Table 2.
Current microbial-based strategies to modulate gut microbiomes and their ecological characteristics.
| Strategies | Relevant characteristics | What can they do | Limitations | How can they be improved | Open questions |
|---|---|---|---|---|---|
| Probiotic/live bio-therapeutic with allochthonous strains | Most survive passage through the GIT tract. Might still be metabolically active for short periods of time. | Although research is inconclusive, effects on gut microbiota composition and function are likely marginal. Can still directly impact the host, e.g. by producing bioactive compounds (if sufficiently active) and through immune modulation. | Originate from extra-intestinal habitats and do therefore lack the necessary traits to be competitive in the gut. | Potential for genetic modification to produce therapeutic compounds [3*]. Non-persistence is an advantage for genetically modified strains for bio-confinement†. | Can allochthones organisms produce enough recombinant products at intestinal sites of interest? |
| Probiotic/live bio-therapeutic with autochthonous strains | Possess traits for both survival and colonization of the gastrointestinal tract | Can engraft into the microbiome if niche is available or if resident member is outcompeted. | Genetic diversity is low. Strains were often selected based on in vitro criteria and were propagated over many generations in artificial conditions (e.g. laboratory), likely leading to ‘trade offs’. | Production of probiotic products should be performed to maximize activity and minimize lagphases in the gut, and to avoid ‘trade offs’. Combine with subtractive therapies (antibiotics, phages). Administered early in life†. | Is persistence of probiotics linked to bacteriophages in the resident microbiome? What genes within probiotic strains determine persistence? Can treatments be personalized? |
| Consortia of autochthonous strains | Higher diversity in traits for both survival and colonization | Genetic diversity is higher than when using single strains alone. If introduced strains come from the same community, facilitative syntrophic interactions between them are likely. | Key members of the intact community are likely to be missing. Inhibition between member strains. | Production of consortia should maximize activity and minimize lagphases in the gut. Composition should be formulated based on target disease. | How does genetic diversity contribute to persistence? Can treatments be personalized? |
| Synbiotics | Probiotic strain(s) combined with a prebiotic substrate. | Provides resources for the incoming microbe, leading to a relaxation of competition. | The resident microbiota competes with the incoming probiotic for the resource. | Synbiotic combinations have to be designed based on strict ecological criOrchidsOteria and focus to identify strain/prebiotic combinations that work under the constrains of the gut ecosystem. | Can synbiotics be formulated to improve persistence and efficacy of probiotics? |
| Fecal Microbiota Transplant (FMT) | Complex mixture of microbes generated from fecal sample(s) of healthy human donor(s) | Introduction of an entire community allows complex networks to be established in the recipient. Phages are present that might contribute to engraftment. High genetic diversity increases chance of engraftment. | Safety and regulatory concerns. Difficult to do, although capsules have been developed. | Combine with subtractive and/or modulatory (substrates) approaches to increase engraftment. Determine differences in donor and recipient microbiomes that determine efficacy. | How efficient are they for diseases other than CI. difficile diarrhea? What are the ecological principles that govern engraftment? What are the exact roles of components (phages, metabolites, etc.)? |
| Subtractive approaches followed by the bio-therapy. | Use of antimicrobial substances or replicating entities (bacteriophages) to remove native bacteria. | Can decrease competitors and open niches for the incoming microbes [39]. Priority effects facilitate engraftment of microbes introduced after subtractive intervention. | Open niches could be exploited by opportunistic native members or pathogenic microbes. Safety and regulatory concerns. | Improve specificity and use targeted instead of broad-spectrum approaches, paired with a consortium of strains that can occupy niches that become vacant. | Would the incorporation of phages and mobile genetic elements increase the risk of native populations to acquire resistance? Are personalized strategies necessary? |
†
Probiotic or live bio-therapeutic strains should be selected based on well-controlled clinical trials, and traits that facilitate their technological applicability (good growth, etc.) should only be considered when the clinical effects are sustained.