Pentanoic acid induces thymic stromal lymphopoietin production through Gq/11 and Rho-associated protein kinase signaling pathway in keratinocytes.

Thymic stromal lymphopoietin (TSLP) plays an important role in allergic skin inflammation. Short-chain fatty acids (SCFAs), including pentanoic acid, are products of bacterial metabolism and are associated with allergic skin disorders. However, whether SCFAs induce TSLP production is still unclear. In this study, we evaluated the effect of SCFAs on TSLP production and found that pentanoic acid was the most efficacious of the tested SCFAs. The Gq/11 inhibitor YM-254890 and the Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibited pentanoic acid-induced TSLP production, as did transfection with Gq/11 siRNA. These results suggested that pentanoic acid-induced TSLP production was mediated by Gq/11 and ROCK, providing insights into a novel TSLP production pathway in keratinocytes. The novel mechanism of TSLP production is expected to support the development of TSLP-regulating approaches in allergic skin disorders.

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

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.