ACADEMIA Letters

Gut Microbiome Modulation in the Management of

Nonalcoholic Fatty Liver Disease
Hassan Heshmati, Endocrinology Metabolism Consulting, LLC, Anthem, AZ, USA

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease world-
wide with a prevalence of approximately 25% among the adult population. The highest preva-
lence is observed in the Middle East (32%) and the lowest prevalence in Africa (13%). More
than 1 billion people are affected by NAFLD worldwide. NAFLD is a disorder characterized
by hepatic steatosis (at least 5% fat deposit) on either imaging or histology, with no excessive
alcohol consumption (< 30 g/day for men and < 20 g/day for women), in the absence of other
causes of steatosis (e.g., viral hepatitis and medications). It is a spectrum of liver disorders
ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Up to 30% of NAFLD
subjects develop NASH. NASH is the aggressive form of NAFLD that can progress to fibro-
sis, cirrhosis, and hepatocellular cancer. The presence of fibrosis is the strongest predictor of
mortality. The pathogenesis of NAFLD is complex and multifactorial, involving both non-
genetic and genetic factors. Pro-inflammatory diet, endocrine disruptors, overweight/obesity,
inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut
microbiome, and impaired intestinal barrier function (increased intestinal permeability or
leaky gut) are important risk factors associated with and/or contributing to NAFLD. There are
several genetic forms of NAFLD including variations in patatin-like phospholipase domain-
containing protein 3, transmembrane 6 superfamily 2, membrane-bound O-acyltransferase
domain-containing protein 7, and glucokinase regulatory protein genes (1-6).

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

1
Gut Microbiome and NAFLD
The gut microbiome is a complex and diverse microbial ecosystem living in the digestive tract,
mainly located in the colon. It is established within the few first years of life. It contains 10
to 100 trillion microbes, mainly bacteria (more than 1,000 species) but also fungi, protozoa,
archaea, and viruses. There is a complex interconnection between the gut microbiome and the
host. The gut microbiome is involved in multiple physiological functions and is essential for
the maintenance of human health. It has an important impact on intestinal barrier function.
The gut microbiome is diverse, varies between individuals, and can fluctuate over time. The
western gut microbiome has fewer species than the non-Western gut microbiome. The gut
microbiome is influenced by several factors including host genetics, mode of birth, age, gen-
der, pregnancy, body weight, diet, medication, and gastrointestinal surgery. The challenges
in the assessments of the gut microbiome are due to the diversity and the inter/intra-individual
variability caused by different factors such as age and diet (7-11).
Important changes affecting the diversity and the abundance of the gut microbiome (dys-
biosis) are associated with several metabolic disorders including obesity, type 2 diabetes, and
NAFLD. The gut microbiome plays a major role in the pathogenesis of NAFLD. Several clini-
cal studies have shown the association of qualitative and quantitative changes in the gut micro-
biome (e.g., increased Lactobacillus and Gram-negative bacteria) with NAFLD and its sever-
ity. The disrupted gut microbiome (e.g., increase in pro-inflammatory bacteria and decrease
in protective bacteria) can promote or aggravate NAFLD through several mechanisms includ-
ing an increase in intestinal permeability and an increase in the amount of absorbed energy
which can cause overweight/obesity and inflammation (important risk factors for NAFLD).
Microbial metabolites and cell components contribute to the development of inflammation
and hepatic steatosis. The increased gut microbiome taxa may produce more short-chain fatty
acids (SCFAs), alcohol, and lipopolysaccharides (LPSs). Increased supply of SCFAs, alcohol,
and LPSs (endotoxins) into the portal circulation is implicated in the pathogenesis of NAFLD
and its evolution to NASH by promoting overweight/obesity and inflammation. Inflammation
occurs mainly through the activated toll-like receptors (TLRs) of hepatic cells. LPSs are the
most prominent TLR activators (5, 6, 10-23).

Treatment of NAFLD through Gut Microbiome Modulation

There are no specific drugs that directly treat NAFLD. The first-line therapy of NAFLD is
currently based on lifestyle intervention including diet and exercise, with weight loss in sub-
jects who have excess body weight. Pharmacotherapy of NAFLD has been focused on the

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

2
improvement of insulin sensitivity, reduction of oxidative stress, and downregulation of fibro-
sis mechanisms. Recently, the gut microbiome became a promising target for the treatment of
several diseases including NAFLD. The prevention and management of NAFLD may benefit
from modulation and correction of the gut microbiome. The gut microbiome can be modulated
through diet, antibiotics, prebiotics, probiotics, synbiotics, and fecal microbiota transplanta-
tion. To optimize the efficacy of these new therapies in NAFLD subjects, the focus should be
on the altered gut microbiome (e.g., taxa responsible for high alcohol and LPS production).

Diet
Diet is an important tool for the modulation of the gut microbiome. The amount of daily
caloric intake, the content of food, and the timing of food intake significantly affect the gut
microbiome. A diet low in calories (when weight loss is indicated), low in fat, and high in fiber
has a beneficial effect on weight control and gut microbiome (increase in richness, decrease
in Firmicutes-to-Bacteroidetes phyla ratio). Therefore, the diet, through the modulation of the
gut microbiome, could be favorable in NAFLD subjects (5, 19, 23, 24).

Antibiotics
Antibiotics can deplete or alter the gut microbiome (e.g., increase in Firmicutes phylum) and
reduce liver disease development. However, the clinical use of antibiotics is limited since they
may eliminate important beneficial bacterial species and cause antibiotic resistance (5, 10, 21,
23).

Prebiotics
Prebiotics are chemicals (nondigestible food ingredients) that can induce the growth and/or
activity of intestinal bacteria (e.g., inulin, lactulose, and resistant starch). Some dietary fibers
are prebiotics. Prebiotics can be found in several foods (e.g., leek, asparagus, onion, soybean,
apple, and banana). Prebiotics lowers the production of LPS. They are able to positively
modulate the gut microbiome and improve NAFLD.
In a clinical study, treatment with oligofructose (16 g/day for 8 weeks) in subjects with
NASH showed a significant decrease of aspartate aminotransferase (AST) (5, 10, 11, 15, 19,
21, 23, 25).

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

3
Probiotics
Probiotics are nonpathogenic living microorganisms with direct or indirect effects on the gut
microbiome. They can be found in different foods (e.g., yogurt, cheese, and milk). Probiotics
reduce the production of LPS. They can positively impact the gut microbiome and improve
NAFLD.
In clinical studies, administration of Lactobacillus rhamnosus strain GG (12 billion CFU/day)
for 8 weeks in children with NAFLD showed a significant decrease of alanine aminotrans-
ferase and treatment with VSL#3 (a mixture of 8 probiotic strains) for 4 months in children
with NAFLD demonstrated a significant decrease of hepatic steatosis (5, 10, 11, 14, 15, 21,
23, 26-29).

Synbiotics
Synbiotics are a combination of prebiotics and probiotics. They have the potential to induce
more effects than prebiotics or probiotics used alone. There are few studies assessing the
effects of synbiotics on NAFLD subjects. They showed several beneficial effects including
reduction of inflammation and hepatic steatosis.
In a clinical study, administration of Bifidobacterium longum with fructo-oligosaccharides
for 24 weeks in subjects with NASH showed a significant decrease of AST, serum endotoxin,
hepatic steatosis, and NASH activity index (5, 10, 11, 21, 23, 30).

Fecal Microbiota Transplantation

Fecal microbiota transplantation consists of the transfer of feces from a healthy donor to a
recipient. The addition of healthy stool can be done through colonoscopy, orogastric tube,
esophagogastroduodenoscopy, or oral capsule. Fecal microbiota transplantation is a promis-
ing therapy with important potential indications. It was first approved by the United States
Food and Drug Administration for the treatment of Clostridium difficile infection. Fecal mi-
crobiota transplantation can modify the gut microbiome to manage obesity and metabolic
disorders. Clinical studies using fecal microbiota transplantation in NAFLD subjects are cur-
rently ongoing (10, 11, 23, 31, 32).
In conclusion, NAFLD is the most common chronic liver disease worldwide. The dis-
ease can be associated with dysbiosis reflected by a reduction of the beneficial species and
an increase in pathogenic microbiota. In the absence of approved pharmacotherapy for the
treatment of NAFLD, in addition to lifestyle intervention with weight loss when excess body
weight is present, modulating gut microbiome with diet, prebiotics, probiotics, synbiotics, and

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

4
fecal microbiota transplantation represents a promising novel treatment. Further prospective
studies are necessary in this area. Special focus should be on the altered gut microbiome taxa
responsible for high SCFAs, alcohol, and LPS production.

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Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

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Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

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Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.

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Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Hassan Heshmati, hassanheshmati@gmail.com

Citation: Heshmati, H. (2021). Gut Microbiome Modulation in the Management of Nonalcoholic Fatty Liver
Disease. Academia Letters, Article 3470. https://doi.org/10.20935/AL3470.