Standards and Oversight in the Field of Microbiome Remodeling

Key Points:

• Due to the highly networked and dynamic nature of complex microbial communities, predictive powers in microbiome remodeling are nascent.
• Bacteria are transmissible, so live biotherapeutics require a high standard of non-harm, not only for direct recipients, but also for hypothetical bystanders of unknown microbiome composition.
• Measures to ensure ideals of non-harm must be enacted for public protection from irresponsible research practices, quality control and quality assurance in large scale live biotherapeutics industries, and potential for bioterrorism threats therein, which may include both acute and subtle chronic disease-causing agents.

Owing to the advent of low-cost efficient sequencing, the preceding decade has seen a revolution in our understanding of the complex microbial ecosystems that coinhabit complex organisms, including humans. Indeed, we are metaorganisms, and our gut microbiome, with metabolic activity rivaling that of the liver, is a vital semiexogenous organ. The human gut ecosystem comprises amazingly complex metabolic networks with important implications to human health. Bacterial species and their metabolites have correlated with numerous physiological outcomes, including atherosclerosis, autoimmune disorders, and neurodegenerative diseases. Thus, correction of aberrant microbial populations, or microbiome remodeling, is an area ripe for biomedical discovery and development. However, perturbation of this population can be likened to chaos theory: these systems assuredly follow decipherable rules of cause and effect, but the systems are so networked and dynamic that some perturbations may shift the equilibrium in a way that is inadvertently detrimental and persistent. Therefore, it is vital that proper governance is in place to guide this field of research and protect consumers and patients from harm from frivolous ideas or practices. Furthermore, gut bacteria are transmissible to varying degrees. Thus, many potential microbiome treatments should be considered to have the potential for issues of epidemiology and heritability, and therefore must meet a very high standard of non-harm. Pressing examples of requirements for non-harm are listed below.

1. Gain of function - Whether by prebiotic, probiotic, selective growth inhibition (bacteriophage, low dose antimicrobial, etc.), or other population remodeling method, the metabolic output of the gut microbiome must gain functions that are beneficial to the host and must not gain functions that are harmful to the host or others (e.g., toxic metabolites, novel antibiotic resistance).
2. Predictability of long-term impacts on the microbial community – This includes, but is not limited to the following: a) no substantial decrease in population diversity without net harm reduction (this is currently violated by the use of high dose antibiotic regimens in treating opportunistic pathogen infections; however, given limitations of current treatments available, requirement for net harm reduction is generally reached); b) no substantial increase in opportunistic pathogens (we may refer to this as the “butterfly (in your gut) effect”). Current knowledge makes this requirement of predictability limiting of ethical available microbiome remodeling practices. However, advances in empirical study, in vitro microbiome assays, and applications of artificial intelligence may expand methods that fulfill this requirement in a manner that is highly personalized and precise.
3. No harm to bystanders by live biotherapeutics – to address concerns regarding transmissibility of live biotherapeutics, relevant treatments should be either a) not persistent (i.e. transient, not capable of stable engraftment into to a gut ecosystem) or b) not logically capable of violating any of the above requirements to a bystander of unknown microbiome composition. An example of fulfilling this logic requirement is probiotics containing bacterial species commonly found in fermented foods, and which have been evidenced to be common contributors to gut health.

The above is an initial draft to guidelines for ensuring non-harm in future therapeutic developments, and is likely to be updated and revised. However, opportunities for harm exist outside the boundaries of the ideals for beneficial products and therapies. Frameworks for harm prevention must also protect the public from irresponsible research practices, poor industrial quality control, and bioterrorism. Therefore, the following framework will work to ensure the above ideals are met for public protection in all areas related to microbiome remodeling:

Research - Research involving microorganism gain of function should require approval by a review board and be accompanied by sufficient biosafety facilities and practices.

Live Biotherapeutics Industry – Companies producing and selling live biotherapeutics should register their products with an oversite committee. All products must be clearly defined with reasonable boundaries of product composition and quality control, and quality assurance must be monitored on a regular basis, including whole genome sequencing. The term ‘live biotherapeutics’ applies equally to products of biotechnological innovation, as well as foods produced and sold at scale, which could act as a vehicle for live microorganisms that cause either acute or chronic disease.