The average human has about the same number of microbes as cells in the body, which stand at approximately 3.8 × 1013 (Sender et al. 2016). These bacteria generally provide many benefits to the host such as protection from colonization by invading pathogenic microbes like Escherichia coli and Salmonella typhimurium.
However, the widespread use of antibiotics has disrupted this symbiotic relationship. Antibiotics function by eliminating the invading pathogenic bacteria, while at the same time removing the beneficial bacteria as well. Consequently, continued antibiotic use results in fewer “good” bacteria in the body to protect against subsequent infections. This developed resistance to antibiotics is well established for many common microbial infections, and is considered by the World Health Organization as a major threat to public health globally. There is currently no new class of antibiotics available to address antibiotic resistance; therefore new therapies are greatly needed.
One approach to address this has been through the use of probiotics, which are beneficial microorganisms (Ouwehand et al. 2016). Probiotics have the potential to induce the protective effects of antibiotics without the unfavorable side effects. They are generally administered as a preventative measure to replace commensal bacteria lost after antibiotic use. Maintaining a balanced microbiota through the use of probiotics has been shown to reduce the risk for specific infectious diseases and thus reduce the need for antibiotics (Ouwehand et al. 2016).
Two seminal studies demonstrating the mechanisms associated with the protective effects of certain probiotic bacteria were published in the journals Science and Science Immunology in 2016 by researchers at the Rockefeller University.
These studies showed that both mice and the roundworm Caenorhabditis elegans were protected from the harmful effects of S. typhimurium infection. The animals were fed Enterococcus faecium before oral infection with S. typhimurium, and although S. typhimurium could still colonize the animals, survival was increased in animals fed E. faecium (Pedicord et al. 2016, Rangan et al. 2016). The mechanism responsible for the protective effects of E. faecium was shown to involve the peptidoglycan hydrolase, secreted antigen A (SagA), which is highly secreted by E. faecium following S. typhimurium infection (Rangan et al. 2016). SagA was also shown to induce this effect when expressed by other bacteria such as Lactobacillus plantarum, which naturally inhabits the human gut.
SagA functions by cleaving bacterial peptide fragments that in turn stimulate the tol-1 protein, a Toll-like receptor 1 (CD281) homolog expressed on intestinal epithelial cells. SagA also protected mice from Clostridium difficile infection, and this was dependent on the gut epithelial expression of antimicrobial peptides such as RegIIIγ and innate immune receptors such as MyD88 and NOD2 (Pedicord et al. 2016).
C. difficile is a leading cause of hospital infections and treatment with antibiotics often leads to relapse. S. typhimurium generally infects the epithelial lining of the gut causing diarrhea, fever, and abdominal cramps in humans. In some instances, S. typhimurium can be fatal. Therefore, use of E. faecium to treat C. difficile and S. typhimurium infections could have significant clinical benefit.
Another recent study demonstrates the beneficial effects of commensal bacteria on the skin (Nakatsuji et al. 2017). Staphylococcus aureus is a pathogenic bacteria associated with atopic dermatitis. Nakatsuji et al. demonstrated that the commensal skin bacteria Staphylococcus epidermidis and Staphylococcus hominis produce an anti-microbial peptide that inhibits S. aureus growth. An autologous transfer of S. epidermidis and S. hominis in patients with atopic dermatitis significantly reduced the S. aureus skin burden and improved the condition. This commensal skin transplant has been approved by the U.S. Food and Drug Administration, and a clinical trial is currently underway for treating atopic dermatitis.
These studies emphasize the therapeutic benefits of commensal bacteria. Antibiotics often eliminate these beneficial bacteria, which further increases susceptibility to antibiotic-resistant infection. Further studies are needed to fully elucidate the mechanisms by which commensal bacteria protect against pathogenic bacteria, as well as to develop novel strategies to reintroduce these beneficial bacteria in patients with debilitating pathogenic microbial infections.
To learn more about mucosal immunity, specifically in the gut, check out our mini-review on The Mucosal Immune Response in Health and Disease. You can also find antibodies to key markers of the intestinal mucosal immune system.
Nakatsuji T et al. (2017). Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 9, pii: eaah4680.
Ouwehand AC et al. (2016). Probiotic approach to prevent antibiotic resistance. Ann Med 48, 246-255.
Pedicord VA et al. (2016). Exploiting a host-commensal interaction to promote intestinal barrier function and enteric pathogen tolerance. Sci Immunol 1, pii: eaai7732
Rangan KJ et al. (2016). A secreted bacterial peptidoglycan hydrolase enhances tolerance to enteric pathogens. Science 353, 1434-1437.
Sender R et al. (2016). Revised estimates for the number of human and bacterial cells in the body. PLoS Biol 14, e1002533.