Precision medicine and gut dysbiosis

Introduction

Clostridioides difficile (C difficile) Infection (CDI) is one of the most prevalent hospital-acquired infections and is the primary cause of antibiotic-associated diarrhea. ^1,2 Clostridioides difficile infection is a gastrointestinal disease caused by the anaerobic, spore-forming bacterium C difficile. The bacterium releases toxins into the bowel resulting in fever, abdominal pain, diarrhea, and in extreme cases, death. ^{1 –3} The infection typically affects those with compromised or altered gut bacteria following antibiotic treatment. ^2,4 The reduction of enteric bacteria following a course of antibiotics allows C difficile to colonize the gut at high levels. ³ Challenges arise when patients become unresponsive to typical antibiotic treatments and experience refractory and/or recurring infections. ⁵ These recurrences pose a challenge for healthcare providers, patients, and caregivers due to limited treatment options and compromised quality of life for both the patients and caregivers. ^6,7

Fecal Microbiota Transplantation (FMT) has shown to be approximately 90% effective in resolving Recurrent CDI (rCDI) by unknown mechanisms. ⁸ However, studies have shown gut composition changes post-FMT, and the replenishment of gut micro-organisms from a donor into the bowel of the affected individual may partly explain its efficacy. ^3,5,8 This resolution improves the overall health and quality of life following FMT. ⁷

The analyses of the microbiome of FMT donors and the recipient-patients, pre-FMT and post-FMT, may result in discovery of key bacteria associated with successful FMT and may lead to better understanding of the link between FMT and overall health. By obtaining a specific list of the microbes necessary for the restoration of the healthy gut microbiota, future research could lead to the administration of pooled beneficial bacteria, providing easily distributable, safer, and targeted microbial therapies for patients with rCDI. Furthermore, patients may also be matched to ideal donors based on required bacterial composition, employing the use of precision medicine to ensure higher success rates even when single dose of FMT is administered rather than requiring multiple FMTs as seen in some patients.

In this article, we provide an up-to-date literature review of the microbiome of donors and pre- and post-FMT of CDI patients. In addition, the findings from our own studies and microbiome changes to the restoration of quality of life in CDI patients are summarized.

Finally, despite robust evidence coupled with high demand, FMT remains unavailable in most healthcare facilities in Canada. We encourage healthcare leaders to employ the LEADS Framework ⁹ and associated Develop Coalitions and Systems Transformation domains to increase partnership in research and implementation of this cost-effective and improved precision medicine treatment option for people with gut dysbiosis, including rCDI.

Patient gut composition pre-FMT and post-FMT

Patients who are infected with C difficile experience significant alterations to their gut flora (microbiota) due to shifts and changes instigated by the antibiotic(s) in majority of cases. ^1,3,10 With the distortion of healthy microbiota, C difficile is able to colonize, multiply, and produce toxins which are responsible for causing symptoms and signs of the infection. ^{2 –5} Of particular notice are the changes in overall bacterial abundances which are shown to be greatly decreased in CDI patients, suggesting a depletion of healthy microbes and overall diversity. ^4,10 When observing the bacteria present in the gut of the patient at specific group levels, certain trends have been consistently observed. At the subclass level, Proteobacteria and Bacilli are found in high abundances in rCDI patients when compared to their noninfected counterparts. ^{6,8,11 –13} Upon further investigation, there are trends within these phyla that show elevated levels of the enterobacteria family along with Lactobacillus, Enterococcus, Streptococcus, and Veillonella genera. ^8,11,14 Bacteria that belong to the Firmicutes and Bacteroidetes phyla have shown to be at particularly low levels in CDI patients prior to FMT. ^12,13

Following successful FMT, there are notable changes in the gut composition of patients. ^{3,5 –7} As a result of gut microbiota restoration, bacterial levels are converted to more complex and diverse microbiomes which more closely resemble that of the FMT donor. ^{5 –7,11,12} Although the overall bacterial compositions in cured patients vary, certain commonalities among treated patients have been noted. The following bacteria that belong in the Clostridia class: Butyrivibrio, Eubacterium, Anaerostipes, Clostridium, and Roseburia genera consistently increase post-treatment. ^6,8,12,14 A distinct increase in Ruminococcus, Bacteroides, and Alistipes has also been seen following successful FMT. ^6,8,13,14 On the contrary, Proteobacteria and Bacilli, especially Lactobacillus, decrease following successful treatment. The balance of these key bacteria may be partly responsible for the restoration of health and improved quality of life in cured patients. ^11,12,14

Donor gut composition

Studies of donor microbiomes have been conducted to determine the role of microbiota and FMT efficacy. Patients who were cured following FMT and their microbiota analyses showed more diverse gut composition similar to the donors compared to pre-FMT and also showed improvements in Health-Related Quality of Life (HRQoL), especially in improved pain scores, compared to their baseline or those who failed FMT. ^4,7,15 In the donor microbiome, the Actinobacteria, Bacteroidetes, Bacteroidia, and Firmicutes were the predominant phyla. ^6,11,13,14 The bacteria at the genus level which were absent in CDI patients initially but present in donors and later found in successfully cured patient were Alistipes, Parabacteroudes, Prevotella, Feacalibacterium, Oscillaspira, Sporobacter, Ruminococcus, Subdoligranulum, Butyrivibrio, and Eubacterium. ⁸

Donor and patient microbiome

In this section, we describe some of the microbiome changes observed in patients and donors from the randomized controlled clinical trial of FMT for rCDI conducted in Ontario and British Columbia ¹⁶ (see Figure 1). Within the Firmicutes, Verrucomicrobia, Bacteria_unclassified, Actinobacteria, and Bacteroidetes were shown to increase in relative abundances in patients from the very low levels present pre-FMT to significantly higher levels as time following FMT progressed. In the 10-day, 5-week, and 13-week timepoints post-FMT, those levels increased to levels that resemble the healthy donor. The phylum, Proteobacteria, reduced greatly from the high levels found in patients pre-FMT to the low levels found in the FMT donors. Verrucomicrobia and Bacteroidetes increased in patients post-FMT to the levels found in that of the donors. Across the six phyla: Firmicutes, Proteobacteria, Verrucomicrobia, Bacteria_unclassified, Actinobacteria, and Bacteroidetes, whether high or low to start in patients pre-FMT, all levels are found to resemble that of the donors as time progressed post-FMT. These changes in gut composition closely resembled the trends described in patients and donors, specifically the increased level of Firmicutes and Bacteroidetes and the decrease in the level of Proteobacteria.

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Figure 1.

Relative abundances of the phyla (A) Firmicutes, (B) Proteobacteria, (C) Verrucomicrobia, (D) Bacteria_unclassified, (E) Actinobacteria, and (F) Bacteroidetes for patients pre-FMT, 10 days post-FMT, 5 weeks post-FMT, and 13 weeks post-FMT as well as donors. FMT indicates fecal microbiota transplantation.

Defining health and HRQoL

Historically, health was defined as an absence of illness but has since been modernized to represent a holistic and multidimensional concept that encompasses physical, mental, emotional, and social well-being. ^17,18 With the emphasis on the mental, emotional, and social aspects of health, a treatment to be successful must be able to restore the HRQoL of the patients and eliminate the physical illness. ^18,19 Health-related quality of life is defined as an individual’s ability to function and their perceived well-being in the physical, mental, and social domains of life and the impacts health has on that ability. ^17,20 Health-related quality of life can be divided into eight different domains: physical functioning, role limitations due to physical health, emotional well-being, role limitations due to emotional health, social functioning, energy/fatigue, general health perceptions, and bodily pain. ¹⁷ Studies have shown that FMT for CDI has had significant positive impact on the eight domains of health, especially in reducing pain scores as early as day 10 from receiving FMT. ^{7,16,21 –24}

Discussion

As the leading cause of death due to infectious diarrhea in the United States and Canada, establishing safe and effective treatments for CDI is essential. ^{2 –4} Fecal microbiota transplantation is one such treatment option, and unlike antibiotic treatment, FMT restores the gut microbiota to a healthy state and prevents future CDI episodes. ^{2 –4,10,12,14} Although the exact bacteria responsible for this improvement are still being investigated, there is evidence to suggest that the increase in Firmicutes and Bacteroidetes as well as the decrease in Proteobacteria are key in restoring the gut microbiome and improving the overall HRQoL of the patients. ^{10 –12}

A thorough understanding of exact gut compositions (pre-FMT, post-FMT, and donor) may lead to establishing a true “microbiota-based” therapy for each individual patient. By selecting a donor with specific microbiome for an individual patient may lead to practicing precision and curing patients with one single FMT rather than multiple doses as is needed by some patients. However, further studies are needed to establish the optimal route of administration, oral capsules, colonoscopy, retention enema and state of FMT, and frozen versus lyophilized (freeze-dried) formulation.

As we gain increased knowledge of the microbiome in general, and for FMT donors and recipients in particular, it is important to maximize the benefit of this research to patients as broadly as possible. We refer to the establishment in the United States, of the Openbiome, through which providers are able to access FMT for their patients. There is currently discussion about establishing a similar network in British Columbia. We point to the alignment here with the Develop Coalitions and Systems Transformation domains of the LEADS framework. ⁹ By collaborating, by forming networks and consortia, we will be able to mobilize knowledge to bring this effective precision medicine treatment to a larger proportion of the population. We also entreat our health leaders to support innovative solutions such as FMT for various gut disorders associated with disrupted microbiota in addition to CDI by expanding intellectual capital and infrastructure to facilitate FMT.

We ask that leaders employ both Develop Coalitions and Systems Transformation capabilities in order to champion the type of change required to improve care for patients presenting with gut dysbiosis within the health system. This requires leaders to go beyond open and purposeful communication internal to individual facilities. What is required is:

implementing systematic processes for identification of patients who will benefit from FMT;

By adhering to these recommendations, we believe that health leaders will take great strides in improving the health and quality of life for this and other patient populations.