During birth, the fetus emerges into the world almost completely sterile of bacterial life. But the end of the first day, the baby has been held to her mother’s breast, has been lifted by nurses and doctors, has taken the first breaths of the air in the maternity ward, and by nightfall, the baby’s gut is already teeming with all manner of prokaryotic immigrants. The first bacterial pioneers of the infant are descendants from the mother’s gut and birth canal. They willingly take residence in the neonatal gut, arriving in waves with each kiss and caress. The first are often the E. coli and the streptococci; by the end of the week, the infant intestine is home to thriving colonies of the Bacteroides, Bifidobacterium, and Clostridium.
These events during infancy resemble the changes that occur in a natural ecosystem. They are a concern to modern medicine – but doctors are hardly ecologists. But we find ourselves borrowing their language, referring to the gut microbes are flora and describe each wave of bacterial transformation as ecological succession and try to define the varying niches. It’s almost as though we are speaking about the growth of saplings in a new forest. But when we talk about infections in the gut, we forget our ecology and talk doctor. “Three days of cipro ought to take care of it,” we say, flipping over a prescription pad and shuttling the patient off to the nearest pharmacy. The ecologist is hardly so naïve.
The Problem of C. Difficile
Infections, the ecologist knows, is a matter of great complexity. For example, finding C. diff in the stool is not always the mark of illness. During the first year of life, more than half of infants may harbor this organism in the gut – in fact – C. difficile is one of the first, natural bacterial pioneers of the infant intestine. The baby is almost never symptomatic. As the year passes by, other organisms grow and evict C. difficile from its narrow anaerobic niche. In nature, C. difficile almost never returns to the gut – its time is restricted to a pioneer occupancy.
But our ignorance of ecology has led to a big problem. Our constant use of antibiotics give us the power to hurtle the adult gut back to its sterile origins, giving C. difficile the opportunity to bloom again, as it did when the patient was an infant. Within a couple days of taking ciprofloxacin, a multitude of species die along with the targeted pathogen. It’s an action akin to burning down a forest in order to kill a single vermin. It’s no surprise that through such repeated firestorms that a more toxigenic and resistant strain of C. difficile has emerged that may be causing up to 20,000 deaths in the United States every year. This is not a problem we can solve if we keep thinking like doctors. The solution is not solely in our discipline. We must delve into the niche of the ecologist.
An Ecologic Solution
This week’s NEJM proposes a solution that transcends medicine and uses ecologic principles to treat adult Clostridium difficile associated disease where our traditional medical approaches have failed. In the gut, the use of antibiotics produces a fallow environment. Clostridium difficile and other species quickly fill this vacancy. To prevent the organism for achieving dominance and causing C. difficile associated disease, ecologic succession can be promoted towards a healthy microbiota through the use of prebiotics (compounds that promote the growth of beneficial microbes), probiotics (specific microbes) targeted antibiotics (that are narrow-range) or – at the greatest extreme – fecal transplantation, in which an entire segment of a donor’s microbial ecosystem is transplanted into the host.
The authors of this week’s study take this approach. As doctors, we are unfamiliar with using biologic ecosystems as treatments (although with the use of antibiotics, we have been fond of destroying ecosystems for almost a century). Fecal transplantation is the most profound form of ecologic manipulation to date. Although the treatment has great efficacy in the resolution of C. difficile-associated diarrhea compared to vancomycin, it remains unclear whether such a treatment confers a stable flora over time. Furthermore, while such profound floral manipulation evicts C. difficile from the gut, its effect on the other ecological niches is unknown. The gut microbiota plays a critical role in the digestion and uptake of nutrients and the metabolism of sugars and fats. Perhaps even more importantly, the gut microbiome is in tight alliance with the large and comprehensive network of immune cells that patrol the other side of the mucosal wall. Perturbations in the flora ripple throughout every ecologic niche in the gut – such ripples are also felt in the local and remote immune system.
Fecal transplantation is, in many ways, the antithesis of treatment with broad-spectrum antibiotics. Both interventions, however, vastly alter microbial ecology. Thus far, we have no practical measures to monitor how the gut flora evolves over time within a single individual. In addition to further clinical trials in fecal transplantation, examing how these ripples affect the host’s ecology, metabolism, and immune system longitudinally are warranted. A comprehensive medical, microbiological, and ecological approach will ensure that we are being led down the right garden.