugars) by consuming the end products of

bacterial fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...

. ''Methanobrevibacter smithii'' is a single-celled microorganism from the Archaea

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function **Domain of holomorphy of a function * ...

. ''M. smithii'' is a

methanogen Methanogens are microorganisms that produce methane as a metabolic byproduct in hypoxic conditions. They are prokaryotic and belong to the domain Archaea. All known methanogens are members of the archaeal phylum Euryarchaeota. Methanogens are c ...

, and a hydrogenotroph that recycles the

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...

by combining it with

carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...

methane Methane ( , ) is a chemical compound with the chemical formula (one carbon atom bonded to four hydrogen atoms). It is a group-14 hydride, the simplest alkane, and the main constituent of natural gas. The relative abundance of methane ...

. The removal of hydrogen by ''M. smithii'' is thought to allow an increase in the extraction of energy from nutrients by shifting bacterial fermentation to more oxidized end products.

Importance in the human gut

The human

gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mi ...

consists of three main groups of hydrogen-consuming microorganisms or hydrogenotrophs: methanogens including ''M. smithii''; various

acetogen An acetogen is a microorganism that generates acetate (CH3COO−) as an end product of anaerobic respiration or fermentation. However, this term is usually employed in a narrower sense only to those bacteria and archaea that perform anaerobic resp ...

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

; and

sulfate-reducing bacteria Sulfate-reducing microorganisms (SRM) or sulfate-reducing prokaryotes (SRP) are a group composed of sulfate-reducing bacteria (SRB) and sulfate-reducing archaea (SRA), both of which can perform anaerobic respiration utilizing sulfate () as termina ...

. The different roles of these microorganisms are helpful in understanding how hydrogen metabolism affects the efficiency of dietary fermentation. Accumulation of hydrogen in the gut reduces the efficiency of microbial fermentation as well as the yield of energy. Methanogenic archaea are therefore particularly significant for the human gut, because they are pivotal in the removal of excess hydrogen. ''M. smithii'' is the most common methanogenic archaeon in the human gut microbiota. ''M. smithii'' is paramount in digestive processes, and has a high prevalence in

human feces Human feces (or faeces in British English) is the solid or semisolid remains of food that could not be digested or absorbed in the small intestine of humans, but has been further broken down by bacteria in the large intestine. It also contains ...

.Bedis, D., Mireille, H. (2009). "High Prevalence of ''Methanobrevibacter smithii'' and ''Methanosphaera stadtmanae'' Detected in the Human Gut Using an Improved DNA Detection Protocol." PLOS One 4(9) e7063. The gut microbiota is dominated by

gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...

Bacteroidota The phylum Bacteroidota (synonym Bacteroidetes) is composed of three large classes of Gram-negative, nonsporeforming, anaerobic or aerobic, and rod-shaped bacteria that are widely distributed in the environment, including in soil, sediments, and ...

, and

Bacillota The Bacillota (synonym Firmicutes) are a phylum of bacteria, most of which have gram-positive cell wall structure. The renaming of phyla such as Firmicutes in 2021 remains controversial among microbiologists, many of whom continue to use the earl ...

(mostly

gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

). Archaea are most prominently represented by the methanogenic ''M. smithii''. ''M. smithii'' is believed to be a therapeutic target for manipulation and an adaptation to the gut ecosystem.Buck, S., Hansen, E., (2007). "Genomic and metabolic adaptations of ''Methanobrevibacter smithii'' to the human gut." Proceedings of the National Academy of Sciences of the United States of America 104, 10643-10648. ''M. smithii'' has significant enrichment of genes involved in the utilization of

(CO₂),

hydrogen gas Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, a ...

(H₂), and

formate Formate (IUPAC name: methanoate) is the conjugate base of formic acid. Formate is an anion () or its derivatives such as ester of formic acid. The salts and esters are generally colorless.Werner Reutemann and Heinz Kieczka "Formic Acid" in ''Ull ...

(HCO₂⁻) for

methanogenesis Methanogenesis or biomethanation is the formation of methane coupled to energy conservation by microbes known as methanogens. Organisms capable of producing methane for energy conservation have been identified only from the domain Archaea, a group ...

. It also has an intact pathway to allow for CO₂ utilization gene cluster for the methanogenic consumption of ''

Bacteroides thetaiotaomicron ''Bacteroides thetaiotaomicron'' (formerly ''Bacillus thetaiotaomicron'') is a species of bacterium of the genus ''Bacteroides''. It is a gram-negative obligate anaerobe. It is one of the most common bacteria found in human gut microbiota and is ...

''-produced metabolite. ''M. smithii'' supports methanogenic and nonmethanogenic removal of diverse bacterial end products of fermentation. The dominant archaeon in the human gut ecosystem affects the specificity and efficiency of bacterial digestion of dietary polysaccharides. This influences the person’s calorie harvest and body fat. ''M. smithii'', along with certain bacteria, is more often found in lean individuals than in those who are overweight. Researchers have sequenced ''M. smithii'' genome, indicating that ''M. smithii'' may be a therapeutic target for reducing energy harvest in obese humans.

Cell wall and cell membrane compared to bacteria

The cell wall and cell membrane of ''Methanobrevibacter smithii'' determine susceptibility to antibiotics and

statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...

s. The cell wall is composed of pseudopeptidoglycan (and not

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

as in bacteria) which makes archaea resistant to

lysozyme Lysozyme (EC 3.2.1.17, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside ...

and many antibiotics that interfere with cell wall synthesis. The cell membrane consists of a

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

or monolayer, the backbone of which is composed of

isoprene Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...

units that are linked to

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again ...

bonds. In contrast, the lipid bilayer of bacteria consists of a

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

backbone that is linked to glycerol by an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

bond. The presence of statin-sensitive isoprene units in the cell membrane of archaea allows statins to selectively interfere with the growth of archaea while leaving the cell membrane of bacteria unaffected. While bacteria do not use isoprene units in their cell membrane they are still required elsewhere. These bacterial isoprene units are, however, synthesized by the

mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...

(MEP) that is not inhibited by statins. Gottlieb, K., Wacher, V., Sliman, J., & Pimentel, M. (2015)
Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders
Alimentary Pharmacology & Therapeutics.

In anorexic patients

In 2009, the largest human study concerning

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

and

to date was conducted. Obesity disorders are the result of an imbalance and have serious consequences such as

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

, and

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowe ...

. The gut microbiota and environment contributes to the energy imbalance because of its involvement in energy intake, conversion and storage. Culture-independent methods have shown that high proportions of methanogens can comprise up to 10% of all anaerobes in the colons of healthy adults. The quantification average of ''M. smithii'' for the anorexic group was much greater than the lean and obese group. Thus, higher amounts of ''M. smithii'' were found in anorexic patients than lean patients. The development of Methanobrevibacter in

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

patients may be associated with an adaptive attempt towards optimal exploitation of the low caloric diet of anorexic patients. Hence, an increase in ''M. smithii'' leads to the optimization of food transformation in low caloric diets. ''M. smithii'' could also be related to constipation, a common condition for anorexic patients.

''M. smithii'' and constipation

Observational studies show a strong association between delayed intestinal transit and the production of methane. Experimental data suggest a direct inhibitory activity of methane on the colonic and ileal smooth muscle and a possible role for methane as a gasotransmitter.

Statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...

s can inhibit archaeal cell membrane biosynthesis apparently without affecting bacterial numbers as demonstrated in livestock and humans. This opens the possibility of a therapeutic intervention that targets a specific etiological factor of constipation while protecting the intestinal microbiome. While it is generally believed that statins inhibit methane production via their effect on cell membrane biosynthesis, mediated by inhibition of the

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and ot ...

, there is accumulating evidence for an alternative or additional mechanism of action where statins inhibit

directly. It appears that this other mechanism may predominate when the

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

form of statins, particularly

lovastatin Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth. ...

, is administered.

References

External links