Probiotic Lactobacillus casei strain Shirota prevents indomethacin-induced small intestinal injury: involvement of lactic acid

Abstract

Inflammatory responses triggered by activation of the lipopolysaccharide (LPS)/Toll-like receptor (TLR) 4 signaling pathway are a key mechanism in nonsteroidal anti-inflammatory drug-induced enteropathy. The aim of this study was to investigate the probiotic effect of Lactobacillus casei strain Shirota (LcS) on indomethacin-induced small intestinal injury. Rats pretreated with viable LcS or heat-killed LcS once or once daily for a week were administered indomethacin by gavage to induce injury. Anti-inflammatory effects of L-lactic acid (1-15 mM) were evaluated in vitro by use of THP-1 cells. One-week treatment with viable LcS prevented indomethacin-induced intestinal injury with increase in the concentration of lactic acid in small intestinal content and inhibited increases in myeloperoxidase activity and expression of mRNA for tumor necrosis factor-alpha (TNF-alpha) while affecting neither TLR4 expression nor the number of gram-negative bacteria in intestinal content, whereas neither heat-killed LcS nor a single dose of viable LcS inhibited intestinal injury. Prevention of this injury was also observed in rats given l-lactic acid in drinking water. Both L-lactic acid and LcS culture supernatant containing 10 mM lactic acid inhibited NF-kappaB activation and increases in TNF-alpha mRNA expression and TNF-alpha protein secretion in THP-1 cells treated with LPS. Western blot analyses showed that both L-lactic acid and LcS culture supernatants suppressed phosphorylation and degradation of I-kappaB-alpha induced by LPS without affecting expression of TLR4. These findings suggest that LcS exhibits a prophylactic effect on indomethacin-induced enteropathy by suppressing the LPS/TLR4 signaling pathway and that this probiotic effect of LcS may be mediated by L-lactic acid.

Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats

“…Escherichia coli Nissle 1917 (EcN) SN stimulated the secretion of the anti-inflammatory cytokines interleukin (IL)-10 and IL-6, 20 in peritoneal cells of rats, while factors released by Lactobacillus casei Shirota inhibited indomethacin-induced nuclear factor kappa B (NFκB) activation and increases in tumor necrosis factor (TNF)-α mRNA expression. 21 The anti-inflammatory properties were attributed to the bacteria-derived lipopolysaccharide and lactic acid production for EcN SN and L. casei Shirota, respectively. 20,21 Similar to EcN SN, Bacillus coagulans secreted factors have been reported to promote IL-10 expression, and inhibit oxidative stress-induced formation of reactive oxygen species (ROS).…”

Lactobacillus reuteri-Specific Immunoregulatory Gene rsiR Modulates Histamine Production and Immunomodulation by Lactobacillus reuteri

“…Investigations into the beneficial effects of probiotics and mechanisms of probiosis have demonstrated that several probiotic species produce metabolites that modulate the host's mucosal immune system. For example, L-lactic acid production by Lactobacillus casei strain Shirota may work via Toll-like receptor 4 (TLR4) signaling to suppress indomethacin-induced myeloperoxidase activity and tumor necrosis factor (TNF) production by human myeloid (THP-1) cells in a rat model of small intestine injury (4). Bifidobacterium breve strain BbC50 and Streptococcus thermophilus strain St065 also secrete small, digestive-enzyme-resistant metabolites that were found to be able to inhibit TNF production from lipopolysaccharide (LPS)-activated THP-1 cells (5).…”

NSAID enteropathy and bacteria: a complicated relationship

“…Several studies have demonstrated beneficial effects of probiotics, including Lactobacillus acidophilus and Lactobacillus casei, in experimental models of NSAID enteropathy [30,35]. There have also been human studies demonstrating preventative effects of a single probiotic (L. casei) [36] or of a cocktail of probiotics [37] against NSAID-induced small intestinal injury.…”

“…It is also possible that metabolites from bacteria can influence these processes. For example, Watanabe et al [35] highlighted the possibility that lactic acid released by L. casei strain Shirota might contribute to the ability of that probiotic to reduce the severity of indomethacin-induced intestinal damage in rats. Kinouchi et al [30] demonstrated that supernatants from cultures of L. acidophilus or B. adolescentis, but not the bacteria themselves, could significantly reduce NSAID-induced intestinal damage.…”