P755 Effect of carboxylic acids of gut microbial origin on host cell proliferation in organotypic tissue cultures
T. Vakhitov1, N. Chalisova2, S. Sitkin*1, 3
1State Research Institute of Highly Pure Biopreparations, Dept. of Microbiology, St. Petersburg, Russian Federation, 2Pavlov Institute of Physiology of the Russian Academy of Sciences, St. Petersburg, Russian Federation, 3North-Western State Medical University named after I.I. Mechnikov, Dept. of Internal Diseases, St. Petersburg, Russian Federation
Intestinal microbiota produce many carboxylic acids, especially short chain fatty acids (SCFA), as a result of carbohydrates, fats, and proteins transformation and which are intermediates in the interactions between gut microbiota and the host metabolism. SCFA (formate, acetate, propionate, and 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), phenylpropionic acid (PPA), phenyllactic acid (PLA) and some other acids, are metabolites of amino acids phenylalanine and tyrosine involved in host adaptation and regulation.
We examined the effect of the carboxylic acids of gut microbial origin (eg, SCFA, BCFA, and PCA) on host cell proliferation in organotypic tissue cultures (Wistar rat spleen explants).
The study showed that almost all biogenic aliphatic carboxylic acids have a positive effect on cell proliferation in rat spleen tissue. Gut microbiota metabolites butyrate and propionate, but not acetate, stimulate the proliferation of spleen tissue explants in concentrations 0.1–10 ng/ml. This fundamentally distinguishes them from amino acids, many of which have an inhibitory effect at the same concentrations. These findings suggest that SCFA, including hydroxy and oxo derivatives, can act as positive regulators of host immune tissues. Some SCFA (butyrate and propionate) stimulate proliferation of normal host cells (immune tissue and intestinal epithelium), but inhibit growth and induce apoptosis in colorectal cancer (CRC) cells (‘butyrate paradox’). Unlike SCFA, phenylcarboxylic acids have a negative effect on host immune tissues explants, and induce apoptosis.
Study results confirm the potential contribution of phenylcarboxylic acids in the pathogenesis of some chronic disorders associated with impaired immune response, including autoimmune diseases such as ulcerative colitis and Crohn’s disease. The authors suggest that phenylcarboxylic acids might serve as early metabolic markers of immune-mediated diseases and chronic inflammation, such as inflammatory bowel disease (IBD), colorectal cancer, chronic liver and kidney diseases, and secondary immunodeficiency. It can be assumed that carboxylic acids are evolutionary precursors of amino acids that have a wide variety of functions and are able to modulate not only proliferation but also apoptosis. The results can be used to study mechanisms of action of probiotic strains and metabiotics (eg, butyrate and propionate-containing formulations), as well as for the development of innovative medicines for IBD and CRC treatment.