Review

Microbiome Modulation in Liver Disease Eamonn M.M. Quigley, M.D., F.R.C.P., F.A.C.P., M.A.C.G., F.R.C.P.I.

The idea that the bacterial inhabitants of the gastro- the host response to the microbiome (be it intact or dis- intestinal tract might play a role in the pathogenesis of turbed) in the basic pathogenesis of nonalcoholic fatty liver disease and its complications is far from new. Small- liver disease (NAFLD), alcoholic liver disease, intestinal intestinal bacterial overgrowth was described in cirrhosis ­failure–related liver disease, and primary biliary cholangi- several decades ago, and the role of bacterial metabo- tis, as well as in the initiation and perpetuation of many lites in the pathophysiology of of the feared complications of chronic liver disease.2-4 The (HE) was defined in the 1950s. The seminal studies that race is on to identify bacterial signatures of real diagnos- established the relationships between certain , tic or prognostic import, and early signs are encourag- circulating ammonia, and the neuropsychiatric symp- ing.5 What does all this mean for the management of the toms of HE and went on to document their amelioration ­patient with liver disease? by still stand as classics in the field. A lot has happened since then, most notably the advent of “the In discussing microbiome-directed therapies, we must microbiome revolution” hastened by the development first cast a backward glance. In HE, the role of antibiot- of a variety of technologies and informatics platforms ics is established, and recent developments have revolved that permit the rapid enumeration of constituents of the around early recognition and optimal agent. One intrigu- microbiome, their putative functions, and metabolic prod- ing side note in relation to the de jour, rifaximin, ucts.1 These technologies—high-throughput sequencing, is its relatively modest impact on the ; it may metagenomics, and metabolomics—have been applied to be effective, but quite how it acts remains somewhat of a the study of a variety of liver diseases and complications mystery.6 Intriguing early studies suggest a potential role of chronic liver disease such as HE, spontaneous bacte- for an even more drastic modulation of the microbiota, rial peritonitis, systemic sepsis, and hepatocellular carci- fecal microbiota transplantation (FMT), in the management noma.2 In animal and human studies, support has accrued of HE.7 A dissection of the bacterial populations that ac- for a pivotal role for the microbiome, its metabolites, and tually confer these benefits, together with the elucidation

Abbreviations: FMT, fecal microbiota transplantation; HE, hepatic encephalopathy; NAFLD, nonalcoholic fatty liver disease. From the Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX. Potential conflict of interest: Dr. Quigley owns stock in and consults for Alimentary Health. He consults for Salix, Axon and Biocodex. He received grants from Vibrant, 4D Pharma and Zealand Pharma. Received May 6, 2019; accepted July 14, 2019.

View this article online at wileyonlinelibrary.com © 2019 by the American Association for the Study of Liver Diseases

149 | Clinical Liver Disease, VOL 14, NO 4, OCTOBER 2019 An Official Learning Resource of AASLD Review Microbiome Modulation in Liver Disease Quigley

>/sZ

ϱ ^ĞŶƐŽƌLJEĞƵƌŽŶƐŝŶƚŚĞ ŶƚĞƌŝĐEĞƌǀŽƵƐ^LJƐƚĞŵ

ϲ ϰ

ϯ Ϯ >LJŵƉŚŽĐLJƚĞƐ

DĂƐƚĐĞůůƐ ϭ

ƉŝƚŚĞůŝƵŵ ;'ƵƚĂƌƌŝĞƌͿ

ĂĐƚĞƌŝĂ ŝĞƚĂƌLJ ŽŵƉŽŶĞŶƚƐ >ƵŵĞŶ

FIG 1 A framework to explain the role of the in liver disease (the microbiota-gut-liver axis). Bacteria, bacterial products, or metabolites generated in the lumen by interactions between digesta and the microbiome (1) gain access to the submucosal compartment via a more permeable epithelium (2), where they activate mast cells and engage with lymphocytes, leading to the release of proteases and cytokines/chemokines, respectively (3). As well as inducing an inflammatory response, these molecules also activate sensory afferents (4), leading to local reflex responses and/or central transmission (5). Simultaneously, bacterial products and inflammatory mediators gain access to the portal and systemic circulations via the submucosal vasculature (6). Interventions that modulate the microbiota will seek to address abnormalities in luminal contents or in interactions between bacteria and dietary components (products of digestion).

of the action of antibiotics in this ominous complication of TABLE 1. inTERVENTIONS THAT MODULATE THE GUT chronic liver disease, could provide very basic insights. MICROBIOME

With regard to the role of the gut microbiome in the Diet Prebiotics pathogenesis of liver disease per se, a somewhat unifying model has emerged that involves the microbiome (intact Single organism Multispecies (cocktails) or disturbed), its metabolites (including those emanat- ( + ) ing from interactions with dietary components), the epi- Antibiotics thelial barrier, and the host immune response. In NAFLD FMT and alcoholic liver disease, attention has been focused, in particular, on the access provided to bacteria and their products to the enteric immune apparatus and the por- barrier function; third, one could dampen a potentially tal and systemic circulations (Fig. 1).8 This model has its deleterious immune response; and finally, one could at- limitations, including oversimplification and a reliance on tempt to prevent or down-regulate the impact of those extrapolation from animal models, which are beyond the metabolites and other molecules that have already ac- scope of this review, but does serve as a useful template cessed the portal or systemic circulations. Our focus will for a discussion of interventions (Table 1). First, one could be on the first of these options and on the interventions modulate the microbiota; second, one could restore gut listed in Table 1.

150 | Clinical Liver Disease, VOL 14, NO 4, OCTOBER 2019 An Official Learning Resource of AASLD Review Microbiome Modulation in Liver Disease Quigley

Diet has been a relatively underexplored avenue for CORRESPONDENCE microbiota modulation in liver disease; with the recogni- Eamonn M. M. Quigley, M.D., F.R.C.P., F.A.C.P., M.A.C.G., tion of the pivotal role of our diet in the ecology of our F.R.C.P.I., Lynda K and David M Underwood Center for Digestive microbiomes, we will soon see a renewed emphasis on Disorders, Houston Methodist Hospital and Weill Cornell Medical this relatively basic intervention. A more targeted dietary College, 6550 Fannin Street, SM 1201, Houston, TX 77030. E-mail: [email protected] approach is provided by the addition of a prebiotic, a dietary component that selectively promotes the growth REFERENCES of potentially beneficial bacterial taxa. Although far less 1) Claesson MJ, Clooney AG, O’Toole PW. A clinician’s guide to micro- studied in the context of liver disease than probiotics, biome analysis. Nat Rev Gastroenterol Hepatol 2017;14:585-595. recent developments in prebiotic research, coupled with a 2) Victor DW 3rd, Quigley EM. The microbiome and the liver: The relatively benign regulatory landscape, may soon see pre- basics. Semin Liver Dis 2016;36:299-305. cisely tailored prebiotic molecules directed at the manage- ment of certain liver diseases. Early data are encouraging.9 3) Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol 2019;16:235-246. The probiotic literature in liver disease, although bur- 4) Sharpton SR, Ajmera V, Loomba R. Emerging role of the gut geoning, continues to present several challenges to the microbiome in nonalcoholic fatty liver disease: From composition critical reader and clinician alike. Many studies are of low to function. Clin Gastroenterol Hepatol 2019;17:296-306. quality, and variations in formulation, dosage, duration of 5) Caussy C, Tripathi A, Humphrey G, et al. A gut microbiome sig- therapy, and outcome measures often leave one more be- nature for cirrhosis due to nonalcoholic fatty liver disease. Nat fuddled than informed. Nevertheless, some positive notes Commun 2019;10:1406. have been struck, most notably in relation to NAFLD10 6) Bajaj JS. Review article: Potential mechanisms of action of rifaximin 11 and complications of cirrhosis. Encouraging as these in the management of hepatic encephalopathy and other complica- observations may be, much remains to be resolved. Does tions of cirrhosis. Aliment Pharmacol Ther 2016;43(suppl 1):11-26. probiotic therapy actually impact on the natural history 7) Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from of liver disease or prevent complications? Are probiotics a rational stool donor improves hepatic encephalopathy: A ran- universally safe in the patient with advanced liver disease domized clinical trial. Hepatology 2017;66:1727-1738. or after transplantation? What is the best strain for a par- 8) Chu H, Duan Y, Yang L, et al. Small metabolites, possible big ticular indication? For how long should the probiotic be changes: A microbiota-centered view of non-alcoholic fatty liver taken? These are questions that can be addressed only by disease. Gut 2019;68:359-370. high-quality prospective clinical trials. 9) Loman BR, Hernández-Saavedra D, An R, et al. Prebiotic and pro- biotic treatment of nonalcoholic fatty liver disease: A systematic Synbiotics, combinations of probiotics and prebiotics, review and meta-analysis. Nutr Rev 2018;76:822-839. have also been studied in certain liver diseases; the funda- mental problem here is an inability to differentiate between 10) Khan MY, Mihali AB, Rawala MS, et al. The promising role of pro- the benefits of prebiotic, probiotic, or their combination. biotic and synbiotic therapy in aminotransferase levels and inflam- matory markers in patients with nonalcoholic fatty liver disease—a The final and most drastic intervention, FMT, has to date systematic review and meta-analysis. Eur J Gastroenterol Hepatol been studied and then in only a limited manner, in HE, as 2019;31:703-715. alluded to earlier. If FMT could reveal the secret of its im- 11) Dhiman RK, Rana B, Agrawal S, et al. Probiotic VSL#3 reduces liver pact here, or indeed elsewhere, more tailored approaches disease severity and hospitalization in patients with cirrhosis: A ran- to “bacteriotherapy” could well be on the horizon. domized, controlled trial. Gastroenterology 2014;147:1327-1337.

151 | Clinical Liver Disease, VOL 14, NO 4, OCTOBER 2019 An Official Learning Resource of AASLD