Summary: A new study reports on the role gasotransmitters play in behavior and psychology.

Source: Lomonosov Moscow State University.

Professor Alexander Oleskin from the Faculty of Biology of the Lomonosov Moscow State University and his colleague Professor Boris Shenderov from the Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology published an article devoted to the review of gaseous neurotransmitters of microbial origin and their role in the human body.

The results of the research were published in Microbial Ecology in Health and Disease.

‘Our brain cannot work without neurotransmitters, i.e., substances that transmit impulses from one nerve cell to another. One of the classes of neurotransmitters are gaseous substances (gasotransmitters). Our brain uses gases such as hydrogen sulfide, ammonia, and even carbon monoxide to transfer information between cells,’ Alexander Oleskin tells.’Bacteria that inhabit our body (and especially the intestine), also form gasotransmitters that affect our brain, mind and behavior.’

Gasotransmitters are gaseous substances produced in various organs and tissues. The name “gasotransmitters” is related to the term “neurotransmitters”. These are substances that serve for the transmission of impulses between nerve cells, including the brain, where such gas transmitters as NO, CO and H2S are generated by means of special enzymes.

The review article provides an extensive analysis of the data related to the mechanisms of action of gaseous substances of microbial origin (among them: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), methane (CH4), hydrogen (H2), ammonia (NH3), etc.). They are considered asregulators ofthe human behavior, neurophysiological and mental disorders. The above mentioned gases are among the smallest biologically active molecules which perform vital functions of both multi-cellular organisms and bacteria.They act as mediators and regulators in intercellular interactions in the bodies of mammals.

Importantly, substances that act as gasotransmitters are synthesized in the gastrointestinal tract both by the cells of the host organism and a variety of gastrointestinal microorganisms that inhabit it, including Archaea, Bacteroides, Bifidobacterium, Butyrivibrio, Clostridium, Collinsella, Coprococcus, Desulfovibrio, Eubacterium, Lactobacillus, Prevotella, Propionibacterium, Roseburia, and others.

The gastrointestinal (GI) tract of an adult contains about 20 ml of various gaseous products, producing from 400 to 1200 ml per day. Nitrogen, oxygen, hydrogen, methane, carbon dioxide and hydrogen sulfide constitute 20-90%, 3.9-10%, 20.9-50% 7.2-10%, 9-30% and 0.00028% respectively of the total volume. Their numbers vary depending on the human’s diet. The gaseous products are formed as the result of various eukaryotic (human) and prokaryotic (bacterial) cells’ activity by enzymatic or non-enzymatic processes, and can also be gripped together with air and food. The majority of the gas molecules is removed from the intestines: they are absorbed and transferred to the bloodstream, and eventually removed from the body through the respiratory system.

Gasotransmitters play a dual role in the body. They may serve as energy sources, also for the inhabiting microbes. For instance, a typical symbiont isthe intestinal bacterium Escherichia coli (E. coli), which lives in the digestive tract, using nitric oxide (NO) generated by the host cells as an energy source for their own metabolism. As nitric oxide is also produced actively by the immune cells during inflammation, it turns out that E. coli is ‘interested’ in thedevelopment of an inflammation in the intestines.

Gasotransmitters are involved both in the communication between microbial cells and the “dialogue” between the microbial “life partners” and the host cells. The nitric oxide (NO)producedby the host organism or microbes regulates the functioning of the immune and cardiovascular systems and acts as a brain neurotransmitter involved inthe regulation of learning and cognitive activities. Under experimental conditions, mice deficient in one of the nitric oxide forming enzymes (neuronal NO-synthase) exhibit increased motor and sexual activity and long-term depression.

Hydrogen sulphide (H2S) at low concentrations regulates a number of processes in various human organs, especially the cardiovascular and nervous systems. Hydrogen sulfide acts as a neuroprotector: the effect of its insufficient concentration on the nervous system was demonstrated in studies with patients with epileptic seizures, psychiatric disorders, or pathological changes in the electroencephalogram. Many of these patients are deficient in enzymes which produce hydrogen sulfide in the body. Patients with the Down syndrome, by contrast, have an increased activity of the enzymes that form hydrogen sulfide.

An excess of ammonia (NH3) in the body (hyperammonemia), may be due to disorders in the gastrointestinal tract microbiota (dysbiosis). It results in accumulation of significant concentrations of NH3 in the brain. This situation is characteristic of liver cirrhosis and poses the threat of hepatic encephalopathy.

Gasotransmitters affect the cell that formed them (autocrine action), adjacent cells (paracrine action), and distant tissues and organs and the whole body systemically (endocrine action). The production of the gas transmitters and the distribution to various areas of the body depends on the activity of the cells forming the material of both of the body and the microbial symbionts. The concentrations and activities of gas transmitters are under a combined influence of the brain and the entire nervous system (including intestinal nerve cells that constitute the enteric nervous system), the immune system.They are also influenced by the gastrointestinal microbiota and that of other body areas (the skin, the respiratory tract, the uro-genital tract etc.).

‘Prospectively the research findings will be implemented in medical and psychiatric practice. They will serve for the treatment and prevention of neuropsychiatric disorders (including depression, increased aggressiveness, and others) using microbial gas transmitters. It seems feasiblefor instance, to attempt to normalize the amount of ammonia with the help of bacteria that will be introduced into the body in a goal-directed fashion’, hypothesizes Alexander Oleskin.

There are some developmentsin this direction. They are based on useful microorganisms, i.e., probiotics that can be consumed with milk products (yoghurt, cheese etc.), or in pharmaceutical formulations. The novelty lies in the approach to the use of such probiotics: they help administering potentially poisonous gases in minute amounts to improve human health and promote adequate behavior. Probiotic strains of lactobacilli, bifidobacteria, and E. coli actively synthesize one of the most important multifunctional gas transmitters – nitric oxide; moreover, probiotics additionally stimulate the nitric oxide production by the cells of the host organism.

The term ‘psychobiotics’ has recently been introduced to designate the probiotic bacterial strains that are used as dietary supplements to optimize functioning of the brain and the whole body activities by making good use of h the beneficial effects of microbial products, including gas transmitters, on the brain and behavior.

Source: Vladimir Koryagin – Lomonosov Moscow State University
Image Source: This NeuroscienceNews.com image is credited to Lomonosov Moscow State University.
Original Research: Full open access research for “Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota” by Alexander V. Oleskin and Boris A. Shenderov in Microbial Ecology in Health and Disease. Published online July 5 2016 doi:10.3402/mehd.v27.30971

Abstract

Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota

The symbiotic gut microbiota plays an important role in the development and homeostasis of the host organism. Its physiological, biochemical, behavioral, and communicative effects are mediated by multiple low molecular weight compounds. Recent data on small molecules produced by gut microbiota in mammalian organisms demonstrate the paramount importance of these biologically active molecules in terms of biology and medicine. Many of these molecules are pleiotropic mediators exerting effects on various tissues and organs. This review is focused on the functional roles of gaseous molecules that perform neuromediator and/or endocrine functions. The molecular mechanisms that underlie the effects of microbial fermentation-derived gaseous metabolites are not well understood. It is possible that these metabolites produce their effects via immunological, biochemical, and neuroendocrine mechanisms that involve endogenous and microbial modulators and transmitters; of considerable importance are also changes in epigenetic transcriptional factors, protein post-translational modification, lipid and mitochondrial metabolism, redox signaling, and ion channel/gap junction/transporter regulation. Recent findings have revealed that interactivity among such modulators/transmitters is a prerequisite for the ongoing dialog between microbial cells and host cells, including neurons. Using simple reliable methods for the detection and measurement of short-chain fatty acids (SCFAs) and small gaseous molecules in eukaryotic tissues and prokaryotic cells, selective inhibitors of enzymes that participate in their synthesis, as well as safe chemical and microbial donors of pleiotropic mediators and modulators of host intestinal microbial ecology, should enable us to apply these chemicals as novel therapeutics and medical research tools.

“Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota” by Alexander V. Oleskin and Boris A. Shenderov in Microbial Ecology in Health and Disease. Published online July 5 2016 doi:10.3402/mehd.v27.30971