Present and future of microbiome-targeting therapeutics

Abstract

A large body of evidence suggests that single- and multiple-strain probiotics and synbiotics could have roles in the management of specific gastrointestinal disorders. However, ongoing concerns regarding the quality and heterogeneity of the clinical data, safety in vulnerable populations, and the lack of regulation of products containing live microbes are barriers to widespread clinical use. Safety and regulatory issues must be addressed and new technologies considered. One alternative future strategy is the use of synthetic bacterial communities, defined as manually assembled consortia of two or more bacteria originally derived from the human gastrointestinal tract. Synthetic bacterial communities can model functional, ecological, and structural aspects of native communities within the gastrointestinal tract, occupying varying nutritional niches and providing the host with a stable, robust, and diverse gut microbiota that can prevent pathobiont colonization by way of colonization resistance. Alternatively, phage therapy is the use of lytic phage to treat bacterial infections. The rise of antimicrobial resistance has led to renewed interest in phage therapy, and the high specificity of phages for their hosts has spurred interest in using phage-based approaches to precisely modulate the microbiome. In this Review, we consider the present and future of microbiome-targeting therapies, with a special focus on early-life applications, such as prevention of necrotizing enterocolitis.

Figure 1. Pathophysiology of NEC and sepsis and potential probiotic effects.

(A) Pathological features of NEC and sepsis include bacterial overgrowth, microbial virulence factors and gaseous fermentation products, and uncontrolled inflammation. Dysregulated TLR4 signaling due to lipopolysaccharide and insufficient mucosal IgA production threatens the integrity of the immature gut barrier and causes enteric nervous system (ENS) dysfunction resulting in dysmotility and abdominal distension. (B) Probiotics, including strains that metabolize human milk oligosaccharides (HMOs), can produce short-chain fatty acids (SCFAs), lactate, and indole-3-lactic acid. These metabolites may strengthen the intestinal barrier by enhancing mucus production, IgA secretion, tight junction integrity, and immune training. Competitive exclusion of pathogens further protects against NEC and sepsis.

Figure 2. Generation of synthetic bacterial communities.

Overview of (A) top-down and (B) bottom-up strategies to design, assemble, and test synthetic bacterial communities for application in preterm infants. MBRA, minibioreactor array.

Figure 3. Pros and cons of phage therapy.

(A) Potential benefits of phage therapy and (B) current limitations to clinical applications.

Figure 4. Conceptual framework for phage therapy to treat and prevent NEC.

(A) Progression of NEC, highlighting points of potential intervention by phage therapy. Preterm birth in at-risk mothers can lead to gut microbiota alterations and inflammation, which may progress to NEC, bacteremia, sepsis, and death. Phage therapy offers a targeted approach to reduce the risk of preterm birth and NEC by targeting pathogenic organisms, restoring gastrointestinal microbial communities, and resolving infections.