Is a Newly Discovered Bacterium Causing Cord Colitis Syndrome?
Abstract & Commentary
By Joseph F John, Jr., MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for Education, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, co-editor of Infectious Disease Alert. Dr. John reports no financial relationships with this field of study.
SYNOPSIS: It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. The authors assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests a newly discovered bacterium, which was provisionally named Bradyrhizobium enterica.
SOURCE: Bhatt AS, Freeman SS, Herrera AF, et al. Sequence-based discovery of Bradyrhizobium enterica in cord colitis syndrome. New Engl J Med 2013;369:5617-28.
We have come into an age of discovering non-culturable pathogens and commensals. Many microbial surprises await. The latest surprise comes from a study of a new entity called cord colitis, a term coined in 2011 via the New England Journal of Medicine. Cord colitis is a diarrheal illness in patients undergoing hematopoietic stem-cell transplantation (HSCT) with umbilical cord cells. The role of the cord cells and the actual cause of the enterocolitis remained unknown. The symptoms of the illness have responded in previous patients to antibacterial agents (ciprofloxacin and metronidazole) so there was a suspicion that the illness was infectious in origin. An army of investigators at Harvard hospitals and Memorial Sloan-Kettering Cancer Center in New York embarked on a molecular journey to discover if there was an infectious component to the disease.
Complex DNA extraction and amplification was performed on 16 of 23 colonic biopsy specimens from 11 patients with cord colitis. Most of the patients had a lymphoma or leukemia, ablation therapy antibiotic therapy and enterocolitis. Initial DNA sequence analysis suggested that the DNA was from a plant bacterium known as Bradyrhizopium, and the new species was named B. enterica. The new genome was pieced together from biopsy specimens using computer software, then compared to a known species, B. japonicum. The size of the genome compared to other bradyrhisopium species with about 7112 potentially expressed proteins. On a phylogenetic tree, B. enterica linked closely to B. japonicum.
In the extracted DNA there was present sequence from other known bacteria but in much less abundance. For example after 600,000 reads for B. enterica, the next most common bacterial DNA were in base pairs fewer by a log 2 and included Delftia acidovorans, Stenotrophermonas maltophilia, other deftia species, Proprionobacterium acnes, Ralstonia pickettii, and several Pseudomonas species. In qualitative analysis searching for B. enterica DNA in control colonic specimens, none was found. In a patient with cord colitis, B. enterica DNA was found not only in colonic specimens but also in gastric and duodenal biopsy specimens. In one patient, the B. enterica DNA intensity decreased by 84% after antimicrobial therapy.
Before this study, bradyrhizopia had not been reported as human pathogens. Indeed, they are nitrogen-fixing species, endosymbionts such as B. japonicum, used in commercial agriculture. The suspected pathogen B. enterica actually has lost its nitrogen-fixing genes and replaced them with ones that are potentially related to pathogenic potential, filamentous hemagglutins used for binding in some pathogens like Bordetella pertussis that causes whooping cough. This new bacterium and perhaps other bacteria from the ecosphere may be evolving into potential human pathogens using mobile genetic elements to survive in human hosts while sacrificing genes vital for survival in the ecosphere.
An excellent accompanying editorial, Eric Pamer, MD, notes that some immune reconstitution is needed for B. enterica to colonize human epithelium cells. He further suggests that a combination of epithelial damage, changes in gut microbiome, and altered immune function may be factors. Thus, the quandary arises whether B. enterica is a causal pathogen or a subsequent commensal (colonizer). Certainly its preponderance suggests the former but we have been fooled before by new organisms appearing to be pathogenic. Let us see the impact of more microbial molecular data in this unusual disease of modern man.
1.Pamer, EG. Cuffed and Exposed — Perp-Walking Bradyrhizobium. Editorial. N Engl J Med 2013; 369:572-574