Inside of each of us, there are ten times as many bacteria and 100 times as many viruses as our own cells. This means we have 300 times more DNA from microbes inside of us than our own DNA (the total DNA has been called the hologenome- see post). Microbe DNA is not quiet, but is producing large amounts of molecules that enter our blood stream and affect every part of our physiology. Intense research is attempting to figure out just what kinds of molecules they produce and what they do.
A previous post described many microbe products that affect our brains. But, little is known about most of the large number of new molecules that are being discovered that could have dramatic effects throughout the body. Also, there is great individual variability in the types of microbes and products in different people. Currently, 14,000 genetic networks have been clearly identified in the microbes in human gut. The great majority of these are not understood and there are undoubtedly, many more. This post describes resent research on new classes of molecules being discovered.
Symbiosis in Nature
For many years the critical importance of symbiosis in biology was not appreciated. In fact, it was ridiculed. Now, it is clear that our own eukaryote cell began as a symbiosis of two or more microbes two billion years ago. The symbiotic relationships throughout evolution have not stopped since that time. The more study that is put in, the more it is recognized that unicellular and multicellular creatures occur in constant communication with horizontal gene exchanges and almost universal symbiosis. All plants and animals are in constant symbiosis with microbes. An important example in plants is cooperation for nitrogen fixation with both bacteria and fungus. We are, in fact, not one type of cell, but the sum of many communities of cells.
The symbiotic nature of humans and microbes is only now being described. Examples include digestion of food and creation of essential amino acids and vitamins. This post describes the production of molecules by microbes in humans and the possible impact this has for microbe-human symbiosis. For detailed information on what is known currently about products that affect the brain see previous post.
Summary of Posts about Microbe Affects on the Brain
There are many effects on the brain that have already been documented (see previous post Microbe Effects on the Brain). Microbe molecules in the gut affect depression, stress, autism, and degenerative illness. Research shows microbe effects on anxiety, mood, depression and social behavior. These are from secreted products, stimulation of the nervous system or travel to the brain. Products transform into hormones and neurotransmitters or they produce neurotransmitters themselves. Microbe effects on the brain include fetal development and neurotransmitter function.
Microbes affect animal behavior, many wih millions of years of symbiotic relationships. Autism, schizophrenia, depression and other degenerative brain diseases co exist with GI problems. A gut microbe metabolite was shown to cause behavioral abnormalities of autism and anxiety.
Microbes boost immune function, fight autoimmune diseases, help to maintain proper weight and decrease or increase stress. Skin microbes stimulate immune function. Gut microbes alter genes in the brain and affect medication effects.
In the brain microbes stimulate many different illnesses. They change animal behavior, often to their advantage:
- Aggressive biting behavior in dogs from rabies virus spreads the virus.
- Toxoplasmosis Gondi infection makes mice friendly to cats.
Gondi increases suicide, and other mental illnesses in humans.
- Cordyceps makes insects expose them to more fungus.
- Microbes behave differently if there is sleep alteration.
- Spinochordodes tellini makes grasshoppers go to water where the parasite invades and produce eggs.
- Schistolcephalus solidus makes stickleback fish move to colder water where the infection increases.
- Infections make animals seek higher ground to help predators find them
- Virus causes crickets to mate increasing transition of the virus.
Many effects of the microbe products:
- Without microbes, much higher hypothalamus stress steroids and lower level of BDNF.
- Microbes have different effects at different times in development of the brain
- Microbes regulate migration of new glia cells in the enteric nervous system.
- Mice without microbes have less important neurotransmitters and factors
- Microbes produce GABA, noradrenaline, serotonin, dopamine and acetylcholine and produce tryptophan and kynurine triggered by inflammatory factors and steroids
- When there are no microbes in the gut, there is less serotonin in the blood and decreased dopamine and GABA.
- Microbes make many neuro modulators or new neurotransmitters including serotonin, dopamine, GABA, epinephrine, acetylcholine and others. These can go into the blood and the CSF.
- GABA is manufactured by microbes and triggers the vagus nerve and travels in the blood
- Microbes produce signals increasing pro inflammatory cytokines.-
Many new Small Molecules
There are a lot of peptides recently discovered from microbes.
A large group of short fatty acid molecules have been described. A previous post described how research is just now discovering the extremely complex ways that fatty acids are used in brain signaling.
Peptides and Proteins that are Altered
Many proteins and peptides are made from ribosomes and then altered once they are translated. These are called ribosomally synthesized post trasnlationaly modified peptides or RiPPs. RiPPs are used by bacteria to communicate with each other and control the complex large societies they live in.
Peptide Antibiotics Produced by Microbes
A class of antibiotic peptides, called lantibiotics, are produced by microbes and used to kill competitors. They have polycyclic thioether amino acids lanthionine or methyllanthionin and unsaturated amino acids dehydroalanine and 2-aminoisobutyric acid. A large number of lantibiotics have been found with less than 40 peptides. After production from the ribosome, then many different links are made between sections of the molecule (post translation modulation). The mechanisms of action are not fully known, but some impair cellular membranes.
Lantibiotics are made by bacteria presumably to fend off similar types of microbes. They are active against Gram positive microbes. But, recently, lantibiotics have been found from Staph aureus and Strep pyogenes, which are dangerous in humans. Another is from Enterococcus faecalis.
Microcins and TOMMS
Another class of produced molecules are microcins that are antibiotics with a narrow range of activity. They have many unusual alterations after manufacture form ribosomes. Microcins are from enterobacteria and can be used to kill similar bacteria. Most that we know of are from E. Coli.
Dangerous Molecule Kills Blood Cells
TOMMS are thiazole/oxazole-modified microcins are a new class of microcines from bacteria and archaea that come from gram positive and negative bacteria. One molecule from a dangerous bacteria S.pyogenes creates streptolysin S, which is a very complex molecule and despite decades of research it is not clear yet how it works. It does kill blood cells by unclear mechanisms with axozole and thiazole chemical configurations. Now, similar complex molecules from other dangerous species have been discovered such as listeriolysin S and clostridiolysin S.
Enterotoxin Targets Human Epithelial Cells
Another is enterotoxin made by E.coli. A derivative of this has been approved as a medication for GI motility. One type, indoxyl sulfate, has very variable production, which can be produced 20 times more than others in some people.
RiPPs described above are targeted to other microbes. Enterotoxin targets human epithelial intestinal cells (see post) causing diarrhea disease. It consists of 14 amino acids connected by internal bonds and is very similar to a human hormone guanylin. It targets the same protein in the cell membrane that guanylin does. This protein that goes through the membrane from outside the cell to inside stimulates more ions to be secreted into the gut lumen.
The approved drug linaclotide has one amino acid difference from the enterotoxin and is used for irritable bowel syndrome. The links are made afterward by an enzyme, whose origin is not clear. This peptide is very stable and survives in a region that destroys most proteins. It affects the body without entering the blood stream through the epithelial cells.
More Amino Acid Products
Because gut bacteria live without oxygen, they need electron transfer to survive. Metabolizing amino acids allows transfer of electrons, but produces large amounts of byproducts, including phenylacetic and phenylpropionic acids. These products, unlike RiPPs are able to go into the cells and the blood stream. There are many different metabolites, only some of which are understood. Many metabolites of these are made in large quantities.
Indole is made from tryptophan by an enzyme of unclear origin. This can be a signal in bacteria communication. It is absorbed into the blood and then travels to the liver where it is metabolized again into a toxin that accumulates when humans have kidney troubles. A metabolite, Indoxyl sulfate, is measured in human urine either in low or high quantities depending on the different microbes in individuals.
Another metabolite of tryptophan is tryptamine, which is a neurotransmitter that is part of the communication between the gut and the brain. A previous post enumerated many different neurotransmitters that are made by different microbes in the gut.
Aliphatic amino acids are, also, metabolized into a large amount of products that are not understood. Aliphatic means they are not polar they are hydrophopic (liking to be in lipids not water.) The larger the molecule (the more carbons in the chain), the more it is hydrophic. Those hydrophopic amino acids prefer to be inside the protein molecule structure and not exposed to the outside, which is near water.
Arginine, proline and ornithine make delta-aminovaleric acid, which transfers electrons. Alpha-aminobutyric acid comes from threonine or methionine. GABA from glutamate is made by many bacteria and is an important neurotransmitter, although the exact mechanism of gut brain effects is not known.
A variety of bacteria in the gut, take elements of our food, such as amino acids, and make specific new molecules, such as taking tryptophan and making it into tryptamine, indole propionic acid, an indoxyl sulfate. Therefore, people who eat the same food can have very different results from the bacteria.
An entirely different type of molecules produced by microbes is oligosaccharides, which have a very large number of variations. These molecules can be used for cellular scaffolding structures, for adhesion properties, and very specific immune regulation. Saccharide is another word for carbohydrate, with a carbon chain with attached hydrogen and oxygen. Oligosaccharides are a carbon chain with a small number of sugars.
These microbe products diffuse out of the lumen into the cells and blood. Most oligosaccharides that have been studied in humans are intracellular, so it is not clear what this large amount of different molecules are doing. Some oligosaccharides sit on the bacteria membrane and are not just structural but are related to cell to cell signaling. These interact with immune cells.
The most prominent class of bacteria in the gut is Bacteroides and they make many different versions of these products that sit on their surface. A large number of these are made from the sugar galactose. The most well known version is an important immune signal that stimulates T cells to make interleukin-10. This decreases T helper cells, which increases some of the microbes and decreases one type of colitis. There are a hundred other versions about which little is yet known. They are probably the common molecules in the human gut.
Streptococcus makes many as well for their surface, which use sialic acid to effect complement and stop macrophages from eating bacteria.
Many appear to be receptors for different unknown effects in immune cells. In fact, some are part of the not well known mechanisms of immune cancer medications.
Glycolipids are another class that are very complex and can, also, be immune signals.
These molecules combine carbohydrates and lipids and so there are an infinite number of possible combinations. They provide energy. They appear on the surface of microbes for recognition and signaling. They extend out from the lipid bilayer of the cellular membrane to act as sensors for many different purposes. They maintain membrane stability and help for tissues by attaching cells together.
LPS (lipopolysaccharide) is a component of the Gram-negative bacteria membranes and is one of the most studied molecules. These are receptors for important innate immune reactions. Two important examples that modulate immune activity are mycolic acid and galactosylceramide.
Alpha- galactosylceramide powerfully stimulates natural killer T cells. Although it was discovered a decade ago and hundreds of papers have explored its activity, its origins and mechanisms are not well known. It does appear that it started among microbes and was then adopted as a trigger of human immune cells.
Mycolic acids are part of the cell wall of dangerous bacteria. They can be long chains of carbon (more than 50) with attached lipids. They attach to polysaccharides in the wall of the cell. They are, also, signals to T cells triggering anti infection response. Other versions trigger macrophages and what looks like a response to vaccination. There are many attachments to the molecule that hide it from immune surveillance. One version is used by tuberculosis bacteria to stop interleukans.
Yet another class are terpenoids made from cholic acid from the human bile. The terpenoids are similar to terpenes from five-carbon isoprene units and altered in thousands of ways. Most bile is secreted into the intestine and then 90% taken up in the ileum. What is left can be at high concentration. There can be large amounts of these in the gut.
Microbes then make a large amount of modifications with many different chemical reactions. A gene cluster uses as many as eight different chemical reactions to make these products. Some terpene products are made by two different microbes, with alterations made sequentially. One is extremely common (deoxycholic acid) and is most of the bile acids in the gut. They are toxic chemicals and can stimulate damage to organs and cancer.
One well known terpenoid class is carotenoids made by two different enzymes. It is made by the dangerous Staph aureus and helps it survive.
Non ribosomal peptides are synthesized by specific enzymes, not made by a ribosome with messenger RNA. They often have a branched or cyclic shape. They are extremely common in soil and ocean bacteria. They have only recently been found in humans. One version is found in Staph aureus and is both part of their pathology and normal non dangerous functions. Another is a major cause of tooth cavities. Another is very important in making biofilms.
Recently, four different complex versions were found to cause human disease—food poisoning, colitis, mitochondrial damage, immune suppression and skin ulcers. A variant of these are used in probiotics.
Another group are called Siderophores (iron carrier), which are the soluble molecules with the most attraction to iron. These exist in many of the bacteria dangerous to humans and their pathology is related to their ability to grab iron.
What We Know Based on Current Technology
It is extremely difficult to find out the effect of one molecule in a very complex system. Of the hundreds of trillions of microbes in the human gut, more than 14,000 small molecules have been found. Many of these have very complex effects on microbes and humans. But, this is a small sample of what actually exists and in up coming years large numbers of other molecules will be found.
Current laboratory techniques are able to uncover the types mentioned here. One of the biggest problems in studying microbes is that we can really only study those that can be cultured. The same is true with these unusual molecules. There are large numbers of molecules that are completely different than anything we are aware of. The molecules are being discovered through a wide range of different methods, but most notably large genomic testing.
Many New Microbe Molecules Discovered in Humans
We are a community of communities with hundreds of times more DNA from microbes than our own human genome. Our cells live in a constant interaction between microbes and our immune system, with the skin and the intestinal epithelial cells leading the integration of signaling. Much of what occurs in physiology is based on signaling (see previous post on The Language of Cells.) The signaling comes from our cells and cancer cells, but, also, a large amount from microbes.
Somehow, our identity as a person is tied to our body, which is in fact a vast symbiotic community. As mind affects our body, it must, also influence this large amount of microbes, who have major effects in every aspect of human physiology.