Nonalcoholic fatty liver disease (NAFLD) is an increasingly common entity, in the United States and throughout the world. The estimated prevalence of NAFLD worldwide is 2.8% to 46%, with one study identifying a prevalence of 31% among American adults.1 There are multiple pathophysiologic pathways involved in NAFLD development, with the role of the gut microbiome being increasingly researched.2

The contributions of the gut microbiome in the development of NAFLD are likely multifactorial and include both the bacteria and their metabolites, for example, butyrate),2 Certain metabolites such as butyrate can assist in decreasing intestinal permeability, thereby limiting the amount of fat such as lipopolysaccharide that can pass through the intestinal membrane and lead to deposition in the liver.2 Prior studies in humans have shown that patients with NAFLD have increased gut permeability compared to controls.3 Therefore, the gut microbiome represents a potentially interesting therapeutic target in NAFLD, especially with limited treatment options currently available.  

Recent research published in the American Journal of Gastroenterology, led by Michael Silverman, MD, of the Department of Microbiology and Immunology at Western University in London, Ontario, Canada, and colleagues, evaluated the effect of fecal microbiota transplantation (FMT) in patients with NAFLD.2 The authors hypothesized that when FMT from a thin, otherwise healthy donor was given to patients with NAFLD, there would be an improvement in insulin resistance, hepatic proton density fat fraction, and small intestinal permeability. 

Dr Silverman and colleagues conducted a double-blind, randomized controlled trial that included 21 patients with NAFLD from a single center in Canada who received either allogenic (n=15) or autologous (n=6) FMT administered via endoscopy to the distal duodenum after the patient completed a bowel preparation. Donor FMT was derived from 3 donors following an extensive screening process. Stool was stored at 4°C and processed immediately before transplantation. Insulin resistance (IR) was calculated using Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), hepatic proton density fat fraction was calculated via magnetic resonance imaging, and small intestinal permeability was calculated using the lactulose:mannitol urine excretion test.


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At 6 weeks post FMT, there was no significant difference in HOMA-IR when comparing allogenic and autologous transplants. Similarly, there was also no difference found in hepatic proton density fat fraction at 6 months post FMT between allogenic and autologous transplantation. Seven patients in the allogenic FMT group had elevated small intestinal permeability pre-FMT, all of whom showed a decrease in permeability post-FMT with 2 patients reaching the “normal range.”  Upon further analysis, there was no relationship found between small intestinal permeability and fibrosis score or specific donors. Overall, there was a significant improvement in small intestinal permeability in the allogenic (P =.018) but not in the autologous FMT group (P =.563).

Additional analyses showed that there was no difference in baseline fecal diversity between insulin sensitivity responders and non-responders with non-responders unexpectedly showing increased microbiome diversity post-FMT. There were no differences found in fasting glucose, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides from baseline and 6 weeks post-FMT in both the allogenic and autologous groups. Similarly, there were no differences in either weight or body mass index between the groups.  

The authors concluded that FMT from lean, healthy donors did not significantly improve either insulin sensitivity or hepatic proton density fat fraction in patients with NAFLD. However, there was a modest improvement in intestinal permeability at 6 weeks post-FMT. 

Despite the statistical significance found in small intestinal permeability in this study, the actual short- and long-term clinical significance of this finding remains to be seen. Although permeability of the small intestine has been implicated in NAFLD development in prior studies, the actual mechanism requires further research and clinical trials to fully elucidate the pathophysiologic mechanism and how it impacts clinical outcomes. If small intestinal permeability becomes a more established mechanism in NAFLD, it could also assist in determining an ideal patient for FMT. This being said, the lactulose:mannitol urinary excretion test may be challenging for patients to complete, compounded by the lack of specialized sites that perform and interpret the test. Therefore, additional research is needed to weigh the clinical importance of small intestinal permeability along with the practicality and affordability of the test.

In addition to the current lack of strong clinical data, there are several other challenges in supporting the routine use of FMT in NAFLD. There were no specific adverse events reported in this study; however the safety profile associated with FMT will continue to be an ongoing topic of discussion. The United States Food and Drug Administration recently posted a safety alert regarding the use of FMT and potential risk for transmission of pathogenic organisms.4 Many patients with NAFLD may be considered immunosuppressed — for example, those who have diabetes — and FMT could place these patients at increased risk of infectious complications.

Outside of safety concerns, the need for specialized centers that perform FMT and the associated costs of these centers may limit how many patients have access to FMT. The current study used upper endoscopy to deliver FMT; however, many studies evaluating FMT in recurrent Clostridium difficile have also used colonoscopy. Colonoscopy, along with encapsulated FMT, may be an interesting area of future research in NAFLD. Researchers may also want to evaluate how repeat FMT affects the efficacy and safety outcomes in NAFLD. Overall, FMT is an exciting area of research, although additional clinical trials are needed before it can be considered a reasonable treatment option for patients with NAFLD.

References

  1. Williams CD, Stengel M, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011;140(1)::124-131.
  2. Craven L, Rahman A, Parvathy SN, et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: A randomized control trial [published online May 15, 2020]. Am J Gastroenterol.  doi: 10.14309/ajg.0000000000000661
  3. Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877-1887.
  4. Fecal Microbiota for Transplantation: Safety Alert — Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms. United States Food and Drug Administration. https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission. Published March 12, 2020. Updated April 7, 2020. Accessed July 24, 2020.