Fecal microbiota transplantation: current challenges and future landscapes

Abstract

SUMMARYGiven the importance of gut microbial homeostasis in maintaining health, there has been considerable interest in developing innovative therapeutic strategies for restoring gut microbiota. One such approach, fecal microbiota transplantation (FMT), is the main "whole gut microbiome replacement" strategy and has been integrated into clinical practice guidelines for treating recurrent Clostridioides difficile infection (rCDI). Furthermore, the potential application of FMT in other indications such as inflammatory bowel disease (IBD), metabolic syndrome, and solid tumor malignancies is an area of intense interest and active research. However, the complex and variable nature of FMT makes it challenging to address its precise functionality and to assess clinical efficacy and safety in different disease contexts. In this review, we outline clinical applications, efficacy, durability, and safety of FMT and provide a comprehensive assessment of its procedural and administration aspects. The clinical applications of FMT in children and cancer immunotherapy are also described. We focus on data from human studies in IBD in contrast with rCDI to delineate the putative mechanisms of this treatment in IBD as a model, including colonization resistance and functional restoration through bacterial engraftment, modulating effects of virome/phageome, gut metabolome and host interactions, and immunoregulatory actions of FMT. Furthermore, we comprehensively review omics technologies, metagenomic approaches, and bioinformatics pipelines to characterize complex microbial communities and discuss their limitations. FMT regulatory challenges, ethical considerations, and pharmacomicrobiomics are also highlighted to shed light on future development of tailored microbiome-based therapeutics.

Keywords: Clostridioides difficile infection; donor screening; fecal microbiota transplantation; human microbiome; microbial engraftment.

Fig 1

Multi-modal impact of indigenous and environmental factors on the gut microbiota. Several factors contribute to the structure and maintenance of a healthy gut microbiota (genetics, diet, birth mode, and lifestyle), while others could disrupt the microbial composition (medications, stress, western diet, and diseases) and trigger inflammatory responses. Microbiome disturbance reduces the thickness of the mucus layer and stimulates the production of inflammatory cytokines IFN-γ, TNF-α, and IL-1β. Intestinal inflammation and microbial disturbance further disrupt the indigenous composition of the host microbiome.

Fig 2

Main pathogenic mechanisms of C. difficile infection. TcdA binds to the host colonic epithelial cells by glycans and sGAGs, while cognate receptors for TcdB include glycans, nectin 3, CSPG4, and FZD1/2/7 (46). The CDT toxin binds to LSR and undergoes proteolytic cleavage, and CDTa accelerates actin cytoskeleton breakdown and may ultimately facilitate C. difficile adherence (47). C. difficile cell wall PG can stimulate CXCL1 production and neutrophil infiltration in a NOD1-dependent manner (48). C. difficile SLPs are involved in DC maturation and stimulation of inflammatory responses through TLR4 activation (49). Moreover, C. difficile flagellin detection by TLR5 stimulates the activation of MYD88 in the host epithelial cells (50). CSPG4, chondroitin sulfate proteoglycan 4; CXCL1, CXC chemokine ligand 1; FZD1, frizzled 1; LSR, lipolysis-stimulated lipoprotein receptor; NOD1, nucleotide-binding oligomerization domain 1; PG, peptidoglycan; sGAG, sulfate glycosaminoglycan; SLP, surface layer protein.

Fig 3

Evolution of FMT in clinical practice and research. The timeline describes the history of FMT-based therapy and key clinical studies for different disorders.

Fig 4

Registered clinical trials of FMT application as of July 2023. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; MDRO, multidrug-resistant organism.

Fig 5

Pre- and post-FMT mechanisms underlying the interplay between microbiota and immune system. Before FMT administration, disturbed microbiota can stimulate immune responses that eventually lead to chronic inflammation. Following FMT, microbial restoration is accompanied by high production of anti-inflammatory cytokines, SCFAs, IgA, IgG, and antimicrobial peptides. Immune and metabolite homeostasis results in inflammation amelioration and repair of mucosal layer and epithelial barriers.

Fig 6

Multi-omics approaches and their application in future studies. (A) FMT procedure from healthy donor microbiota to clinical outcomes of the recipient. (B) 1. In a reductionist approach, only one organ is considered, while a holistic approach considers multiple organs at the same time. 2. Due to genetic and environmental variations between human and animal models, organ-on-a-chip can provide new approaches in microbiome studies. 3. Types of artificial intelligence strategies currently used for omics data analysis and interpretation. 4. An example of data integration by multi-omics approach.