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

Materials and Methods

A search on PubMed was performed to find studies published on NAFLD-NASH and the association with gut microbiota. The search terms included: NAFLD, NASH, non-alcoholic fatty liver disease, steatohepatitis; combined with microbiome, microbiota, gut bacteria, probiotics and prebiotics. Other articles were identified through review of the references cited in the research articles and reviews included by the above described search method. Only articles in English were included. Results were manually reviewed and discussed studies were selected based on relevance to answer the question whether probiotics, prebiotics and synbiotics are potential treatments for NAFLD-NASH.

Direct Evidences of Microbiota Contribution to NAFLD-NASH Pathogenesis

Different human studies aiming to identify differences in intestinal microbiota composition between healthy individuals and patients with NAFLD or NASH have been performed (using 16S sequencing based techniques), however, they failed to find a common signature in presence of NAFLD. Many of them are underpowered or are affected by potential NAFLD associated features such as obesity, T2DM and dyslipidaemia. In a cross-sectional study, Mouzaki et al compared stool samples of adults with biopsy-proven NAFLD, both simple steatosis and NASH, with healthy controls. They found that patients with NASH had a lower percentage of Bacteroidetes compared to healthy subjects and patients with simple steatosis. Furthermore, a higher percentage of Clostridium coccoides, a species from the phylum Firmicutes, was found compared to simple steatosis. No differences were observed in the other examined microorganisms: Clostridium leptum, Bifidobacterium, Escherichia coli and Archaea. After adjusting for BMI and dietary fat intake, only the reduced percentage of Bacteroidetes in NASH retained significance. This implicates an inverse and BMI-dependent association between the percentage of Bacteroidetes in stool and the presence of NASH, providing a hypothesis which components of the microbiome may protect from the development of NASH.[14] Boursier et al studied gut microbiota signature in subjects with NASH and different stages of fibrosis.[15] They could confirm, in line with Mouzaki et al, a lower abundance of Bacteroides, accompanied by a lower abundance of Ruminococcus and a decrease in Prevotella in the subjects with significant high fibrosis compared with the subjects with simple steatosis. The authors identified that Bacteroides are independently associated with NASH and Ruminococcus with significant fibrosis. Zhu et al compared the microbiota composition in faecal samples of children with NASH, obese children with no clinical suspicion of NASH, and healthy normal weight children. In addition to microbiota composition alterations, Zhu et al found increased serum ethanol levels in the children with NASH, which has a detrimental effect on the progression of NAFLD.[16] Besides alterations in composition, small intestinal bacterial overgrowth (SIBO) is commonly detected in patients with NASH.[7,17–20] Taken together all the above discussed studies demonstrate that there is shift in microbiota composition-function in the presence of NAFLD or NASH. However, it is challenging to interpret how these alterations exactly relate to liver disease because the available data are just observational and are affected by potential bias in the study design, methods and endpoints. Some more insights into the role of microbiota in NAFLD are provided by interventional studies such as the study by Mardinoglu et al, which showed that by changing dramatically the diet we can affect the microbiota composition and this can drastically affect NAFLD by reducing liver fat and other cardiometabolic risk factors.[21]

Several mechanisms might be underneath the microbiome contribution in NAFLD-NASH pathogenesis. First of all, gut microbiota is known to influence energy harvesting from diet. Bäckhed et al observed that young adult mice with a normal microbiota (conventionally raised, CONV-R) have 40% more total adiposity than germ free (GF) mice when fed the same diet.[22] Transplantation of caecum contents from CONV-R donor's mice to GF mice increased the body fat content to levels equivalent to the COVN-R mice. In line, Turnbaugh et al showed that colonisation of GF mice with microbiota from leptin deficient obese mice results in a significantly greater increase in total body fat than colonisation with microbiota from lean mice.[23] Taken together these data indicate that the obese microbiome has an improved ability to harvest energy from the diet.

Subjects with NAFLD have a microbiota-dependent altered intestinal permeability (leaky gut).[24] In addition to useful metabolites also harmful compounds such as lipopolysaccharide (LPS) may pass through the barrier due to increased intestinal permeability. These pathophysiological changes might be underneath the increased low grade inflammation observed in the presence of metabolic diseases such as NAFLD.[5,24] LPS is a major component of the membrane of Gram-negative bacteria.[25] Multiple studies, mainly using animal models, provided evidence that LPS can stimulate macrophages and monocytes to produce proinflammatory and profibrogenic cytokines such as TNF-α and IL-8.[7] TNF-α can induce insulin resistance by affecting insulin-receptor signalling in insulin sensitive tissues. LPS induced TNF-α and IL-8 production can trigger hepatic recruitment of neutrophils and monocytes, ultimately leading to hepatic injury and systemic inflammation.[26] Besides LPS, other microbial metabolites, including ethanol and hepatotoxic volatile compounds, might enter the circulation and be involved in mechanisms that lead to the progression of NAFLD.[16,27,28]

Beside LPS other, known microbially produced metabolites can affect the host and NAFLD-NASH onset. Disturbed bile acid metabolism is another factor associated with NAFLD-NASH.[29,30] The gut microbiota is essential for the metabolism of bile acids.[31] Bile acids act as signal molecules involved in the regulation of glucose, lipid and energy metabolism. The effects of bile acids are mediated trough their binding with the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein coupled cell surface receptor TGR5.[32] It has been shown that FXR activation requires microbiota in order to influence the onset of metabolic disease and NAFLD in mice.[33] Recent evidences are pointing also towards short chain fatty acids (SCFAs) as potential microbial produced molecules able to affect inflammation and thereby in the progression of NAFLD-NASH. SCFAs are ligands for the G-protein coupled receptors Gpr41 and Gpr43, which are expressed in several cell types including immune cells, endocrine cells, and adipocytes in a wide variety of host tissues including gut epithelial cells. This makes that SCFA are considered to have a role in the regulation of energy metabolism, immunity, and adipose tissue expansion and the modulation of cancer development.[31,34–36] It has recently been shown that phenylacetic acid is a microbially produced metabolite that is increased in the serum of women with NAFLD. When administrated in vitro and in vivo in experimental models it can induce some features of NAFLD, suggesting its causative role in the onset of NAFLD.[20] In addition, these known metabolites, there may be multiple of unknown microbially produced metabolites that can affect NAFLD-NASH.[37,38]

In addition to altered intestinal permeability and microbially produced metabolites, another mechanism that is suggested to be involved in the pathogenesis of NAFLD-NASH is microbiota induced choline metabolism. Choline is an essential nutrient which plays multiple important roles in human metabolism.[39] Choline deficient diets are associated with health problems in humans, including increased hepatic steatosis.[40–42] Dumas et al showed that high-fat diet in mice affects microbiota composition and choline metabolism. The gut microbiota produces enzymes that catalyse the first step in the conversion of dietary choline to the metabolites dimethylamine and trimethylamine. These metabolites can be absorbed and transported to the liver. Here, trimethylamine is largely cleared before it enters the system circulation. However, dimethylamine can both mimic a choline deficient diet by reducing the bioavailability of choline. This may result in the inability to synthesise phosphatidylcholine, which is necessary for the assembly and secretion of VLDL. Furthermore, methylamine can act as an inflammatory toxic metabolite for the host that influences insulin resistance.[40]

Taking this all together, the gut microbiota is an environmental factor that affects the onset of metabolic disorders, including NAFLD and its progression to NASH. Thus, it seems reasonable to target microbiota as a potential new target for the treatment of NAFLD and NASH.

Antibiotics Treatment in NAFLD-NASH

Antibiotics are used with the intention to remove or prevent a particular bacterial infection or colonisation in the human body, but they also affect the gut microbiota. Antibiotics can have a dramatic effect on the gut microbiota composition.[43] In healthy individuals treated with antibiotics the gut microbiota composition was shown to be recovered within 1.5 months to near-baseline levels, although nine common species remained undetectable for most of the subjects after 180 days.[44] In ob/ob mice antibiotics treatment can affect NASH severity, liver triglyceride production and lipogenesis and glucose metabolism independently of weight changes.[45] In line, Cani et al showed that antibiotic treatment can improve features of NAFLD in mice by reducing LPS levels in the faeces in both ob/ob and high-fat diet fed mice.[46] In human, the administration of rifaximin is shown to decrease levels of circulating endotoxin, IL-10, ferritin, alanine amino transferase (ALT) and aspartate transaminase (AST) levels in patients with biopsy proven NASH.[47] However, rapidly increasing multidrug resistant pathogens are an increasing health problem. Also, antibiotic treatment can deplete specific beneficial bacteria species such as butyrate producing bacteria. Vrieze et al showed that vancomycin reduced the abundance of Gram-positive bacteria, including butyrate-producing bacteria, in patients with the metabolic syndrome. This reduction was associated with reduced insulin sensitivity.[48] Although the authors failed to find similar effects in a larger group, it was interesting to note that the baseline difference in baseline gut microbiota diversity between both studies might explain the difference in antibiotic effect on insulin resistance.[49] Therefore, prescribing antibiotics to treat NAFLD-NASH should be carefully considered and efforts should be taken to develop alternative options.

Faecal Microbiota Transplantation in NAFLD-NASH

Recently, there has been growing interest in faecal microbiota transplantation (FMT) as potential treatment of patients with chronic diseases including the metabolic syndrome.[50] FMT is shown to result durable alterations of microbiota composition.[51] Studies are currently ongoing to answer the question whether this technique is efficacious to treat NAFLD-NASH. Vrieze et al transplanted faecal microbiota from lean donors to insulin resistant patients with the metabolic syndrome.[52] This resulted in significant improved of peripheral insulin sensitivity associated with increased numbers of butyrate-producing bacteria including Roseburia and Faecalibacterium spp. in faeces and Eubacterium hallii in the intestinal lumen. A subsequent three-time larger study reproduced these findings and showed that baseline microbiota diversity was the driver of treatment efficacy regarding insulin sensitivity.[53] FMT appears to be safe and has relatively few adverse effects.[50] However, this method also has drawbacks: processing samples and selecting appropriate donors is time consuming and challenging.[54] Moreover, FMT is not a patient-friendly treatment considering the burdensome procedure involving a nasogastric tube. Therefore, it is desirable to develop treatments with more accessible administration procedures (including oral administration via capsules).

Bariatric Surgery as a Treatment for NAFLD-NASH

A number of medical and surgical strategies are available or under development for the manipulation of the gut microbiome, including bariatric surgery. Bariatric surgery is one of the most efficient procedures to treat morbid obesity. It results in drastic weight loss and improvement of metabolic and inflammatory status, which is associated with alterations in gut microbiome composition.[43] However, after jejunoileal bypass procedures, which were performed in the past to treat morbidly obese patients, both SIBO and NASH were frequently observed.[17] Other important limitations are potential nutrient deficiencies and surgical complications.[55] Hence, this does not outweigh the effect of the intestinal microbiota in reversing NAFLD-NASH. Therefore, it only a suitable option in selected patients.

Probiotics

Probiotics are living, non-pathogenic microorganisms that are thought to provide benefits when consumed in sufficient amounts.[56] Probiotics effect on gut microbiota is widely known, but evidence showing an effect of probiotics on NAFLD-NASH has only recently been shown in humans. The main probiotics on the market are Lactobacilli, Streptococci and Bifidobacteria. These can be used to prevent the expansion of Gram-negative bacteria.[57] Therefore, it is not surprising that most of the research to find treatments for NAFLD-NASH is focusing on the use of these probiotics.

Lactobacillus is a genius of Gram-positive bacteria which are able to convert sugars into lactic acid.[57] Various animal studies showed a glucose metabolism improvement and anti-inflammatory effects of Lactobacillus casei supplementation. Okubo et al investigated the effect of 6 weeks supplementation of the Lactobacillus casei Shirota (LcS) strain in methionine-choline-deficient (MCD) diet induced NASH mice. Moreover, supplementation improved the symptoms of NASH as in improved hepatic histology. In high-fat diet induced and genetic db/db obese mice supplementation with LcS significantly improved insulin resistance and plasma levels of LPS binding protein.[58,59] Wagnerberger et al showed in a mouse model that LcS treatment protected against NAFLD induced by fructose consumption by suppressing the activation of the TLR4 signalling cascade in the liver.[60] Taken these results together, the proposed underlying mechanisms of the beneficial effects of LcS are the improvement of endotoxaemia. Another strain of Lactobacillus that has been shown to be beneficial in NAFLD-NASH is Lactobacillus paracasei. Sohn et al treated NASH mice with L paracasei and reported significant lower hepatic fat deposition and serum ALT levels in the treatment group compared with the control group.[61] Besides, a lower expression of TLR-4, NADPH-oxidase-4, TNF-α, monocyte chemotactic protein-1, IL-4, PPAR-γ and PPAR-δ was observed in the treatment group. In line with the other Lactobacillus species, some other studies showed that L plantarum strains were effective in lowering serum lipids, improving liver function and decreasing hepatic fat accumulation in animal models.[57] In addition, several other species of Lactobacilli bacteria have shown beneficial effects in NAFLD-NASH prevention in animal models.[57]

Although these animal studies show interesting findings, the effects of Lactobacilli in human is less pronounced. Only three studies including Lactobacillus are found in literature, using different Lactobacillus species. Vajro et al included 20 obese children with persisting hypertransaminasaemia and mild to moderate ultra-sonographic proven fatty liver in a double blind, placebo-controlled study. Patients received either Lactobacillus rhamnosus strain GG or a placebo for 8 weeks. After 8 weeks, treatment with the probiotic did not have an effect on visceral adiposity but a significant decrease in ALT aminotransferase was observed. On the same side, Monem observed a significant decrease in ALT and AST after treatment with a Lactobacillus acidophilus in NASH patients compared to the placebo.[62] However, it should be noticed that, Lactobacilli are widely used within the livestock industry to induce weight gain in animals.[63,64] These effects have also been shown in both in children and adult humans.[65,66] Thus, treatment with Lactobacilli in humans should be carefully considered.

Bifidobacterium belongs to the Bifidobacteria genera and is another frequently used probiotic. Cano et al studied the effect of a probiotic consisting of Bifidobacterium pseudocatenulatum in both wild type and high-fat diet-induced mice compared to placebo after 7 weeks.[67] In high-fat diet fed mice the supplementation of Bifidobacterium was associated with beneficial effect (ie lower food intake and reduced adiposity, insulin resistance, steatosis and a reduction in serum inflammatory markers). No studies concerning the effects of Bifidobacterium as single probiotics on NAFLD-NASH in human have been found.

Xue et al analysed the effects of combined probiotics on the LPS/TLR4 pathway.[68] First, they showed in a rat model that serum LPS and liver TRL4 were highly increased during the progression of NAFLD. Then, they showed that the supplementation of a combined probiotic (Bifidobacterium infantis, Lactobacillus acidophilus, and Bacillus cereus) improved gut dysbiosis and downregulated serum LPS and liver TLR4. Liang et al showed in SD rats on a high-fat diet treatment with a probiotic mixture of six Lactobacillus and three Bifidobacterium strains significantly reduced body weight and the levels of serum free fatty acids, TG, ALT, TNF-α, IL-1β and IL-18, compared to a control group. Furthermore, in the high-fat diet fed rats expression of Gpr109a was significantly increased in the liver and adipose tissue, the probiotic mixture significantly reduced this. Additionally, they demonstrated that faecal butyrate was elevated.[69] Proposing that the probiotic mixture might inhibit systemic adiposity and inflammation trough butyrate and Gpr109a. VSL#3, a combination of eight types of bacteria (Bifidobacterium breve, Bifidobacterium longum, B infantis, Streptococcus thermophilus, L plantarum, L acidophilus, L paracasei and Lactobacillus delbrueckii spp. bulgaricus). VSL#3 has been shown promising for the treatment of various diseases including NAFLD-NASH. Experimental data has shown that VSL#3 could lower inflammation via modulation of the NF-κB pathway, reduce hepatic fat accumulation and ALT levels and improve insulin sensitivity in NAFLD mice models.[57]

Until now, data on the beneficial effects of probiotics in NAFLD-NASH comes mainly from experimental models. Some data from human intervention studies show promising results. Wong et al investigated the effect of 6-month treatment with probiotics consisting of multiple bacteria species (L plantarum, L delbrueckii spp. bulgaricus, L acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum) or placebo in adult patients with biopsy-proven NASH (n = 20).[70] Subjects treated with probiotic displayed a significant reduction in liver fat content which was associated with a shift in microbiota composition, while the placebo group did not. On the same side, recent data on NAFLD-NASH patients treated with probiotics showed an improvement of γ-glutamine transferase levels, AST and ALT levels and cytokine levels after short term, 4-12 weeks, supplementation of different combinations of different Lactobacillus, Bifidobacterium and Streptococcus species.[71–74]

Alisi et al examined the effects of VSL#3 in a randomised double-blind controlled study in obese children with biopsy-proven NAFLD. Four months supplementation of VSL#3 resulted in significantly improved liver function and increased levels of glucagon like peptide (GLP) 1/active GLP-1. However, no improvement in triglycerides, HOMA and ALT were observed. These results suggest that the effects of VSL#3 might be GLP-1 dependent. It is suggested that VSL#3 treatment results in reduced intestinal permeability, increased production of SCFAs and anorexigenic gut hormones (including GLP-1 and GLP-2) and enhancement of insulin sensitivity.[75] Loguercio et al included 22 subjects with NAFLD in their study aiming to evaluate whether chronic therapy with VSL#3 affects plasma levels of cytokines, oxidative/nitrosative stress parameters and liver damage in patients with various liver diseases.[76] After 3 months, plasma levels of lipid peroxidation markers malondialdehyde and 4-hydroxynonenal were improved in the subjects with NAFLD, as well as the results of routine liver damage tests, suggesting an improvement in oxidative stress. However, also studies with negative results are reported. In a small study with four subjects with NAFLD 4 months supplementation with VSL#3 resulted in an increase in hepatic fat accumulation rather than improvement of their liver conditions in three out of four subjects. After washout, a decrease in liver fat was observed.[77]

Besides the conventionally used probiotics, butyrate producing bacteria might also be a potential target. Butyrate producing bacteria gained attention because of their potential anti-inflammatory role which could slow down the progression from NAFLD to NASH. Butyrate producers are shown to be reduced in T2DM and FMT has been shown to improved insulin resistance in T2DM patients which is associated with an increase in butyrate producing bacteria.[52,78] Endo et al examined the effect of treatment with MIYAIRI 588, a butyrate producing Clostridium strain, on the progression from steatosis to hepatocarcinogenesis in mice with choline-deficient/L-amino acid-defined (CDAA)-diet-induced NAFLD.[79] They observed a decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis. Hepatic lipid deposition and endotoxin levels in the portal vein were significantly reduced. Furthermore, the levels of tight junction proteins were restored to levels compared with the control group. Additionally, MIYAIRI 588 increased the activation of AMPK and Akt and the expression of lipogenesis or lipolysis related proteins. Also, the production of nuclear factors involved in hepatic oxidative stress was induced. This study revealed that treatment with MIYAIRI 588 has beneficial effects in the prevention of the progression of CDAA induced NAFLD to states of liver carcinogenesis in rats. Furthermore, it shows that probiotics can not only alter the gut microbiota composition but also modulate the metabolic activity of microbiota. Gao et al studied the effect of butyrate supplementation in dietary induced high-fat diet fed obese mice.[80] They showed that supplementation prevented the development of insulin resistance. Fasting blood glucose, fasting insulin, and insulin tolerance were all prevented in the mice treated with butyrate. The authors propose that the mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondrial function. The treated mice showed enhanced adaptive thermogenesis and fatty acid oxidation and an increase in mitochondrial functioning. Additionally, blood lipids (triglycerides, cholesterol, and total fatty acids) were decreased. However, when oral butyrate was given for 4 weeks to human subjects, only lean subjects showed an increase in insulin sensitivity whereas obese insulin resistant subjects did not show any effect.[81]

One of the butyrate producing bacteria of particular interest for the use as probiotic is the anaerobic, Gram-positive E hallii, belonging to the Lachnospiraceae of the phylum Firmicutes. Vrieze et al observed an increase in small intestinal E hallii when insulin resistant subjects received faecal solutions from healthy subjects, which was associated with an improvement in peripheral insulin resistance. To further assess the effects of E hallii on insulin sensitivity, Udayappan et al[82] orally treated obese and diabetic db/db mice with 108 CFU alive E hallii and glycerol or heat-inactive E hallii as control. With insulin tolerance test and hyperinsulinaemic-euglycemic clamp experiments they showed that alive E hallii treatment improved insulin sensitivity compared with the control treatments. In addition, increased energy expenditure was observed in db/db mice treated with alive E hallii bacteria. Besides, treatment with active E hallii increased faecal butyrate concentrations and was shown to modestly modify SCFA production and bile acid composition. Besides improvement in insulin sensitivity, Udayappan et al showed that supplementation with E hallii resulted in significantly reduced hepatic triglyceride levels. This was also reflected in the expression pattern of genes involved in lipogenesis and gluconeogenesis. Besides, E hallii can be grown very well in industrial media and produces, making it a suitable candidate as a probiotic.

Prebiotics

Prebiotics are non-digestible but fermentable food substances which can be fermented by bacteria and thereby promote their growth.[43,83] Improvement of liver diseases after prebiotic feeding was found in several animal models as well as human subjects and various mechanisms have been proposed to explain the beneficial effects of prebiotics on NAFLD-NASH including reduced de novo lipogenesis, body weight and fat loss, SCFA production, improved glycaemic control, microbial modulation and reduced inflammation.[84] High-fat diets are associated with an increase in LPS containing gut microbiota and a lower amount of Bifidobacteria.[25] Prebiotics containing oligofructose are shown to stimulate specifically the growth of Bifidobacteria and normalise plasma endotoxin levels. Subsequently this leads to improved glucose tolerance, increased satiety and weight loss in human subjects. Besides modulating LPS, oligofructoses can alter the metabolism in various other ways such as modulation of GLP-1 or PYY and by increasing SCFAs levels, including butyrate. Lactulose is a prebiotic which is able to promote the growth of Bifidobacterium, Lactobacillus and Gram-positive bacteria, thereby it has an inhibitory effect on Gram-negative bacteria. A reduction of Gram-negative bacteria means also a reduction of endotoxaemia.[7] Yan et al showed that 6 weeks of oral administration of lactulose reduced inflammation and improved liver injury in a NASH rat model on a high-fat diet by reducing LPS levels.[85]

Less is known about prebiotics supplementation in NAFLD in humans. Parnell et al reviewed the effect of five different intervention studies. Out of these five, two intervention studies reported a decrease in serum triglycerides or cholesterol after supplementation in healthy subjects, whilst three others did not show any difference. In patients with T2DM, improvements after inulin or oligofructose were more robust and reported in six of eight studies.[84] Furthermore, oligofructose supplementation, in combination with energy intake reporting, resulted in weight loss in humans and improvements in glycaemia and modifications in plasma GLP-1, PYY and ghrelin.[86] Daubioul et al investigated the effect of daily administation of oligofructose in a randomised double-blind crossover study with seven liver-biopsy confirmed NASH patients.[87] Compared to placebo, treatment with oligofructose significantly decreased serum ALT and AST after 8 weeks and decreased insulin levels after 4 weeks. However this did not include assessment of post-treatment liver histology. Together, these findings may implicate therapeutic potential of prebiotics in the treatment of NAFLD. Nevertheless, more large-scale studies with sufficient duration should be performed in humans in order to better understand the potential of prebiotics as future treatment. Furthermore, the actual changes in gut microbiota composition and the effects on liver histology should be determined.

Synbiotics

The combination of probiotics and prebiotics are known as synbiotics. The prebiotics are used to optimise the effects of the probiotics. Few data on prebiotics is available in human in NAFLD and NASH. Eslamparast et al investigated the effects of 28 weeks supplementation with a synbiotic containing seven bacterial strains (L casei, L rhamnosus, S thermophilus, B breve, L acidophilus, B longum, and L bulgaricus) combined with oligofructose in individuals with NAFLD.[88] This resulted in significantly decreased ALT levels, inhibition of NF-κB activation and reduced TNF-α production. In line with this, Manzhalii et al found a reduction in ALT and liver stiffness in NASH patients after treatment with five of these bacteria (L casei, L rhamnosus, S thermophilus, B breve, L acidophilus, B longum, L bulgaricus) and oligofructose.[89] Malaguarnera et al reported that the combination of lifestyle intervention and a synbiotic containing B longum and oligofructose resulted in a much greater improvement in NASH patients compared with lifestyle intervention alone.[90] They observed similar effects; a reduction of serum TNF-α, CRP, endotoxin and AST levels. Furthermore, an improvement in insulin resistance and NASH activity index was observed. Additionally, treatment with synbiotics showed improvements in levels of fasting blood glucose, TAG, and inflammatory cytokines in lean individuals with NAFLD.[91] Asgharian et al studied the effects of the same synbiotic, however, they did not report changes in ALT or AST levels after treatment,[92] yet they did find an ultrasonographic reduction in hepatic steatosis compared to placebo.

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