Microbial-Based and Microbial-Targeted Therapies for Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBD), including Crohn's disease, ulcerative colitis, and pouchitis, are chronic, relapsing intestinal inflammatory disorders mediated by dysregulated immune responses to resident microbiota. Current standard therapies that block immune activation with oral immunosuppressives or biologic agents are generally effective, but each therapy induces a sustained remission in only a minority of patients. Furthermore, these approaches can have severe adverse events. Recent compelling evidence of a role of unbalanced microbiota (dysbiosis) driving immune dysfunction and inflammation in IBD supports the therapeutic rationale for manipulating the dysbiotic microbiota. Traditional approaches using currently available antibiotics, probiotics, prebiotics, and synbiotics have not produced optimal results, but promising outcomes with fecal microbiota transplant provide a proof of principle for targeting the resident microbiota. Rationally designed oral biotherapeutic products (LBPs) composed of mixtures of protective commensal bacterial strains demonstrate impressive preclinical results. Resident microbial-based and microbial-targeted therapies are currently being studied with increasing intensity for IBD primary therapy with favorable early results. This review presents current evidence and therapeutic mechanisms of microbiota modulation, emphasizing clinical studies, and outlines prospects for future IBD treatment using new approaches, such as LBPs, bacteriophages, bacterial function-editing substrates, and engineered bacteria. We believe that the optimal clinical use of microbial manipulation may be as adjuvants to immunosuppressive for accelerated and improved induction of deep remission and as potential safer solo approaches to sustained remission using personalized regimens based on an individual patient's microbial profile.

Keywords: Diet; Dysbiosis; Fecal microbiota transplantation; Live biotherapeutic products; Microbiota; Pouchitis; Prebiotics; Probiotics; Synbiotics.

Figure 1.

Graphic overview. The concept of manipulating microbiota to correct dysbiosis is a relatively new approach to treating inflammatory bowel disease (IBD). This review updates the status of current microbial-based and microbial-targeted therapies and prospects for future treatments in IBD. Tx: therapy, 5-ASA: 5-aminosalicylic acid, MTX: methotrexate, JAK: Janus kinase, IL: interleukin, TNF: tumor necrosis factor, SCFA: short chain fatty acid, PXR: pregnane X receptor, PPAR: peroxisome proliferator activated receptor, Treg: regulatory T cell, GOS: galacto-oligosaccharide, FOS: fructo-oligosaccharide, GBF: germinated barley foodstuff, OI: oligofructose-enriched inulin, BGS: bifidogenic growth stimulator, FODMAP: fermentable oligosaccharide, disaccharide, monosaccharide and polyol, FMT: fecal microbiota transplant, LBP: live biotherapeutic product, PolyP: polyphosphate, KFXL: Kangfuxin liquid, path: pathogenic, AIEC: adherent-invasive Escherichia coli, Images of antibiotics and prebiotics are adopted from KEGG. Image of prebiotic diet is adopted from Monash University (https://www.monashfodmap.com/blog/a-low-fodmap-mediterranean-style-diet/). Red: aggressive microbial species and cells, blue: protective microbial species and cells.