In addition to playing a crucial role in physiological processes such as digestion of food and vitamin synthesis, the commensal gut microbiota may modulate host susceptibility to enteric pathogens. However, the specific mechanisms by which individual bacterial species contribute to pathogen tolerance are poorly studied.
A recent report, led by Dr. Howard C. Hang from the Laboratory of Chemical Biology and Microbial Pathogenesis at The Rockefeller University in New York (USA), has highlighted the role of protective intestinal bacteria in enhancing pathogen tolerance. The researchers used Caenorhabditis elegans (a worm) as a model organism to elucidate the protective mechanisms underlying the probiotic activity of Enterococcus faecium against a bacterial strain known to bring about typhoid-like symptoms, Salmonella enterica Typhimurium (S. Typhimurium). Worms treated with multiple strains of E. faecium before S. Typhimurium infection had increased survival rates and a lack of intestinal tissue damage compared to those that did not receive the bacteria.
When exploring if specific factors produced by E. faecium were sufficient for protection, researchers found that secreted antigen A (SagA), an enzyme critical to cell survival, was the most abundant protein found in E. faecium cultures. Worms treated with SagA isolated from E. faecium showed improved resistance to Salmonella infection pathogenesis, suggesting that enzymatic activity of SagA is required for enhancing pathogen tolerance. Besides this, in order to determine the protective role of SagA in the mammalian microbiome, the researchers transferred SagA into the non-pathogenic bacteria Lactobacillus plantarum and administered the bacteria to mice. SagA L. plantarum successfully inhibited Salmonella infection in the rodents, underscoring the conserved function of SagA across microbes. These results indicate that C. elegans is an effective model with which to explore the protective mechanisms of intestinal bacteria, and that enzymatic activity of SagA is required for protecting C. elegans and mice from enteric pathogens.
A complementary study, led by Dr. Daniel Mucida from the Laboratory of Mucosal Immunology at The Rockefeller University in New York (USA), has found that specific factors from commensal bacteria may be involved in improving host intestinal barrier function and limiting the pathogenesis of enteric infections.
The researchers used worm and mouse models to study the role of promoting intestinal barrier function as a method by which E. faecium protects against S. Typhimurium and Clostridium difficile infection pathogenesis. Intestinal epithelial cells (IECs) synthetize protective proteins and antimicrobial peptides to strengthen the intestinal barrier and prevent foreign pathogens from escaping the intestine and infecting distant organs. Hypothesizing that IECs may facilitate E. faecium’s defense, the researchers analysed IEC genetic profiles in groups of mice treated with E. faecium that previously had been given an antibiotic cocktail to clear other resident gut microbiota which could potentially interfere with the effects of E. faecium.
Antibiotic treatment usually dampens the activity of IEC proteins; however, IEC proteins in E. faecium-treated mice were restored, thus enhancing intestinal barrier integrity and immunity in response to S. Typhimurium and C. difficile. In contrast, mice without E. faecium were deficient in the same IEC proteins and suffered liver invasion by pathogens, indicating breaches in the intestinal barrier. In agreement with the Rangan et al. study, the researchers also demonstrated that E. faecium-based protection was mediated by SagA, although in a different manner, which requires epithelial expression of pattern recognition receptor components and antimicrobial peptides.
On the whole, these data provide scientific evidence that a commensal bacterium found in the intestines of mammals can be used to improve host intestinal barrier function and limit the pathogenesis of infections caused by S. Typhimurium and C. difficile.
Pedicord VA, Lockhart AAK, Rangan KJ, et al. Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Science Immunology. 2016; 1(3):pp. eaai7732. doi: 10.1126/sciimmunol.aai7732.
Rangan KJ, Pedicord VA, Wang YC, et al. A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science. 2016; 353(6306):1434-1437. doi: 10.1126/science.aaf3552.
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