American Journal of Gastroenterology Lecture

Intestinal Microbiota and the Role of Fecal Microbiota Transplant (FMT) in Treatment of C. difficile Infection

Lawrence J Brandt MD; MACG

Disclosures

Am J Gastroenterol. 2013;108(2):177-185. 

In This Article

CDI and FMT: Pathophysiology and Rationale

The rationale for FMT in patients with recurrent CDI lies in the belief that CDI results when the community of organisms residing in the gastrointestinal tract is perturbed and that persisting imbalance, or dysbiosis, explains the high CDI recurrence rates of 10–20% after initial antibiotic therapy and up to 40–65% in patients who are retreated for a second episode.[32] It is believed that reintroduction of normal flora via donor feces corrects the imbalance, restores both phylogenetic richness and colonization resistance, and thereby enables recovery of normal bowel function; this contrasts with the chronic use of antibiotics, which, in a sense, perpetuates the very condition that lead to the initial episode of CDI, namely an altered intestinal microbiome. In an elegant series of experiments, Lawley et al.[33] treated mice with clindamycin for 7 days and then infected them with C. difficile (genotype 027/BI) isolated from hospitalized patients. They showed that the mice went on to develop highly contagious, chronic disease with persistent dysbiosis characterized by: (1) a simplified microbiota with reduced phylotypic diversity; (2) opportunistic pathogens (e.g., Klebsiella pneumonia, E. coli, Proteus mirabilis, Parabacteroides distasonis, and Enterococcus faecalis— all of which have been identified in the microbiota of humans with chronic CDI;[34] (3) upregulated pro-inflammatory genes—particularly those known to promote neutrophil infiltration; (4) and altered metabolite production, similar to that which occurs in the human immune response to CDI. Specifically, they demonstrated a disturbance in fecal short- chain fatty acids, which are the end-products of intestinal bacterial metabolism of ingested complex carbohydrates. This disturbance included a reduction in butyrate and acetate, which are the main nutrient sources for the colon and an increase in succinate levels; of note, there was an increase in P. disasonis, which is a succinate producer. Acetate and butyrate influence a wealth of functions in the colon; acetate: crypt cell proliferation, motility, blood flow, adipogenesis, and cellular immunity; butyrate: colonocyte health, inflammation, intestinal permeability, inflammation, apoptosis, cell growth and differentiation, and barrier function, to name but a few.[35] Lawley et al.[33] then demonstrated that vancomycin administration was associated with suppression of C. difficile excretion and that upon cessation of treatment relapse occurred, just as in the human who has recurrent CDI. FMT using homogenized feces from a healthy mouse and given by oral gavage, suppressed C. difficile shedding for months. Finally, these authors reasoned that introduction of a phylogenetically diverse but limited bacterial mixture might trigger recovery of the intestinal ecosystem and disrupt the stability of the microbiota of the mice with chronic CDI. Ultimately they fashioned a mixture of six physiologically diverse species including both obligate and facultative anaerobes that resolved the CDI. This series of experiments addresses the major concepts involved in trying to understand the pathophysiology of the effectiveness of FMT in treating patients afflicted with chronic, recurrent CDI. (Figure 3): (1) perturbation of the intestinal microbiota, (2) colonization and establishment of C. difficile, which allows (3) persistence of a disturbed intestinal microbiota with (4) altered intestinal fermentation, and (5) loss of nutrients to the bowel; (6) FMT induces re-establishment of microbiota diversity and (7) termination or suppression of C. difficile colonization. It is likely that the colitis seen with chronic CDI is also associated with increased colonic permeability that is worsened by the reduction in butyrate and acetate and which then facilitates colonic protein loss with hypoalbuminemia, and bacterial translocation with sepsis, especially in cases of severe CDI.

Figure 3.

Role of antibiotics and C. difficile in perturbing Intestinal homeostasis and the corrective effect of fecal microbiota transplantation (FMT). Intestinal homeostasis (a) is characterized by a diverse, stable microbiota. Antibiotic perturbation (bc) kills susceptible bacteria resulting in a less diverse community structure with loss of colonization resistance. In the absence of opportunistic infection, the microbiota usually recovers its diversity (d) to re-establish homeostasis and colonization resistance (a). Exposure to C. difficile (e) after antibiotic perturbation (b), however, can lead to persistent dysbiosis (f). Bacteriotherapy or FMT can disrupt the dysbiosis (g) allowing clearance of C. difficile (h) and re-establishment of intestinal homeostasis (a). Modified from Lawley et al. 33

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