Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

Abstract

Fecal microbiota transplantation (FMT) is a successful method for treating recurrent Clostridioides difficile (C. difficile) infection (rCDI) with around 90% efficacy. Due to the relative simplicity of this approach, it is being widely used and currently, thousands of patients have been treated with FMT worldwide. Nonetheless, the mechanisms underlying its effects are just beginning to be understood. Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C. difficile, but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids. Moreover, the modulation of the strong inflammatory response triggered by C. difficile after FMT seems to rely on a pivotal role of regulatory T cells, which would be responsible for the reduction of several cells and soluble inflammatory mediators, ensuing normalization of the intestinal mucosal immune system. In this minireview, we analyze recent advances in these immunological aspects associated with the efficacy of FMT.

Keywords: Clostridioides difficile; Dysbiosis; Fecal microbiota transplantation; Immunity; Mechanism; Pseudomembranous colitis.

Figure 1

Advantages and disadvantages of non-classical preparations methods of donor’s fecal material prior to fecal microbiota transplantation. ¹Classical preparation consist in dissolve donor’s fecal material by blending with saline water and filter out residual solid feces through gauze or fabric. ²Isolation of different bacteria strains directly from donor’s fecal material. ³Basically, this method consists in consecutively centrifugation of microbiota from donors to remove the supernadants. ⁴Uses filtration systens to retain debris and bacterial load from the donor’s fecal material. SCFAs: Short-chain fatty acids; AMPs: Antimicrobial peptides; BAs: Bile acids.

Figure 2

The immune response during recurrent Clostridioides difficile infection and after fecal microbiota transplantation treatment. A: During recurrent Clostridioides difficile (C. difficile) infection, the depletion of commensal microbiota results in higher levels of primary bile acids (BAs). These molecules are known to trigger the C. difficile vegetative state and its expansion, resulting in production of toxin (Tcd) A, TcdB, and TcdC, which cause apoptosis of enterocytes and release of interleukin (IL)-1 and IL-8 in the lamina propria (LP). Consequently, there is extensive recruitment of neutrophils dendritic cells, and macrophages and type 1 innate lymphocytes (ILC-1) in an attempt to cope with the infection. These cells produce pro-inflammatory cytokines including IL-6, IL-23, interferon (IFN)-γ, which induce Th17 and Th1 differentiation. This inflammatory state dominated by IL-17 and IFN-γ promotes tissue damage, which could spread along the intestines, and is accompanied with absence of innate ILC-2 and reduction of peripheral T regulatory (Treg) cells; B: The therapeutic effects of FMT involve the reestablishment of a wide variety of commensal microorganisms that directly and indirectly antagonize C. diffcile. Commensal strains that produce secondary Bas and short chain fatty acids are re-established, as well as the production of antimicrobial peptides by epithelial cells together with the reconstitution of the barrier integrity. These effects allow to reduce the activation of innate immunocytes, the expansion of Treg cells which produce IL-10, and subsequent normalization of Th1 and Th17 cell frequencies in the LP. IL: Interleukin; FMT: Fecal microbiota transplantation; TNF: Tumor necrosis factor; INF: Interferon; SCFAs: Short-chain fatty acids; AMPs: Antimicrobial peptides; TGF: Transforming growth factor; pBAs: Primary bile acids; sBAs: Secondary bile acids; DCs: Dendritic cell; ILC: Innate lymphoid cells; rCDI: Recurrent Clostridioides difficile infection; Treg: T regulatory; Macs: Macrophages.