EFFECT OF CARBOXYLIC ACIDS OF GUT MICROBIAL ORIGIN ON HOST CELL PROLIFERATION IN ORGANOTYPIC TISSUE CULTURES.

Abstract

Intestinal microbiota produces many carboxylic acids, especially short chain fatty acids (SCFA) as a result of carbohydrates, fats and proteins fermentation and which are intermediates in the interaction of the microbiota and the host. SCFA (formate, acetate, propionate, butyrate) are formed by the anaerobic carbohydrates fermentation and branched-chain fatty acids (BCFA), such as isobutyric and isovaleric acids, are derived from amino acids valine and leucine. Phenylcarboxylic acids (PCA), such as phenylacetic acid (PAA), phenyipropionic acid (PPA), phenyllactic acid (PLA) and some other acids, are metabolites of amino acids phenylalanine and tyrosine involved in host adaptation and regulation. ma unique experiment, the authors first examined effect of the carboxylic acids on host cell proliferation in organotypic tissue cultures (rat spleen explants). The study showed that almost all biogenic aliphatic carboxylic acids have a positive effect on cell proliferation in rat spleen tissue. This fundamentally distinguishes them from amino acids, many of which have an inhibitory effect at the same concentrations. These findings suggest that SCFA, including hydrox~ and oxo derivatives, can act as positive regulators of host immune tissues. Some SCFA (for example, butyric acid), stimulate proliferation of normal host cells (immune tissue, intestinal epithelium), but inhibit growth and induce apoptosis in colorectal cancer cells ('butyrate paradox'). Unlike SCFA, phenylcarboxylic acids have a negative effect on host immune tissues explants and induce apoptosis. These data confirm the potential contribution of phenylcarboxylic acids in the pathogenesis of chronic disorders associated with impaired immune response, including autoimmune diseases. The authors suggest that PCA may serve as early metabolic markers of sepsis, immune-related diseases and chronic inflammation, such as inflammatory bowel disease (iBD), colorectal cancer, chronic kidney disease and liver, secondary imrnunodeficiency. It can be assumed that carboxylic acids are evolutionary precursors of amino acids that have a wide variety of functions and able to modulate not only proliferation but also apoptosis. The results agree well with the data obtained in the study of Actoflor-C (microbial metabolites complex) and can be used to study mechanisms of action of probiotic strains and metabiotics (e.g. butyrate and propionate-containing formulations), as well as for the development of innovative medicines.