Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases

Abstract

The intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients' intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.

Keywords: Host Genetics; Inflammatory Bowel Disease; Microbiome; Mucosal Immunity; Preclinical Therapies.

Figure 1.. Genetic factors that affect the intestinal microbiome.

Variants genes that affect risk for IBD have been associated with alterations in the composition of the microbiome. Mutations in NOD2, ATG16L1, and LRRK2 reduce secretion of antimicrobial peptide (AMP) by Paneth cells. Variants in CLEC7A and CARD9 have been associated with decreased abundance of Lactobacillus, possibly due to altered activities of dendritic cells and macrophages. Variants in NOD2 are associated with increased abundance of Escherichia species and Bacteroides vulgatus and reductions in Faecalibacterium species. Impaired ATG16L1 signaling has been associated with increased production of IgG and IgA against commensal microbiota, resulting in a loss of tolerance to intestinal microbes. Polymorphisms in MHC class II or HLA genes affect production of IgA in response to microbes. Defects in mucus production alter the intestinal microbiome and increase susceptibility to colitis. Gene names in red have variants associated with CD and UC; gene names in orange have variants associated with only CD; and gene names in purple have variants associated with only UC.

Figure 2.. Effects of the Microbiome on Intestinal and Immune Cells.

The intestinal microbiome and its products modulate immune responses, via induction of dendritic cells (DCs) and lymphocytes (such as Th17 cells, Treg cells [Tregs in figure], and innate lymphoid cells (ILCs)), and cytokine production (IL10, IL22). Intestinal bacteria can also modulate immune signaling pathways, such as expression of NOD2, and epithelial repair. Specific microbes can increase susceptibility of mice to colitis.

Figure 3.. Challenges to Development of Therapeutic LBPs.

Compared with small molecules, LBPs have different challenges at each stage of drug development. Challenges are presented to drug discovery, preclinical studies, and clinical studies. A. In contrast to small molecules, which usually target a specific protein or class of feature of proteins, LBPs are identified based on their association with a disease phenotype in humans or mouse models. B. Small molecules require extensive toxicity studies, whereas LBPs are believed to be non-toxic but require assessments for virulence or antibiotic resistance. Preclinical studies of LBPs are not informative for bioavailability, but focus on viability or bioactivity, which can require specific encapsulation methods, adjuvants, or genetic modifications. C. Trials of LBPs require specific attention to adverse events related to transmission of the microbe, loss of its bioactivity, or off-target effects. Small molecules can also have off target effects, but these may be easier to predict, based on finding from preclinical studies. Early-phase studies of LPBs might be important for final formulation, because bioavailability and potential mechanisms can be assessed based on findings from small groups of patients.