In the mammalian gut, microbial populations can act as puppet masters of the immune system, influencing host response in health and disease. Antibiotics can disrupt these communities, reconfiguring the microbiome to favor pro-inflammatory bacteria. Once this shift has occurred, newly dominant bacteria send signals to promote their own survival even after antibiotic treatment is completed, according to Eric Pamer of the Memorial Sloan- Kettering Cancer Center in New York, N.Y. This signaling prevents anti-inflammatory microflora from repopulating, and can lead to chronic inflammation and heightened immune responses, damaging host tissues and organ systems.

Pamer and other researchers convened at the "Microbiota and Mucosal Immunity: The Interface of Health and Disease" meeting in San Francisco, Calif., last April to discuss findings that highlight how microbiome disturbances influence chronic diseases in the host. Some participants suggest that antibiotic- induced changes in gut microflora account for the increasing prevalence of chronic conditions such as obesity, diabetes, and autoimmune disorders.

Pro-inflammatory bacteria in the gut may trigger inflammatory bowel disease (IBS), attributed to autoimmune attack of the small intestine in Crohn's disease or the colon in ulcerative colitis, according to another meeting participant, Thaddeus Stappenbeck of Washington University in St. Louis, Mo. The host gene Atg16L1, which increases the risk for IBS by 50%, impairs innate antimicrobial defenses and reduces the output of mucus from gut epithelial cells, creating an environment where pro-inflammatory, gram-positive bacteria thrive, he says. Indeed, the microbiomes of IBS patients are skewed heavily towards such species.

The possibility that antibiotics might correct such responses by controlling bacterial populations in the gut of IBS patients is now being testing in clinical trials. However, such treatments may further perturb the situation, according to Marta Wlodarska of the University of British Columbia in Vancouver, British Columbia, Canada. Thus, for example, metronidazole might do more harm than good by promoting the growth of Clostridium and exacerbating colitis in mice-a model for IBS in humans.

Antibiotics may prove similarly damaging for leukemia and lymphoma patients. Before such patients receive bone marrow transplant (BMT), they or other BMT recipients are treated with drugs and irradiation to shut down the immune system, preventing rejection of transplanted cells. Because this treatment leaves such patients especially vulnerable to infections, they typically also are treated with antibiotics to protect against bacterial pathogens. However, according to Robert Jenq and Carlos Ubeda of the Memorial Sloan-Kettering Cancer Center, ampicillin treatment may favor pro-inflammatory bacteria in the gut, generating hyperactive immune responses and thus driving graft versus host (GVH) disease. GVH occurs when donor immune cells that are part of the BMT attack recipient tissues, including skin, liver, lungs, gastrointestinal tract and exocrine glands, leading to serious complications and death. As a possible remedy, Jenq and Ubeda are evaluating whether administering probiotic Lactobacillus after antibiotics can help to maintain a healthy microbiome and reduce the incidence of GVH.

Meanwhile, other antimicrobial agents, including vancomycin, neomycin, and metronidazole, promote the growth of pro-inflammatory bacteria in the gut, according to Pamer. In the context of BMT, however, using them to treat patients may increase their risk of developing vancomycinresistant enterococcus (VRE) infections. Thus, antibiotic treatments aimed at preventing infections may do just the opposite, suggesting that something is wrong with this standard of care, he says. As a potential alternative, he is investigating supplementing antibiotics with purified molecular components from gram-negative bacteria, such as lipopolysaccharide and flagellin. These molecules provide signals that might help to promote survival of anti-inflammatory microflora and to prevent growth of VRE. In mice, such treatments significantly reduce systemic VRE infections, he says.

Shannon Weiman
Shannon Weiman is a freelance science writer based in San Francisco, Calif.