Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

Abstract

Beneficial microorganisms hold promise for the treatment of numerous gastrointestinal diseases. The transfer of whole microbiota via fecal transplantation has already been shown to ameliorate the severity of diseases such as Clostridium difficile infection, inflammatory bowel disease, and others. However, the exact mechanisms of fecal microbiota transplant efficacy and the particular strains conferring this benefit are still unclear. Rationally designed combinations of microbial preparations may enable more efficient and effective treatment approaches tailored to particular diseases. Here we use an infectious disease, C. difficile infection, and an inflammatory disorder, the inflammatory bowel disease ulcerative colitis, as examples to facilitate the discussion of how microbial therapy might be rationally designed for specific gastrointestinal diseases. Fecal microbiota transplantation has already shown some efficacy in the treatment of both these disorders; detailed comparisons of studies evaluating commensal and probiotic organisms in the context of these disparate gastrointestinal diseases may shed light on potential protective mechanisms and elucidate how future microbial therapies can be tailored to particular diseases.

Keywords: Clostridium difficile; fecal microbiota transplantation; microbiota; probiotics; ulcerative colitis.

FIG 1

The gastrointestinal mucosa in health, CDI, and UC. (A) The healthy mucosa is characterized by a diverse microbiota that confers colonization resistance and proper immunomodulation; few freely available nutrients; low levels of primary bile salts relative to secondary bile salts; secretory antibody capable of sequestering commensals, pathogens, and other antigens; an intact barrier with healthy epithelial cells and thick layers of mucus containing antimicrobial peptides; few immune cells; and a cytokine milieu dominated by anti-inflammatory cytokines such as IL-10 and TGF-β. (B) Disruption of the microbiota results in increased nutrients permissive for C. difficile growth (1) and high concentrations of primary bile salts relative to secondary bile salts (2). These changes promote C. difficile spore germination and growth to high concentrations within the intestine. C. difficile toxins damage epithelial cytoskeletal components, leading to cell death and ulcerations (3). Probiotics may promote colonization resistance through multiple mechanisms, including competition for nutrients and the generation of secondary bile salts that prevent C. difficile germination. Probiotics may also directly inhibit the growth of C. difficile by producing bacteriocins or other inhibitory compounds. Some probiotics produce antitoxin proteases and may stimulate antibody production to sequester C. difficile and toxin. Reinforcing epithelial barriers and modulating inflammation may also promote healing and limit injurious host responses to infection. (C) Ulcerative colitis is characterized by an altered microbiota of decreased diversity (1), damage to the gastrointestinal epithelium (2), as well as aberrant, overly inflammatory host immune responses (3). By helping to maintain a normal microbiota and reinforce the barrier function of the epithelium, probiotics may limit exposure to inflammatory signals. Modulation of the mucosal immune system, including the cytokine milieu, neutrophil infiltration and function, and T cell differentiation, may also help redress aberrant responses to luminal antigens and prevent host-mediated damage to the mucosa. Abbreviations: IEC, intestinal epithelial cell; IFN, interferon; IL, interleukin; TcdA and TcdB, C. difficile toxins A and B, respectively; TGF, transforming growth factor; TNF, tumor necrosis factor.

FIG 2

Summary of bile salt metabolism. Primary bile salts (1°) produced by the host liver are modified and deconjugated by intestinal bacteria to form secondary bile salts (2°). Bile salts that stimulate the germination of C. difficile spores and thus increase susceptibility to CDI are shown in red. Bile salts that are known to inhibit the sporulation or outgrowth of C. difficile and therefore contribute to colonization resistance are shown in blue. Probiotics with 7-hydroxysteroid dehydrogenase activity may enhance colonization resistance by decreasing the intestinal levels of glycocholate, taurocholate, and cholate and by increasing the levels of deoxycholate.

FIG 3

Epithelial cell junctional complex. Junctional complexes hold together adjacent epithelial cells. Tight junctions at the apical end of junctional complexes are composed of occludin and claudin proteins that span the intercellular space and bind intracellular adapter proteins, such as zonula occludens (ZO) complex proteins. Adherens junctions are composed of E-cadherins and adapter proteins. Desmosomes are formed of desmoglein and desmocollin proteins that bind internal adapter proteins. Adapter proteins associated with tight junctions, adherens junctions, and desmosomes in turn bind components of the cytoskeleton, including F-actin or intermediate filaments.