It has become evident over the past decade that humans (host) are inseparably intertwined with the host-associated microbiome. The microbiome coats our external surfaces such as the skin and gastrointestinal tract, exchanges metabolites with us, protects us from infectious pathogens, and is necessary for the normal development of the immune system (1–3). Our microbiome can also react to us and become altered (“dysbiotic”) in human illness and disease (2,4,5). The exchange between the host is constant, bidirectional, and integral to health and disease. It is easy to understand why there has been substantial interest in microbiome-based therapies for a broad array of human conditions.

The “microbiome” is colloquially taken to mean the relative abundance of the genera and species that constitute the gut bacteria (“taxonomy”); however, the microbiome in its broadest sense encompasses bacterial taxonomy, gut fungi (“mycobiome”) and viruses (“virome”), and the totality of their functional and metabolic state (2,5,6). The “microbiome” is multitiered ecology, and any approach that modifies any component of this ecology can be considered microbiome-based treatments (MBTs) (7). Currently, the most common MBTs are (i) fecal microbiota transplantation (FMT), (ii) a defined consortium of known microbes delivered orally or instilled in the gastrointestinal tract, and (iii) supplementation of microbial metabolites (for example, short-chain fatty acids, butyrate) (7). In the future, this may include alternative approaches such as phage therapy or genetically modified bacteria that produce agents for local delivery (8–10).

In all circumstances, the intent is to use MBTs, some of which may be bioactive, as drugs (“agents or articles for the diagnosis, cure, mitigation, treatment, or prevention of human disease or to affect the structure or function of humans”). In the United States, drugs and bioactive agents including MBTs used with therapeutic intent for specific disease states fall under the jurisdiction of the US Food and Drug Administration (US FDA) (11). Thus, the US FDA may regulate FMT or bacterial consortium delivered by any route and bacterial metabolites. However, the US FDA does not regulate probiotics, prebiotics, or dietary supplements, all of which may be MBTs, but do not claim to have therapeutic potential in specific disease states (Figure 1). Furthermore, the US FDA does not regulate diet, although diet modifies the microbiome. As with any drug, clinical trials of MBTs require an investigational new drug (IND) application, which requests permission from the US FDA to administer a potentially therapeutic product to humans (11). Clinical trials of MBTs are also expected to adhere to the laws and regulations that protect human subjects participating in trials and to the standards of trial outcomes for the disease state in question. So FMT for inflammatory bowel disease requires an IND and trial outcomes that conform to standard outcomes for inflammatory bowel disease trials.

Figure 1.:

Chart.

The microbiome is inseparable from humans. It is involved in human health, and disease and encompasses the host-associated bacteria, fungi, and viruses and their collective functional and metabolic state. Any agent that modifies this ecology can be considered an MBT. Therefore, we believe that an MBT used for therapeutic intent to treat specific human diseases should be regulated by the US FDA and require an IND before clinical trial.

CONFLICTS OF INTEREST

Guarantor of the article: Shrinivas Bishu, MD.

Specific author contributions: S.B.: drafted the initial version. The manuscript was critically reviewed by all authors, including the ACG FDA committee.

Financial support: None to report.

Potential competing interests: None to report.

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