Just another crappy commentary: the future of fecal microbiota transplantation

KEYWORDS:

• Fecal microbiota transplant
• FMT
• Clostridia difficile
• microbiome
• bacteria
• autoimmunity

The journey through life is laden with ironies.

Table 1. Proposed indications for FMT based on a search of Clinicaltrials.gov

Acute myeloid leukemia

Alcoholic hepatitis

Amyotrophic lateral sclerosis

Ankylosing spondylitis

Anorexia nervosa

Autism

Bipolar disorder

Chronic fatigue syndrome

Depression

Diabetes mellitus, type II

Epilepsy

Hepatitis B infection

HIV infection

IgA nephropathy

Immune thrombocytopenia

Kidney transplantation

Liver transplantation

Malnutrition

Melanoma

Multiple myeloma

Multiple sclerosis

Non-alcoholic steatohepatitis

Obesity

Pancreatitis

Parkinson’s disease

Peanut allergy

Pouchitis

Rheumatoid arthritis refractory to methotrexate therapy

Sjogren’s syndrome

Squamous cell cancer

Urinary tract infection

Trials for some of the listed indications may have been terminated.

In some cases, FMT is an adjunctive rather than primary therapy.

(Table excludes indications for which publications already exist as listed in the manuscript)

But perhaps the greatest irony of all is that feces, which are disgusting to virtually everyone, are also absolutely vital to life. Fecal microbiota transplant (FMT) has proven to be a lifesaving technique for Clostridia difficile infection [1,2]. And it might have therapeutic value for a host of other incompletely treated conditions. A search of the website, Clinicaltrials.gov, on 27 May 2019 with the keywords, fecal transplant, found listings for 307 trials. Pubmed lists nearly 2000 manuscripts on this topic. Quite a few physicians and scientists apparently now accept that disgusting and lifesaving are not mutually exclusive terms.

Joshua Lederberg coined the term, microbiome, for the microbes living in and on each of us [3]. In addition to bacteria, the microbiome includes viruses, fungi, and sometimes other organisms such as helminths. We now appreciate that the microbiome is essential for health. Our microbes are a source of vitamins and neurotransmitters. Most importantly, our microbes educate our immune system. Mice which are raised in a germ free environment have shrunken lymphoid organs and an impaired immune response [4]. We should not forget that our gut microbiome metabolizes many of the medications that we ingest [5,6]. The microbiome even alters the efficacy of anti-cancer therapy, such as checkpoint inhibitors [7,8]. Anyone who has ever taken an antibiotic knows that drugs alter bugs, but the range of drugs altering bugs is being increasingly explored. And we are just starting to explore how bugs alter drugs. Acetaminophen was one of the first recognized examples [5], but many more have followed [6].

Medical literature includes reports on FMT for C. difficile colitis [1] and other refractory bowel infections [9], ulcerative colitis [10,11] Crohn’s disease [12], irritable bowel syndrome [13,14], sclerosing cholangitis [15], constipation [16], cirrhosis [17], hepatic encephalopathy [18,19], psoriatic arthritis [20], graft versus host disease [21], diabetic neuropathy [22] and metabolic syndrome [23–25], although data are sparse and sometimes negative or inconclusive for some of these indications. Additional indications are under study or were under study based on listings with clinicaltrials.gov and as shown in Table 1.

While FMT is a movement with tremendous momentum (pun intended), we are lacking many answers. What is the best route (e.g. oral, rectal, jejeunal) to deliver FMT? (For C. difficile infection, delivery by colonoscopy appears to be superior) [2]. How frequently must FMT be repeated? How durable is the effect? Can FMT be used as a strategy for prevention rather than treatment? Does pretreatment with antibiotics help or hinder the engraftment of FMT? Are there risks from future antibiotics? How safe is FMT? Could there be unanticipated long-term side effects? Not all healthy donors are equally effective for specific diseases; more work needs to be done to identify the bacteria or ratio of bacteria that result in benefit. In addition, recently Khoruts and Brandt appropriately contended that intestinal microbiota transplantation might be a more appropriate designation for this therapeutic approach [26].

FMT is invaluable as a proof of concept regarding the microbiome’s role in health and disease, but it is clearly not the ultimate approach to treat microbiome-driven diseases. One obvious problem is the esthetics of fecal transplant. But there are also dangers. FMT can certainly transmit viral diseases [27] and in theory, it could transmit prions or other incompletely detected infectious vectors. On 13 June 2019, the New York Times reported that the Food and Drug Administration was investigating an FMT-related death from E. Coli sepsis in an immunocompromised host in a trial in which guidelines were not followed. (https://www.nytimes.com/2019/06/13/health/fecal-transplant-fda.html). As a consequence, some FMT clinical trials were being halted. It should also be emphasized that some stool banks screen more rigorously than others for disease. Data support the safety of FMT even in immunocompromised hosts [28].

The mechanisms by which FMT could restore health are multiple. In the case of C. difficile, FMT might simply restore a healthy gut ecosystem such that the pathogen no longer has a major competitive advantage. In obesity, gut bacteria affect the metabolism of ingested food and therefore have a profound effect on the availability of food derived calories. But bacteria could also affect neurotransmitters and thus have a fundamental effect on appetite. Bacterial mimicry of self-antigens, enhanced bowel permeability, changes in immune homeostasis such as a reduction in regulatory T cells or an expansion of TH17 T cells, and activation of lymphocytes or other immune cells from the lamina propria to remote organs are additional explanations as to how the intestinal microbiome contributes to health or disease [29].

If the gut microbiome is vital to health, but FMT is not likely to be the ultimate solution, what alternatives exist? Rather than extracts of feces, we could deliver a defined consortium of bacteria. Such an approach would provide for greater uniformity, a critical component for judging efficacy, and could easily avoid unknown pathogens. We can also alter the microbiome through diet [30]. The ecosystem represented by gut bacteria is greatly influenced by the substrates provided by what we ingest, although diet is complex and the impact of dietary changes is incompletely defined. If a disease is driven by a single microbe, vaccination against that microbe could have beneficial effects. Such an approach has proven successful in a mouse model of systemic lupus [31]. The mechanisms by which the gut microbiome could cause disease are multiple. One frequently invoked mechanism is an increase in bowel permeability leading to dispersion of bacterial products. If this mechanism does indeed contribute, then a strategy that repairs the leakiness of the bowel could be effective without any knowledge of specific bacteria. Finally, we might not need to know which bacteria are responsible for disease. If we understand metabolically how the bacteria are contributing to disease, blocking of a specific bacterial enzyme could be salutary. Such a paradigm has been described in laboratory animals to prevent bacteria from generating Trimethylamine-N-oxides (TMAOs) which are atherogenic [32,33].

Considering that the efforts to catalog our microbiome through the Human Microbiome Project in the US [34] and the Meta Hit Project in Europe [35] are arguably still in their infancy, it is remarkable how rapidly interest in fecal transplantation has grown.

Having a crappy day truly has found a new meaning because crappy can be life-saving.

Declaration of interest

JT Rosenbaum is a collaborator with Viome. He also consults for Abbvie, Santen, Gilead, Roche, Novartis, Janssen, Corvus, Celldex, and Horizon on topics not related to this commentary. The author receives royalties from UpToDate. OHSU receives clinical trial support funds from Pfizer for a trial conducted by the author and not related to this submission. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One of the peer reviewers has declared research support from Finch/Crestovo for research in Intestinal Microbiota Transplantation, other research support from Roche, Takeda, Celgene and Diasorin, and speaking/consulting honoraria from Abbvie. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by NIH Grant EY029266, the Grandmaison Fund for Autoimmunity Research, the William and Mary Bauman Foundation, Research to Prevent Blindness, the Rheumatology Research Foundation and the Stan and Madelle Rosenfeld Family Trust.