Restoration of the gut microbial habitat as a disease therapy

David A Relman¹

Journal name:: Nature Biotechnology
Volume:: 31,
Pages:: 35–37
Year published:: (2013)
DOI:: doi:10.1038/nbt.2475

Published online: 09 January 2013

An intestinal infectious disease that is difficult to treat is cured by a defined set of bacterial species.

Microbial communities associated with humans or other animals tend to resist invasion by exotic species. But when 'colonization resistance' is lost, owing to antibiotic use, immunosuppression or other causes, the result can be difficult-to-control infections by invasive species or 'blooms' of indigenous opportunistic pathogens. The subsequent disease promotes further disruption of the gut microbiome, which in turn perpetuates the pathology. Thus, the disease might be both prevented and treated by manipulating the composition of the microbial community. A recent paper by Lawley et al.¹ in PLoS Pathogens describes a useful experimental mouse model of colitis associated with Clostridium difficile, a pathogen that causes debilitating and sometimes fatal disease in humans. Using this model, the authors characterized healthy and diseased murine intestinal microbiota and showed that administration of a set of bacterial species representative of those in healthy animals succeeded in curing this recalcitrant infection.
The robustness of complex microbial communities to invasion is especially common in human- and animal-associated communities, and arises because both the microorganisms and the host act to limit the niche opportunities for 'outsiders'^{2, 3, 4}. Competitive exclusion of invasive species by the gut microbiota was first demonstrated in the 1950s and 1960s by studies in which pretreatment of animals with antibiotics was shown to markedly enhance the ability of invasive exotics, such as Salmonella spp., to colonize the intestinal tract and cause disease⁵. Today, one of the most clinically important examples of an invasive bacterial species is C. difficile. In addition to producing toxins that elicit a profound inflammatory response in the colon, it destabilizes the indigenous microbiota and diminishes intestinal microbial diversity, leading to a new, alternative and disease-associated stable state⁶. C. difficile is not native to the human intestinal microbiota but is well-equipped to invade and proliferate in the ecological niche that emerges after antibiotic treatment. Clostridium difficile–associated disease (CDAD) is difficult to treat, and if suppressed, often relapses.
In recent years, increasing numbers of treatment-resistant or recurrent cases in humans, and growing frustration—even desperation—by clinicians and patients have prompted a resurgence of interest in a therapeutic approach with roots in medical practice of old, namely fecal microbial transplantation. CDAD has been cured by instilling feces from healthy donors into either the upper or lower intestinal tracts with a tube. In a study of colonoscopic fecal transplantation with a mean of 17 months of follow-up, diarrhea resolved in 74% of patients within 3 days and in 91% within 90 days⁷. The resulting taxonomic composition of the intestinal microbiota resembles that of the fecal donor and presumably reflects whole-scale replacement of the microbial community. Nevertheless, long-term stability of this transplanted community in human recipients has not been confirmed, and questions about possible transmission of pathogens (including viruses), lack of standardization and poor characterization of the donor material means that this procedure leaves much to be desired.
The development of effective treatments for CDAD has long been thwarted by both an inadequate understanding of the factors that maintain infection with this bacterium and the lack of a good model for studying disease pathology and treatment strategies. Lawley et al.¹ began by developing a new animal model of CDAD that recapitulates many key features of the human disease. They introduced a particularly virulent, epidemic strain of C. difficile into mice, followed by a 1-week course of antibiotics. This induced a disturbance in the intestinal microbiota, proliferation of C. difficile and a persistent 'supershedder' state lasting months, accompanied by intestinal disease, an altered intestinal microbiota with reduced diversity and a prolonged contagious period.
The similarities of pathogenesis and disease progression in this model to the course of CDAD in humans make this a good model for testing potential therapies. Notably, the authors were able to reproduce the beneficial effects of fecal microbial transplantation, allowing them to test the efficacy of simplified mixtures of fecal isolates from healthy mice. From among the set of mouse microbiota strains that they were able to cultivate, they chose to inoculate strains that were representative of the community diversity in healthy mice. They found that a mixture of six phylogenetically diverse bacteria (Staphylococcus warneri, Enterococcus hirae, Lactobacillus reuteri and three novel species, Anaerostipes sp. nov., Bacteroidetes sp. nov. and Enterorhabdus sp. nov.), but not a mixture of Lactobacillus and Bacteroides species alone, was successful in suppressing the C. difficile supershedder state, eliminating pathology and contagiousness, and shifting the community composition back toward the profiles associated with health (Fig. 1).