Re-equilibrating the Microbiome
We all know that the bacterial cell population of the human body
outnumbers the body’s own cells by about ten to one, but it now seems that the
health of that bacterial population may have a direct bearing on the health of
the host, particularly around the guts. Interventions
that can re-equilibrate the gut flora have the potential to treat a number of
distressing and persistent conditions. Re-infection
of the intestines and bowel of a patient with a faecal sample from a healthy
donor (Faecal Microbiota Transplantation or FMT) has become of so much interest
to health providers in recent times that both the FDA and NICE have felt
compelled to issue new guidance documents for its use in the last two months. Questions arise as to how it works, what
conditions it could treat, and how it can be delivered and regulated.
Discussion of this potential treatment seems to be held back for two
very different reasons: on one hand, the general public regards it as bizarre
and unpleasant, and it suffers from a general schoolboy humour (Private Eye
published a cutting in its “Funny Old World” section only last week, where the
humour lay merely in the concept itself); on the other hand, the reasons behind
the actual therapeutic effect remain unclear, with no identifiable active
ingredient, no large-scale clinical trials published, and the perhaps unfair
perception that it is quackery. It thus
falls between two stools.
While the concept of FMT has been around for a number of years, it has
been given real impetus recently by the massive rise in genome sequencing
power, which has allowed the effects of various conditions to be mapped via the
changes in the gut flora – this microbiome sequencing has been a feature of a
number of publicly-funded initiatives worldwide and is also one of the main
targets of Craig Venter’s latest vehicle, Human Longevity Inc.’s Biome Health
division. The initial promise of FMT has
been for the treatment of C. difficile
infections, where a previously minor and unregarded bacterium takes advantage
of external factors, particularly over-dosing of antibiotics, to out-compete
and swamp the other occupants of the gut.
However, it seems that the population make-up of the gut flora could
also play a significant factor in the development of other intestinal and bowel
diseases, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease
(IBD). Whilst treatment for C. difficile infections could be the
starting point for greater clinical use of FMT, and provide the confirmation of
efficacy and method of action, it is the promise of treatment for these other
long term, distressing and debilitating diseases that most excites clinicians.
This promise has
led to the setting up of a service, called OpenBiome in October 2013, at the
Microbiome Health Research Institute of MIT, to create a frozen storage
facility for donated stool samples, screened for enteric bacterial pathogens, viruses
and parasites. These can then be supplied
to physicians wishing to try the procedure on patients infected with C. difficile. OpenBiome charges $250 for a 250 mL sample,
more than enough to treat the patient and considerably cheaper than a further
course of antibiotics-of-last-resort.
The Regulatory position for FMT is changing rapidly. FDA originally treated FMT as any new
investigational drug, requiring physicians to request an IND for any use. In May 2013, this was changed to allow
physicians to exercise enforcement discretion, opening up the field for further
development. Further new draft
guidelines, issued in February 2014, seem to close this window again, requiring
not just informed consent of the patient, but also that the FMT product is
obtained from a donor “known to” the patient or the healthcare provider, and
that the stool donor and stool are qualified by screening and testing
first. This new guidance seems to
prevent the use of the anonymous donor samples from OpenBiome, unless the
“known to” restriction is interpreted very broadly.
NICE’s own guidelines on FMT for recurrent C. difficile infections, issued in March 2014, require UK clinicians
to keep records of both donor and recipient, as well as to screen for
pathogens. This seems closer to the
rules regarding tissue donation for transplantation. Defining the treatment and its most
appropriate regulatory regime are still to be finalised. The best delivery method also remains unclear
– enema, nasal feeding tube, and enteric-coated capsule have all been used or
considered.
The microbiome of the average human gut contains thousands of different
micro-organisms, in variable amounts and with their own niches. 16S ribosomal RNA sequencing has identified
many bacteria which have never been isolated, and which may not ever be able to
be cultured separately in the laboratory.
Understanding the synergy of the populations will be an enormous task. A recent publication on the microbiome of 447
patients with Crohn’s disease showed diminished microbial diversity and
over-representation of certain bacterial species compared with 220 control
samples, and that certain species were particularly associated with deep
intestinal ulcers, although the researchers could not determine whether this
was causative or simply colonisation of an already existing suitable
environment. Given the interdependencies
within the microbiome and the spread of human conditions caused by their
perturbation, it may be that the essentially empirical nature of FMT may become
the standard of care for many years, before we truly appreciate the exact
causes and treatments for diseases such as ulcerative colitis.
However, given that there are well-documented cases of patients with
recurrent C. difficile infections,
close to death after up to nine courses of antibiotics, being completely cured
with FMT, then this is clearly a treatment which is going to become both more
widely applied and better accepted.
Links to References
FDA Guidance in February 2014
NICE Guidance in March 2014
Human Longevity Inc.
OpenBiome at MIT
Microbiome in Crohn's disease
NICE Guidance in March 2014
Human Longevity Inc.
OpenBiome at MIT
Microbiome in Crohn's disease
Labels: C. difficile, faecal transplant, microbiome
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