<i>Breaking Bad</i>– the two sides of gut microbiota in portal hypertension

The main protagonist of the Emmy award-winning television series ‘Breaking Bad’, chemistry teacher Walter White, is famously noted for his ambiguous nature as both ‘hero’ and ‘anti-hero’. In a similar vein, the ambiguous influence of microbiota on liver disease has been an active area of discussion in hepatology circles, not least at the recent EASL meeting. Various authors have described the gut microbiota as ‘the forgotten organ’1 and ‘the hottest subject in medicine’2. In parallel, the pathobiology of portal hypertension, and the role of gut microbes and innate immune signalling in exacerbating intrahepatic resistance, has also been the subject of a renaissance of interest 3. In this issue of Liver International, Rincon and colleagues bring these threads together by exploring the effects of modulating gut flora on portal hypertension in the context of decompensated cirrhosis. An association between bacterial infection and portal hypertension in cirrhosis has been known for some years. Indeed, bacterial infection is an independent predictor of the occurrence of variceal haemorrhage (VH), and is also the strongest independent factor associated with failure to control VH, earlier re-bleeding, coagulation abnormalities and mortality 4, 5. A broader role for gut microbiota in the development of certain complications of cirrhosis, such as hepatic encephalopathy and spontaneous bacterial peritonitis (SBP), has been recognized for some time. Indeed, it was appreciated some years ago that the small intestine of cirrhotic patients is frequently colonized with coliform bacteria that may translocate and cause infection 6. However, the gut microbiota, and the complex effects of host–microbiome interactions, have only recently become the target of intense scrutiny with novel genomic, microbiological and immunological techniques. With regard to bacterial translocation, this has been shown to be a common event in advanced cirrhosis, and may therefore be a key event in several complications of cirrhosis 7. Previous studies using antibiotics to modulate gut flora and reduce portal pressure yielded mixed results. Two early studies demonstrated a beneficial effect on portal pressure, although neither was placebo controlled 8, 9. The subsequent two controlled studies did not reproduce a beneficial effect, although both showed a trend towards reduction in HVPG, which may reflect that they were inadequately powered to demonstrate an effect 10, 11. From a mechanistic perspective, there is evidence to support the hypothesis that downstream pro-inflammatory signals following bacterial translocation may lead to increased intrahepatic resistance. Serum bacterial DNA levels, as a surrogate marker of bacterial translocation, are correlated with severity of inflammation and portal hypertension in cirrhosis 12. Moreover, in patients with SBP, elevated levels of catecholamines and TNF-α are associated with higher HVPG 13. Thus, although a causal relationship remains to be fully established, the basis for modifying the gut microflora to prevent bacterial translocation and consequent complications of portal hypertension is founded on consistent and robust observations. The alternative strategies for modifying this process with antibiotics or anti-inflammatory agents would be limited by bacterial resistance or toxicity concerns. Rincon and colleagues have, instead, taken an approach to modify the gut microbiota using probiotics, hence producing a less ‘toxic’ flora. Of course a ‘healthy’ microbiome is not yet fully defined, and by implication, the constituents of ‘therapeutic’ probiotics also remain to be defined. Nevertheless, probiotics have been shown in varying settings, such as infectious diarrhoea and necrotizing enterocolitis, to improve intestinal integrity, and modulate gut-derived inflammatory responses 14, 15. The mechanisms of these beneficial effects remain to be ascertained, but proposed pathways include suppressing growth of pathogenic bacteria, blocking epithelial attachment by pathogens, enhancing mucosal function and directly modulating host immune responses 16. One of the most commonly used probiotic preparations is VSL#3, a multispecies probiotic consisting of eight strains of bacteria. This preparation has been used in rodent models and in humans with liver disease, with some favourable results in non-alcoholic steatohepatitis, and hepatic encephalopathy. Moreover, VSL#3 has also been shown to improve liver function tests, pro-inflammatory cytokines and degree of oxidative stress in cirrhotic patients. In the context of portal hypertension, two groups have evaluated its use in differing stages of cirrhosis. The Alberta group previously showed no significant benefit of VSL#3 supplementation on HVPG in small placebo-controlled studies comprising compensated and early decompensated patients, although a trend towards HVPG reduction was noted 17, 18. By contrast, Gupta et al. demonstrated a significant beneficial effect of VSL#3 when added to propranolol, in a larger double-blind, placebo-controlled study 19. This group found that the addition of VSL#3 to propranolol, increased the HVPG response rate from 31 to 58%, compared to propranolol alone, associated with a favourable reduction in peripheral vein and hepatic vein TNF levels. Taken together, these prior findings support a small additive effect on portal pressure, of similar magnitude to that seen with simvastatin, and likely only to be of clinical significance when combined with beta-blockers. The study by Rincon and colleagues is therefore a welcome addition to the literature on this subject. This group adopted a similar approach to the Alberta group, using VSL#3 as monotherapy among a group of patients with decompensated cirrhosis with ascites. Although this study was not placebo controlled, Rincon et al. showed a statistically significant reduction in HVPG, of greater than 10% in the majority of patients associated, importantly, with improvements in systemic haemodynamics. Although small and uncontrolled, this study adds further weight to the hypothesis that bacterial translocation in advanced cirrhosis is a key mediator of hepatic and systemic vascular dysfunction. Of course, this small study has a number of limitations – apart from the small, uncontrolled trial design, a number of patients dropped out before the second HVPG study. In addition, this study does not shed any light on the potential mechanism for probiotics in this situation. The absence of change in pro-inflammatory cytokines may reflect problems with the sensitivity of the assays used, or may suggest an alternative pathway of action of VSL#3. Possibilities include increased populations of Treg lymphocytes induced by altered gut microbiota, leading to decreased Kupffer cell activation 20. This hypothesis requires further attention. A further observation of increased serum sodium following VSL#3 therapy also requires further study, as measures of plasma renin activity or aldosterone were not available in these patients. The field of portal hypertension is the most active as it has been for some years. Several therapeutic strategies have been proposed that modify intrahepatic pro-inflammatory responses, including the bile acid FXR receptor agonist obeticholic acid (OCA). This agent has been shown to lower portal pressure in cirrhotic rodents, and also in an early, uncontrolled human phase 2a human study 21, 22. More recent studies in FXR-deficient mice have implicated altered gut microbiota as the mechanism of action for some of the metabolic effects of FXR pathway signalling 23. It is therefore tempting to speculate that favourably altered gut flora are also involved in the beneficial effects on liver diseases seen with this new class of agents. This fascinating area of research is moving at some pace, helped by large-scale projects to bring together genome, microbiome, metabolome and clinical data, such as the Human Microbiome Project in the USA and the 1 00 000 genomes project in the UK. In the interim, translational studies, such as that by Rincon et al., continue to shed light on ways to modify the ‘two sides’ of gut microbes to benefit our patients with advanced liver disease. Conflict of interest: The authors do not have any disclosures to report.

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