Probiotics & NAFLD/NASH: Emerging Therapeutic to Enhance Standard of Care

Autumn vegetables, lentils, beans, raw ingredients for cooking on trendy yellow and green background. Embodying the benefits of probiotics on clinical measures or NAFLD/ NASH.
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Nonalcoholic fatty liver disease (NAFLD), an independent cardiovascular risk factor, is a multifactorial metabolic disorder that was first described in 1980. It involves hepatic fat accumulation and inflammation in the liver without significant alcohol intake or evidence of viral hepatitis.1,2 NAFLD represents a spectrum of pathologies that, in some patients, will progress from simple steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma (HCC).1 20% of individuals with NAFLD have NASH, and 20% of these individuals may progress to cirrhosis over three to four decades.3

(Note: As a replacement for the term NAFLD, the term metabolic dysfunction–associated fatty liver disease (MAFLD) has been proposed and endorsed by several societies specializing in the study of liver disease).

NAFLD is estimated to afflict one billion individuals globally—approximately 25% of the world’s adult population—across various geographic regions of the world, with the Middle East and South America having the highest prevalence rates.4 In the US, up to 80 million individuals may have NAFLD, and the prevalence is rising, particularly among children and adolescents.3

The leading chronic liver disease worldwide, NAFLD is closely related to systemic metabolic diseases.5 Obesity is a well-known risk factor, and the prevalence of NAFLD increases as BMI increases; however, despite being closely linked with obesity, NAFLD can also manifest in non-obese individuals.1 Genetics may play a part in disease development.5 In addition to cardiovascular disease, NAFLD is also an independent risk factor for type 2 diabetes, metabolic syndrome, chronic kidney disease, and malignant tumors.5 Interestingly, the majority of individuals with NAFLD are asymptomatic, and the disease may remain silent until it has progressed to cirrhosis.3 The most common symptoms noted at initial referral among individuals with NAFLD include right upper quadrant pain and fatigue.3

Despite ongoing research, there are limited therapeutic options for the disease and its progression; standard of care remains diet modification and regular exercise.4 However, in recent years, a line of evidence has suggested a close linkage between the intestine and liver diseases such as NAFLD/NASH.3,6 Accordingly, the gut microbiome has emerged as a potential therapeutic target in combating these diseases.2-3,7-8

This research has led to a growing interest in probiotic supplementation as a potential treatment for NAFLD/NASH, as probiotics have been shown to regulate the composition of intestinal flora and the production of antibacterial factors, as well as change the permeability of the epithelium of the intestine to affect disease development and progression.9 Probiotics may also exert effects on NAFLD by modifying endotoxemia, inhibiting inflammatory response, and regulating the immune system.9 What is the connection between the gut microbiota and NAFLD/NASH, and can the use of probiotics affect the clinical measures of this disease?

Gut Microbiota & NAFLD/NASH

Recent breakthroughs in the understanding of the pathogenesis of NAFLD/NASH have pointed to gastrointestinal dysbiosis as an underlying factor.7,8 A dysbiotic environment can lead to a series of problems, including the overgrowth of detrimental bacteria, increased gut barrier permeability, bacterial translocation, and the flow of metabolites to the liver.8 This plays a critical role in NAFLD onset and progression via the gut-liver axis.2 Small intestinal bacterial overgrowth (SIBO) and inflammation are main causes of increased intestinal permeability in NAFLD.8,10

The gut-liver axis enhances interactions between metabolites of the intestinal microbiome and receptors on the liver and plays a critical role in NAFLD onset and progression.2,8 When the gut is in a dysbiotic state, this can trigger a series of events that culminate in insulin resistance, inflammation of the liver, and eventually the development of liver fibrosis.8 The portal vein is the anatomical and functional link between the gut and the liver and is the direct venous outflow from the intestines.8 Thus, when the intestinal mucosal barrier is compromised, it exposes hepatic tissue to toxic factors derived from the intestines.8

Various metabolites produced by intestinal bacteria that reach the liver have been linked to the manifestation of simple steatosis, NAFLD, and NASH.8 Interestingly, higher intestinal permeability has been observed in children with steatohepatitis compared with children with steatosis, indicating that the level of intestinal permeability may also be related to the different stages of NAFLD.10

A link between NAFLD/NASH and the gut microbiome is supported by several recent studies.3,6,11-14 However, it is important to note that some studies comparing the specific bacterial taxonomic compositions between patients with NAFLD and control subjects have contradictory findings.6 A common finding in NAFLD patients is an increase in Lactobacillus and Escherichia and a decrease in Coprococcus.6 NAFLD-related advanced fibrosis is associated with an overall decrease in microbial diversity, including Bacteroides and Escherichia, secondary to an increase in gram-negative bacteria.15

Emerging Intervention: The Use of Probiotics

Therapeutic manipulations with probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management.2 A 2023 systematic review and meta-analysis of 41 randomized controlled trials suggests that the use of prebiotics, probiotics, and synbiotics significantly improved liver steatosis (measured by ultrasound grading) (SMD: 4.87; 95% confidence interval [CI]: 3.27, 7.25), fibrosis (SMD: -0.61 kPa; 95% CI: -1.12, -0.09 kPa), and liver enzymes, including alanine transaminase (SMD: -0.86 U/L; 95% CI: -1.16, -0.56 U/L), aspartate transaminase (SMD: -0.87 U/L; 95% CI: -1.22, -0.52 U/L), and gamma-glutamyl transferase (SMD: -0.77 U/L; 95% CI: -1.26, -0.29 U/L).16

A 2022 systematic review and meta-analysis also suggests that the use of probiotics, prebiotics, and synbiotics may be associated with small to moderate positive effects on glucose, insulin, sugar, lipid, and protein metabolism, as well as levels of total cholesterol and low-density lipoprotein cholesterol.9 They can also exert effects on NAFLD by modifying endotoxemia, inhibiting inflammatory response, and regulating the immune system.9 There is further evidence that probiotics may have a positive effect on the clinical measures of NAFLD/NASH. Specifically:

  • In a randomized clinical trial, probiotic therapy with VSL#3 (a high-concentration, multi-strain probiotic mix) not only improved but ameliorated hepatic parameters in a 2022 randomized clinical trial, including a statistically significant decrease in triglycerides and high-sensitivity C-reactive protein.17 Aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT), widely used markers of liver disease, were significantly lower in the probiotic group. All 60 patients reported an improvement or the disappearance of hepatic steatosis.17
  • A randomized, double-blind, proof of concept study in 2019 was the first human study to show the histological efficacy of a probiotic in patients with a biopsy-proven diagnosis of NAFLD.18 The inclusion of an exercise intervention and dietary restriction, along with a high-concentration multistrain probiotic, significantly improved liver histology, including a decrease in leptin levels, serum ALT, and inflammatory cytokines, compared to diet and exercise interventions alone. Since there was no significant change in either body weight or components of metabolic syndrome in either group, significant improvement in histological parameters, ALT, and cytokine profile in the probiotic group would suggest the beneficial effect of probiotics rather than the effect of the lifestyle interventions.18

There is no consensus in the literature as to what strains of probiotics are most effective; more research is needed with a focus on specific strains. Probiotics are an exciting and promising treatment option and can be used in combination with the standard of care, which includes diet modification and regular exercise.

Dietary Guidelines for NAFLD/NASH

Improved dietary composition by itself, weight loss of 5-10% of the initial body weight, and moderate exercise can make a difference for NASH patients in terms of improvement of all histological features.19 Lifestyle interventions that focus on reduced energy intake and improved dietary pattern are the mainstay of NAFLD management.20 Dietary factors and patterns also play a critical role in the modulation of gut microbiota.2 Current guidelines, as outlined by the National Institute of Diabetes and Digestive and Kidney Diseases, includes limiting the intake of fats, replacing saturated and trans fats with unsaturated fats, eating more low-glycemic index foods (such as vegetables and whole grains), and avoiding foods and drinks that contain large amounts of simple sugars, especially fructose.21

The most substantial evidence available for lifestyle intervention in NAFLD/NASH is weight reduction and the Mediterranean dietary pattern, which is characterized by a plentiful intake of olive oil, vegetables, fruits, nuts, legumes, whole grains, fish, and seafood and a low intake of red meat and especially processed meat, along with reduced carbohydrate intake (40% of the calories vs 50-60% in a typical low-fat diet), especially sugars.19-20

A recent 18-month trial with 294 participants suggests the Mediterranean diet may be enhanced by additional green plants rich in polyphenols.19 The green-Mediterranean diet reduced hepatic fat by 39% compared with 20% for the Mediterranean diet, despite similar weight loss, and both diets did better than controls provided only with healthy dietary guidelines. The importance of increased phenolic acid intake (from fruits and vegetables, nuts, green tea, and coffee) is independently associated with lower prevalence of insulin resistance, NAFLD, and fibrosis.19

A 2022 systematic review and meta-analysis found that when compared with standard care, calorie restriction interventions improved ALT, hepatic steatosis measures, and liver stiffness measurement.20 There was a dose-response relationship between degree of calorie restriction and beneficial effects on liver function and weight loss, suggesting that this approach should remain the cornerstone of NAFLD management.

It is interesting to note that, over two weeks, a carbohydrate-restricted diet reduced liver fat more than a calorie-restricted diet. While there is currently no clear definition in the medical literature of a low-carbohydrate diet for NAFLD/NASH, the <20g carbohydrate diet used in this trial may be regarded as a very low-carbohydrate, potentially ketogenic diet.20

Functional Medicine Considerations

The functional medicine (FM) model helps practitioners utilize a systems biology approach to link seemingly disconnected organ systems through a common underlying cause: chronic inflammation. At IFM’s Cardiometabolic Advanced Practice Module (APM), practitioners will get a review of modifiable drivers of chronic inflammation through advanced training in nutritional biochemistry and exercise physiology. In addition to teaching clinicians how to help patients optimize lifestyle modifications, FM-certified educators will also elaborate on underdiagnosed yet prevalent etiologies of prolonged inflammation. When treatment is personalized, these novel strategies can reduce liver transplantation and extrahepatic disease risks for those with NAFLD/NASH.

The Cardiometabolic APM provides a logical method to identify the unique drivers of each patient’s cardiometabolic disease using common lab markers and genetic principles. Learn about the discrete mechanisms that underpin these diseases and how to implement personalized care plans, which may include such interventions as an anti-inflammatory food plan, a personalized exercise prescription, or probiotics. Functional medicine can help clinicians implement evidence-based interventions to ultimately reverse NAFLD and improve patient outcomes.

Learn More About Cardiometabolic Function

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  1. Zarghamravanbakhsh P, Frenkel M, Poretsky L. Metabolic causes and consequences of nonalcoholic fatty liver disease (NAFLD). Metabol Open. 2021;12:100149. doi:1016/j.metop.2021.100149
  2. Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin Biochem. 2015;48(13-14):923-930. doi:1016/j.clinbiochem.2015.06.023
  3. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184(10):2537-2564. doi:1016/j.cell.2021.04.015
  4. Babu AF, Csader S, Lok J, et al. Positive effects of exercise intervention without weight loss and dietary changes in NAFLD-related clinical parameters: a systematic review and meta-analysis. Nutrients. 2021;13(9):3135. doi:3390/nu13093135
  5. Kang SH, Lee HW, Yoo JJ, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2021;27(3):363-401. doi:3350/cmh.2021.0178
  6. Sharpton SR, Ajmera V, Loomba R. Emerging role of the gut microbiome in nonalcoholic fatty liver disease: from composition to function. Clin Gastroenterol Hepatol. 2019;17(2):296-306. doi:1016/j.cgh.2018.08.065
  7. Perumpail BJ, Li AA, John N, et al. The therapeutic implications of the gut microbiome and probiotics in patients with NAFLD. Diseases. 2019;7(1):27. doi:3390/diseases7010027
  8. Saltzman ET, Palacios T, Thomsen M, Vitetta L. Intestinal microbiome shifts, dysbiosis, inflammation, and non-alcoholic fatty liver disease. Front Microbiol. 2018;9:61. doi:3389/fmicb.2018.00061
  9. Li S, Liu J, Wang Z, et al. The promising role of probiotics/prebiotics/synbiotics in energy metabolism biomarkers in patients with NAFLD: a systematic review and meta-analysis. Front Public Health. 2022;10:862266. doi:3389/fpubh.2022.862266
  10.  Yao M, Qv L, Lu Y, Wang B, Berglund B, Li L. An update on the efficacy and functionality of probiotics for the treatment of non-alcoholic fatty liver disease. Engineering. 2021;7(5):679-686. doi:1016/j.eng.2020.01.017
  11.  Caussy C, Tripathi A, Humphrey G, et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. 2019;10(1):1406. doi:1038/s41467-019-09455-9
  12.  Oh TG, Kim SM, Caussy C, et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab. 2020;32(5):878-888.e6. doi:1016/j.cmet.2020.06.005
  13.  Ottosson F, Brunkwall L, Ericson U, et al. Connection between BMI-related plasma metabolite profile and gut microbiota. J Clin Endocrinol Metab.2018;103(4):1491-1501. doi:1210/jc.2017-02114
  14.  Loomba R, Seguritan V, Li W, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease [published correction appears in Cell Metab. 2019;30(3):607]. Cell Metab. 2017;25(5):1054-1062.e5. doi:1016/j.cmet.2017.04.001
  15.  Caussy C, Hsu C, Lo MT, et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology. 2018;68(3):918-932. doi:1002/hep.29892
  16.  Rong L, Ch’ng D, Jia P, Tsoi KKF, Wong SH, Sung JJY. Use of probiotics, prebiotics, and synbiotics in non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2023;38(10):1682-1694. doi:1111/jgh.16256
  17.  Derosa G, Guasti L, D’Angelo A, et al. Probiotic therapy with VSL#3® in patients with NAFLD: a randomized clinical trial. Front Nutr. 2022;9:846873. doi:3389/fnut.2022.846873
  18.  Duseja A, Acharya SK, Mehta M, et al. High potency multi-strain probiotic improves liver histology in non-alcoholic fatty liver disease (NAFLD): a randomized, double-blind, proof of concept study. BMJ Open Gastroenterol. 2019;6(1):e000315. doi:1136/bmjgast-2019-000315
  19.  Dufour JF, Anstee QM, Bugianesi E, et al. Current therapies and new developments in NASH. 2022;71(10):2123-2134. doi:10.1136/gutjnl-2021-326874
  20.  Haigh L, Kirk C, El Gendy K, et al. The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Clin Nutr. 2022;41(9):1913-1931. doi:1016/j.clnu.2022.06.037
  21.  National Institute of Diabetes and Digestive and Kidney Diseases. Eating, diet, & nutrition for NAFLD & NASH: how can my diet help prevent or treat NAFLD? National Institutes of Reviewed April 2021. Accessed October 17, 2022.

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