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

Abstract and Introduction

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver condition. A major current research effort is ongoing to find potential strategies to treat NAFLD-non-alcoholic steatohepatitis (NASH), with special attention to the gut microbiota. Multiple animal studies and pilot clinical trials are assessing different gut microbiota modulating strategies such as faecal microbiota transplantation, antibiotics, probiotics, prebiotics and synbiotics.

Aim: To review the role of microbiota in NAFLD-NASH and determine whether pro- and prebiotics have potential as treatment

Methods: Information was obtained from critically reviewing literature on PubMed on targeting the gut microbiota in NAFLD. Search terms included NAFLD, NASH, non-alcoholic fatty liver disease, steatohepatitis; combined with microbiome, microbiota, gut bacteria, probiotics and prebiotics.

Results: Animal studies and the first emerging studies in humans show promising results for both the common probiotics Lactobacillus, Bifidobacterium and Streptococci as for short chain fatty acid (SCFA) butyrate-producing bacteria. Also, prebiotics have positive effects on different mechanisms underlying NAFLD-NASH.

Conclusions: The most promising strategies thus far developed to alter the microbiome in NAFLD-NASH are probiotics and prebiotics. However, pre- and probiotic treatment of NAFLD-NASH is relatively new and still under development. Actual understanding of the involved mechanisms is lacking and changes in the intestinal microbiota composition after treatment are rarely measured. Furthermore, large clinical trials with comparative endpoints are unavailable. Personalised treatment based on metagenomics gut microbiota analysis will probably be part of the future diagnosis and treatment of NAFLD-NASH.

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver condition.[1] NAFLD encompasses a wide range of liver disease all characterised by the presence of significant increase of liver fat accumulation (more than 5%) and ranges from isolated steatosis (non-alcoholic fatty liver, NAFL), to non-alcoholic steatohepatitis (NASH) in case of associated presence of liver inflammation and injury of hepatocytes (ballooning) which can lead to the potential deposition of collagen fibres and thus fibrosis.[2–4]

It is commonly accepted that the cause of NAFLD is linked to the obesity epidemic and the metabolic syndrome, which is described as increased energy intake and reduced energy expenditure due to a change in lifestyle. NAFLD it is not only considered as the hepatic manifestation of the metabolic syndrome but also as one of the earliest signs of the metabolic syndrome which is associated with features including, type 2 diabetes mellitus (T2DM), insulin resistance and dyslipidaemia.[2,3,5] However not all obese individuals develop NAFLD or NASH, and it has also been reported in lean individuals, so simply increasing the energy harvest is not sufficient to induce NAFLD-NASH. The onset and progression of NAFLD is driven by alterations in several fundamental biochemical and immunological processes in lipid and glucose metabolism and results from the interaction between environmental factors, diet and genetic factors.[5] Insulin resistance seems to have a crucial role in the development of NAFLD by causing increased lipolysis at the level of the adipocyte, leading to an increased flux of non-esterified fatty acids from adipose tissue to the liver.[6,7] In addition, hepatic insulin resistance could promote hepatocyte injury and inflammation which leads to NASH. However, despite substantial research the pathogenesis of NAFLD remains incompletely understood. Besides the metabolic syndrome, there is a high burden of other comorbidities associated with NAFLD.[2] Subjects with NAFLD-NASH have an increased risk to develop atherosclerotic cardiovascular disease and an increased risk for liver-specific mortality due to end stage liver disease and its sequels.[8,9]

Up to now the only effective treatment for NAFLD are lifestyle interventions, involving exercise and weight loss.[10] To increase chances of successful recovery, one should also focus on reducing inflammation in addition to lowering BMI when aiming to treat NAFLD-NASH. Hence, there are no pharmacological effective treatments available yet for NAFLD. Therefore, it remains important to identify new therapeutic targets and develop new treatments. Increasing evidences are pointing towards the gut microbiota as a new environmental factor that can affect NAFLD. The composition of the gut microbiota has been shown to be different in subjects with NAFLD and this affects several histological features of NAFLD.[11] The microbiota is shown to affect energy uptake in the gut, which can when increased lead to obesity and subsequently play role in the onset of NAFLD.[12] In addition, different studies have shown that the gut microbiome can contribute to all histological components of NAFLD: hepatic steatosis, inflammation and fibrosis.[13] Thus, it seems reasonable to target microbiota for the treatment of NAFLD. Here, we will review the current knowledge on different microbiota modulation strategies for the treatment of NAFLD-NASH.

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