Review Article

Can Bugs be Drugs? The Potential of Probiotics and Prebiotics as Treatment for Non-alcoholic Fatty Liver Disease

Nienke Koopman; Antonio Molinaro; Max Nieuwdorp; Adriaan G. Holleboom

Disclosures

Aliment Pharmacol Ther. 2019;50(6):628-639. 

In This Article

Discussion

Evidence for the role of the gut microbiota in the onset and progression of NAFLD-NASH is emerging. However, most of the evidences are limited to explorative studies showing association rather than causality.[93] Moreover, it remains to be shown whether NAFLD progression to NASH and subsequent cirrhosis is seen in all patients, or that NAFLD and NASH are two distinct non-connected liver disease types. Nevertheless, the gut microbiota cannot be ignored when aiming to find potential new targets for the treatment of NAFLD and NASH.

Of the strategies discussed above probiotics and prebiotics have been shown to have the most potential for a widespread use in order to manage the upcoming NAFLD epidemic. Supplementation of the diet is a more specific approach to change the microbiome compared with FMT and this strategy is less invasive and can be applied on a broader scale. Although many studies show promising results, until now, most knowledge relies on studies in animal models. Furthermore, data literature included numerous different formulations and compositions of probiotics and prebiotics. Thus, it is really difficult to validate the effects of certain bacteria species on NAFLD and NASH. The majority of research to unravel the mechanisms involved in the pathogenesis of NAFLD-NASH have been performed in animal models. However, these models are significantly different from the human NAFLD-NASH phenotype.[5,94] It is necessary to question how reliable these results are and whether these models reflect human disease since mice have a different core microbiota composition, develop NAFLD in different ways; they need to be challenged with specific diets or genetic knock-out models should be used to induce NASH.

Moreover, most studies described in this review did not assess the actual changes in intestinal microbiota composition and the effects on a longer term. Probably, not all intestinal microbiota species are detected yet.[2,31,94] In addition to bacteria, bacteriophages probably play a major role in the homeostasis of the gut microbiota, but their true contribution remains difficult to establish. At this stage, it is still unclear whether bacteriophages indeed contribute to disease development, and in particular to the development of NAFLD-NASH.[95] Besides, technical challenges associated with phage therapy such as manufacturing, delivering bacteriophages, and systemic side effects require new strategies.[96] Another role might be for fungi, which are less extensively studied then the gut bacteria. Libraries for alignment of fungi data are still poorly implemented. Improvement of them will bring more knowledge to the topic the next years. Until now, as far our search went, no studies regarding the role of fungi in NAFLD-NASH are published yet. Extensive research is needed to identify the full range of involved microbes, including fungi and bacteriophages, the metabolites they produce, and the pathways they affect.

In principle, probiotics should reconstitute a healthy microbiome. However, the number of bacteria living in the gut is much higher than the number in the supplement. It is likely that the bacteria given by probiotics are insufficient to displace all of the resident bacteria. NASH patients often have small bowel overgrowth, which even increases the number of bacteria that needs to be competed by the probiotic.[97] The question remains whether the effects persist over time or whether the NAFLD-NASH phenotype will recur. It might be that life-long use of probiotics is required in individuals with NAFLD to maintain the efficacy.[98] Studying the effects of a certain pre-, pro- or synbiotic supplements in humans is affected by confounding factors such as genetics, diet and other environmental factors. The variation in therapeutic outcomes of studies in human with pro- and prebiotics might due to an interpersonal variability in microbiota composition among NAFDL-NASH patients.[57] Humans are highly heterogeneous in terms of diet, genetic background and gut microbiota composition. This leads to different responses to the same pro- or prebiotic intervention. The study of Zmora et al showed that this might be related to differences in colonisation pattern.[99] It is also known that in other settings there is an individual response.[93] Until now, the colonisation of the gut during the use of probiotics has not been studied extensive yet in human.[100] For now, most of the time the only indication of colonisation we have are the abundances in the stool, which indeed not always provide an accurate and sufficient insight in the colonisation of the gut. More studies, including long-term follow-up after the intervention, are needed to get insight in the mechanisms underlying colonisation of the gut and the interactions between probiotics and the host's pre-existing gut microbiome. Understanding the mechanisms underlying the colonisation resistance of an individual may enable counteracting this resistance and is needed in order to go in the direction of personalised medicine: precision therapy based on host, microbiome and diet. Metagenomics analysis of the pathways and genes involved in combination with analysis of microbial metabolites may predict an individual's benefit from a certain supplement: true personalised medicine. Future research should include large, randomised, placebo-controlled human clinical trials in order to avoid potential power issues and confounding factors, when aiming to determine the effects of different probiotics in different combinations and formulations, and whether or not combined with prebiotics.[101] Long-term follow up is needed to find out if probiotics are an efficacious and cost-effective strategy to treat NAFLD-NASH. Finally, Bafeta et al reported that harms reporting in published reports of RCT assessing probiotics, prebiotics, and synbiotics is often lacking or inadequate.[102] In future studies this should be improved in order to conclude whether pre-, pro- and synbiotics are safe interventions.

In addition, knowledge should be obtained around the (an)aerobic culture, GMP manufacturing and commercialisation of pre- and probiotic supplements. Especially, culture and administration of anaerobic species can be a challenge. Currently, only liver biopsy is considered as a gold standard for the diagnosis. This is an invasive method which would barely suit as a tool for the diagnosis of NAFLD in its upcoming epidemic spread.

Further research on the identification of patients at risk of advanced NAFLD by genetic and gut microbiota composition profiling is needed. This approach would identify those subjects with NAFLD who would benefit the most from a certain microbiota driven treatment. Making progress in the development of an affordable and broadly applicable treatment for NAFLD-NASH is of major importance because at the moment there is no approved treatment available yet while the epidemic is still rising in many countries.[9]

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