Serotoninergic system targeting in multiple sclerosis: the prospective for pathogenetic therapy.

Serotonin (5-hydroxytryptamine) (5-HT) is a neurotransmitter, which mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of 5-HT on gut microbiota functions, which play an essential role in developing CNS inflammatory diseases. Finally, 5-HT is a direct mediator of neuroimmune interaction. The article reviews the literature data on the role of 5-HT in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of 5-HT and selective serotonin reuptake inhibitors (SSRIs) on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of serotoninergic drugs as a pathogenetic therapy of MS, are discussed.

Probiotics and Psychobiotics: the Role of Microbial Neurochemicals.

In light of recent data, microorganisms should be construed as organisms that are capable of communication and collective behaviors. Microbial communication signals are involved both in interactions among microbial cells within microbial social systems, including the human body-inhabiting microconsortium, and the dialog between the microbiota and the host organism. The microbiota inhabits various niches of the host organism, especially the gastrointestinal (GI) tract. Microorganisms release diverse signal molecules and, in addition, specifically respond to host signals. This enables them to constantly interact with the nervous system including the brain and the immune system of the host organism. Evolutionarily conserved signals that are involved in the communication between microbiota and the host include neuroactive substances (neurochemicals) such as peptides, amino acids, biogenic amines, short-chain fatty acids, and gaseous substances. This ongoing dialog may either stabilize the host's physical and mental health state or, alternatively, cause serious health problems. Attempts are made to correct imbalances in the brain-gut-microbiota axis with probiotics including their subgroup called psychobiotics that release neuroactive substances directly influencing the human brain, psyche, and behavior. A number of recent review works address the microbiota-host system and its communication signals. Some of the publications focus on the involvement of neurochemicals in the bidirectional communication within the host-microbiota system. However, this work concentrates on the impact of bacterial cell components, metabolites, and signal molecules as promising alternatives to the currently widespread probiotics that have both advantages and disadvantages. Such biologically active agents of microbial origin are referred to as postbiotics or, alternatively, metabiotics (the term preferred in this work).

Mitochondria-targeted quinones suppress the generation of reactive oxygen species, programmed cell death and senescence in plants.

This work focuses on the effect of mitochondria-targeted quinones (SkQs) on plants. SkQs with antioxidant properties are accumulated in the mitochondria of pea cells and suppress the generation of reactive oxygen species. At nanomolar concentrations, SkQs prevented the death of pea leaf epidermal or guard cells caused by chitosan, bacterial lipopolysaccharide or KCN. The protective effect of SkQs was removed by a protonophoric uncoupler. SkQs at micromolar concentrations inhibited the O2 evolution by illuminated chloroplasts and stimulated the respiration of mitochondria. SkQs slowed down the senescence and the death of Arabidopsis thaliana leaves and improved the wheat crop structure.

Role of Neurochemicals in the Interaction between the Microbiota and the Immune and the Nervous System of the Host Organism.

This work is concerned with the role of evolutionary conserved substances, neurotransmitters, and neurohormones, within the complex framework of the microbial consortium-immune system-nervous system axis in the human or animal organism. Although the operation of each of these systems per se is relatively well understood, their combined effects on the host organism still await further research. Drawing on recent research on host-produced and microbial low-molecular-weight neurochemicals such as biogenic amines, amino acids, and short-chain fatty acids (SCFAs), we suggest that these mediators form a part of a universal neurochemical "language." It mediates the whole gamut of harmonious and disharmonious interactions between (a) the intestinal microbial consortium, (b) local and systemic immune cells, and (c) the central and peripheral nervous system. Importantly, the ongoing microbiota-host interactivity is bidirectional. We present evidence that a large number of microbially produced low-molecular-weight compounds are identical or homologous to mediators that are synthesized by immune or nervous cells and, therefore, can bind to the corresponding host receptors. In addition, microbial cells specifically respond to host-produced neuromediators/neurohormones because they have adapted to them during the course of many millions of years of microbiota-host coevolution. We emphasize that the terms "microbiota" and "microbial consortium" are to be used in the broadest sense, so as to include, apart from bacteria, also eukaryotic microorganisms. These are exemplified by the mycobiota whose role in the microbial consortium-immune system-nervous system axis researchers are only beginning to elucidate. In light of the above, it is imperative to reform the current strategies of using probiotic microorganisms and their metabolites for treating and preventing dysbiosis-related diseases. The review demonstrates, in the example of novel probiotics (psychobiotics), that many target-oriented probiotic preparations produce important side effects on a wide variety of processes in the host organism. In particular, we should take into account probiotics' capacity to produce mediators that can considerably modify the operation of the microecological, immune, and nervous system of the human organism.

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.