TRANSLATIONAL MEDICINE : BENCH TO BEDSIDE

Clostridium difficile infection (CDI) affects a broad population and has become sowidespread the Centers for Disease Control and Prevention rated C. difficile as an urgent threat in 2013. Recent basic-science research has focused on understanding the pathogenesis of the disease and alterations in the microbiome causing susceptibility. This manuscript will address two studies likely to influence future understanding and management. Symptomatic CDI results from the bacterial production of two main toxins, toxin A and toxin b (tcdA/B). By increasing colonic mucosal permeability via disruption of cell signaling and their tight junctions, these toxins cause cytoskeletal degradation and death. One therapeutic target for CDI is neutralization of tcdA/B, however, treatment with broad intravenous immunoglobulin has had disappointing results. Successive studies showed that patients who are able to elevate their serum immunoglobulin to tcdA are 48 times less likely to have symptomatic initial CDI and following CDI less likely to get recurrent disease. Serum immunoglobulins targeting the tcdA/B have become a target for vaccinations and treatment. Human monoclonal antibodies (HMabs) to C. difficile tcdA/B have shown promising results in the treatment of CDI in hamster and piglet models. In humans, this supplementary infusion to primary antibiotics has shown remarkably lower recurrence rates. Given these encouraging findings, a study was designed to clarify how these targeted serum antibodies access the colonic lumen. In total, 23 gnotobiotic piglets were randomized into three groups. Twelve received a pathogenic CDI, nine a non-pathogenic strain and two no C. difficile; HMab to tcdA/B were given to each piglet. The piglets were then euthanized 2–4 days after antibody infusion and samples taken of the serum, gastrointestinal contents, and the gastrointestinal tissue. Using enzyme linked immunosorbent assay, concentrations of the infused antibodies in each location were measured and compared. All animals had a similar distribution and concentration within the mucosa of the small and large bowel. HMab was only in significantly elevated concentrations within the colonic lumen of those with pathogenic CDI. When comparing the active study subjects with four historical controls receiving pathogenic CDI with HMab that was irrelevant, those given HMab targeting tcdA/B had less severe disease (defined by ratings of histopathology and symptom score) and lower mortality despite similar colonic concentrations of pathogenic bacteria. The mechanism of translocation remains unclear but a priori hypotheses included either direct leakage across the colonic lumen or active transport through neonatal Fc receptors (FcRn). FcRn are selectively expressed during various infections and have a significant role regulating IgG transport into the colonic lumen. In CDI, FcRn are expressed in both pathogenic and non-pathogenic disease. As HMab was found luminally only in those with pathogenic CDI, transmucosal passage via FcRn is a less likely explanation. Access to the colonic lumen via direct leakage across the inflamed mucosa is the most probable process enabling access of HMab to the colonic lumen where blockage of tcdA/ B occurs. Therapy for CDI must be luminally active, which is why only oral vancomycin is effective, whereas both oral and intravenous metronidazole are metabolized by the liver and excreted in an active form within the biliary tree and the fecal stream. Cohen et al. showed the selective colonic distribution of HMAb to tcdA/B in those with pathogenic CDI showing the toxicity of the infection directing therapeutic distribution. By having targeted access to the active inflammatory sites of infection, this therapy is believed to temper the inflammatory response preventing severe infection and resultant poor outcome. Further investigation is required to clarify HMab’s colonic concentrations when antimicrobial therapy has minimized the inflammatory response and why this treatment seems to be associated with decreased rates of recurrence. It is possible that by containing the inflammatory response, this therapy can enhance the antibiotic’s efficiency of CDI eradication, reducing the post-treatment bacterial volume thereby minimizing recurrence. These exciting findings by Cohen et al. support this therapy’s efficacy and could be utilized for the development of future targeted treatment. CDI therapy ideally targets C. difficile alone minimizing effects on the remainder of the microbiome. HMab to tcdA/B is not believed to have bactericidal or bacteriostatic function making monotherapy unlikely to be effective. Without antibacterial properties, this therapy doesminimize the effects on themicrobiomemaking it an ideal supplement to standard therapy. Where this fits in the therapeutic spectrum remains unclear with an ongoing phase III trial in humans underway. Depletion of colonization resistance is a significant risk factor for both initial and recurrent CDI. By replacing the depleted microbiome of an individual with C. difficile, fecal microbiota transplantation has been shown to be an effective therapy for Citation: Clinical and Translational Gastroenterology (2015) 6, e92; doi:10.1038/ctg.2015. 13 & 2015 the American College of Gastroenterology All rights reserved 2155-384X/15