Page 14 - Introduction to FMT

FMT Introduction

Clostridium dificile

Gut Microbiota and Host Metabolism

Whereas inter-individual microbiota composition can vary dramatically, a conserved set of bacterial
functional gene profiles are present in all healthy individuals, implying a role for the microbiome in
physiological gut functioning [1,14,15]. Alterations of this complex physiological bacterial population
associated with negative functional outcomes or disease, known as dysbiosis, can cause low-level
inflammation and altered intestinal homeostasis. Dysbiosis is linked to a variety of ailments, including
obesity and its associated metabolic disturbances [16].

The mechanism by which dysbiosis leads to metabolic disturbances is not well understood. Leading
theories include changes in the microbiome’s digestive efficiency and perturbed intestinal signaling
through alterations of luminal metabolites, low molecular weight signaling chemicals, released by
bacteria in the intestinal lumen such as secondary bile acids (BAs) and short-chain fatty acids (SCFAs)
[17]. The gut microbiome is essential for fermenting indigestible foodstuffs into products that can be used
by, or modulate, the intestine (e.g. complex carbohydrates into SCFAs) [18]. In murine models, obesity-
related microbes are able to harvest greater energy from ingested material [19]. In addition, the
microbiome’s metabolism of primary BAs to secondary BAs affects host metabolism by modulating
activation of the farnesoid X receptor, a master regulator of hepatic triglyceride and glucose homeostasis
[20], as well as G-protein coupled BA receptors, which can increase metabolic rate in brown adipose
tissue [21-23]. Lastly, diet accounts for 57 percent of structural variation in the mouse gut microbiome [24],
which shifts tremendously in response to the host’s gender, diet, circadian rhythms, and feeding pattern
[25-28], suggesting that it is a malleable system amenable to manipulation for therapeutic advantage.

Fecal Matter Transplant Methodology

Currently, only recurrent CDI is approved by the FDA for FMT therapy without requiring an investigational
new drug (IND) approval. Therefore, the majority of FMT recipients have been treated for severe CDI.
These individuals failed repeated treatment with antibiotics and had few therapeutic options left. In
addition, FMT has been studied in inflammatory bowel disease (IBD) since the etiology of this disease, at
least in part, results from dysbiosis. However, there have been few controlled, randomized trials for IBD
patients and there is no evidence that FMT improves clinical outcomes. In all, FMT has been performed in
primarily ill individuals who are at high risk for complications. Hence, the potential risks and complications
for relatively healthy patients with obesity or metabolic syndrome remain hypothetically lower compared
to previous studies performed in patients with refractory, recurrent CDI or IBD.

FMT Introduction