The gut microbiome: a clinically significant player in transplantation?

Abstract

The intestinal microbiome is critical to digestion, metabolism and protection from pathogenic organisms. Dysbiosis, or alteration of this microbiome, can result in Clostridium difficile infection and may play a role in other conditions. Patients undergoing solid organ transplantation (e.g., kidney, lung, liver, small bowel) and hematopoietic stem cell transplantation have a shift in the gut microbiome with a decrease in predominant organisms, a loss of bacterial diversity and emergence of a new dominant population. This translates into increased morbidity and mortality with risk of infection and rejection. We discuss the changes seen in the microbiome and its possible consequences. It may be important to develop strategies to restore the normal microbiome in such patients.

Keywords:

• Clostridium difficile
• fecal microbiota transplant
• gastroenterology
• intestinal microbiome
• transplantation

Multiple studies have examined the intestinal microbiome with growing research on the composition and diversity of this population. At baseline, the microbiome has many functions, including digestion of food, modulating metabolism, promoting angiogenesis and regulating the immune system [1–3]. Additionally, the existing bacteria are essential for protection from pathogenic organisms, also known as colonization resistance.

Disruption of this bacterial homeostasis can result in Clostridium difficile infection (CDI); prior exposure to antibiotics may be a trigger, although there is an increasing prevalence of community-acquired CDI as well. Dysbiosis may also be associated with other conditions such as inflammatory bowel disease, allergies, obesity, diabetes and autoimmune diseases [1,3]. The cause for this dysbiosis is likely multifactorial, but intestinal barrier disruption and bacterial translocation are believed to play a major role.

Several studies have assessed the intestinal microbiome in transplant patients, both for solid organ transplant (e.g., kidney, lung, liver, small bowel) and hematopoietic stem cell transplant for blood cancers (e.g., leukemia).

Regardless of the organ transplanted, multiple studies have demonstrated a significant shift in the intestinal microbiome comparing pre- and post-transplant fecal specimens [4–10]. Typically, there is a decrease in the baseline predominant organism and a loss of diversity with the emergence of a new dominant bacterial population. This shift coupled with high-level immunosuppression, increased exposure to infection (especially if neutropenic) and the frequent use of prophylactic and treatment doses of antibiotics (frequently β-lactams, metronidazole, vancomycin, fluoroquinolones) increase the risk of post-transplant infection [5,9]. Interestingly, loss of microbial diversity in the lung microbiome in post-lung transplant patients is similarly associated with increased risk of infection [11].

This shift in gut microbiome has also been seen in the allogeneic hematopoietic stem cell population. The loss of bacterial diversity has an impact on morbidity and mortality following transplantation by increasing the risk of infection and graft-versus-host disease [9,12,13]. Taur et al. stratified patients by the level of microbiome diversity in fecal specimens following transplant: high diversity in 32.5% of patients, intermediate diversity in 25% and low diversity in 42.5% [9]. Low diversity individuals had more frequently received stronger conditioning regimens, tended to receive more antibiotics and had C. difficile infection during their course. More concerning, at 3-year follow-up, only 36% of low diversity microbiome populations were alive compared with 67% in the high diversity group; deaths were mostly due to graft-versus-host disease and infection [9]. Although patients with low diversity may have been sicker affecting the overall outcome, this study illustrates there is clearly a correlation between microbiome diversity (and the microorganisms that contribute to that diversity) and transplant complications.

Specifically, transplant recipients have a reduction in the prevalence of Lactobacillus spp. (up to 100-fold decrease) with a concurrent increase in Enterobacteriaceae and Enterococcus spp. (up to 100-fold rise) compared with healthy controls [4,5]. This is particularly relevant as Lactobacillus spp. provides benefit to the microbiome by helping to prevent overgrowth of enteric pathogens (including Enterobacteriaceae and Enterococcus spp.) that may contribute to post-transplant opportunistic infections. Worse, these enterococci are frequently vancomycin-resistant and more challenging to treat [12]. Although less clear, in patients with end-stage renal or liver disease pre-transplant, the microbiome appears to start deviating from the healthy control microbiome with even more significant changes post-transplant [4,5,10].

So, does transplant redefine the intestinal microbiome forever? This does not appear to be the case. In liver transplant recipients, the gut bacterial population reverted back to its original composition with restoration of Lactobacillus spp. after 13–24 months; however, Enterococcus spp. remained significantly greater than baseline 2 years post-transplant (p < 0.05) [4].

Evaluating and explaining this shift in the gut microbiome is challenging and plagued by multiple confounders. Of all transplants, small bowel transplant (SBT) may offer the best information about changes in microbiome. Patients receiving SBT are at high risk for rejection of the transplanted graft and bacteremia. While ‘decontaminated’ pieces of small bowel were transplanted historically, we now transplant bowel directly from host to recipient creating a new bacterial ecosystem for the patient [6]. Since SBT patients temporarily have an ileostomy, we have the ability to survey ileal effluent and the changes in microbial composition. Interestingly, Hartman et al. found two distinct bacterial populations. When the ileostomy was present, presumably with oxygen entering the ostomy, facultative anaerobes (i.e., lactobacilli and enterobacteria) dominated; however, post-ostomy closure, the population shifted to a strictly anaerobe community (i.e., clostridia and bacteroides), which is similar to the ileal environment at baseline [6]. The impact of this population change is less clear clinically, although decreases in Firmicutes (specifically Lactobacillales) with increases in Proteobacteria (mostly Enterobacteriaceae) was associated with rejection (p < 0.01) [7]. These are similar to changes seen in some patients with recurrent CDI. It is thus interesting to speculate on the role of the presence or absence of oxygen.

If this microbiome shift increases the risk of morbidity and mortality, should we try to prevent or treat it? There are various approaches that may be taken to prevent and treat dysbiosis and the associated health effects. The ultimate goal would be to restore the intestinal microbiome back to its baseline, pre-transplant status. This is challenging, particularly in the setting of high levels of immunosuppression and frequent use of antibiotics either for prophylaxis or treatment of infection (especially in neutropenic patients).

One essential preventative approach to dysbiosis is through elimination of unnecessary broad-spectrum antibiotic use. While ‘selective bowel decontamination’ significantly decreases populations of aerobic Gram-negative bacilli and Gram-positive cocci resulting in a 10-fold decrease in intestinal bacteria, this translates into a decrease in infections related to these organisms [14,15]. But, Bacteroidetes and Proteobacteria persist despite antibiotics, often harboring resistance genes. Additionally, this reduced microbiome with less diversity increases the risk of post-transplant infection [5]. Any avoidance of antibiotics would be beneficial in protecting gut diversity.

More advanced, if we can identify the makeup of a post-transplant patient’s microbiome, it may inform us of the risk of infection and/or rejection. As suggested by Oh et al., there is the potential for microbiome profiling as a marker for allograft rejection, or at least identifying persons who may be at risk of rejection [7]. Among stem cell transplant patients, intestinal domination preceded bacteremia by 7 days; therefore, identifying the microbiome population of patients in the early post-transplant period may help to identify those patients at greatest risk of complications [12]. This approach is still in the early stages but may play a more significant role in the future.

Since the ultimate goal is restoration of an altered microbiome, some may consider a role for prebiotics and probiotics. The use of these in combination (e.g., synbiotics) has been shown to decrease infections in post-living donor liver transplant recipients; however, there was no significant change in the bacterial composition [16,17]. Moreover, while probiotics are widely regarded as safe, we know these living organisms can cause fatal infections in immune-suppressed individuals and thus may be best avoided in these patients. Using diet and prebiotics to alter the microbiome is likely safe; we also know that diet, including the types and quantities of fats and polysaccharides, plays an important role in microbiome development [3]. As research continues to progress, we will learn more about the role of regulatory T cells and pattern recognition receptors, such as Toll-like receptors (immune receptors responsible for identifying microbial components and metabolites) as they relate to bacterial–host interactions and immune system regulation [3]. Perhaps certain diets can be tailored to transplant patients that promote the development and restoration of the pre-transplant microbiome.

A more rapid approach to microbiome restoration is through fecal microbiota transplant which has demonstrated highly successful results in the treatment of recurrent C. difficile infection without significant complications [18]. Despite fears of increased infection risk from donor stool, a retrospective review showed no significant increase in bacteremia, including among immunocompromised patients [19]. The transplant population is similarly immunocompromised; fecal microbiota transplantation (FMT) may benefit patients with recurrent CDI (RCDI) when other treatment options fail. We are aware of two case reports of FMT in stem cell transplant patients with RCDI with successful results and no infection post-FMT [8,20]. In this instance, FMT is worth considering as a treatment for a disease resulting from significant dysbiosis. Other uses of FMT are speculative, but may merit study.

Financial & competing interest’s disclosure

The findings and conclusions in this editorial are those of the authors and do not necessarily reflect the views of the University of Washington. The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.