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Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

Article  in  Advances in Nutrition · March 2017

DOI: 10.3945/an.116.013151

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 REVIEW

Nonalcoholic Fatty Liver Disease, the Gut

Microbiome, and Diet1,2
Zeinab Mokhtari,3 Deanna L Gibson,4 and Azita Hekmatdoost3,5*
3
Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology
Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Department of Biology, University of British Columbia, Okanagan
Campus, Kelowna, British Columbia, Canada; and 5Department of Gastroenterology, Hepatology, and Nutrition, University of British Columbia,
Vancouver, British Columbia, Canada

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ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the world, yet the pathogenesis of the disease is not well
elucidated. Due to the close anatomic and functional association between the intestinal lumen and the liver through the portal system, it is
speculated that the gut microbiome may play a pivotal role in the pathogenesis of NAFLD. Furthermore, diet, which can modulate the gut
microbiome and several metabolic pathways involved in NAFLD development, shows a potential tripartite relation between the gut, diet, and
the liver. In this review, we summarize the current evidence that supports the association between NAFLD, the gut microbiome, and the role of
diet. Adv Nutr 2017;8:240–52.

Keywords: nonalcoholic fatty liver disease, gut microbiota, diet, NAFLD, NASH, probiotics

Introduction
Nonalcoholic fatty liver disease (NAFLD)6 is the most com-
mon cause of chronic liver diseases in the world (1). NAFLD
is defined as a liver pathologic spectrum, which is initiated
by steatosis that may progress to nonalcoholic steatohepati-
tis (NASH). NASH manifestations beyond steatosis include
necro-inflammation and fibrosis (2). The disease can prog-
ress to cirrhosis and eventual hepatocellular carcinoma
(3). The reported prevalence of NAFLD is 30% in Western
countries (1, 4) and 12–24% in Asia (5), which shows the
global importance of understanding the disease pathology.
In addition to genetic background, environmental factors
such as diet and the intestinal microbiome should be consid-
ered critical factors in the development of NAFLD (6, 7).
The gut microbiome, the trillions of microbes living in
the gut, may contribute to the pathogenesis of liver diseases
(8, 9). Increasing evidence in recent decades shows that the
gut microbiome plays a significant role in metabolism,
1
The authors reported no funding received for this study.
2
Author disclosures: Z Mokhtari, DL Gibson, and A Hekmatdoost, no conflicts of interest.
*To whom correspondence should be addressed. E-mail: a_hekmat2000@yahoo.com.
6
Abbreviations used: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ASC,
apoptosis-associated speck-like protein; FAS, fatty acid synthase; FIAF, fasting-induced ad-
ipocyte factor; FOS, fructo-oligosaccharide; GLP1, glucagon-like peptide 1; GPR, G-protein–
coupled receptor; HFD, high-fat diet; LPL, lipoprotein lipase; NAFLD, nonalcoholic fatty liver
disease; NASH, nonalcoholic steatohepatitis; PYY, peptide YY; RS, resistant starch; SREBP-1,
sterol regulatory element binding protein 1; TLR, toll-like receptor.
health, and disease of the host (10), which suggests that
the gut microbiome is a metabolic organ in the host. Con-
sidering that the anatomy of the liver facilitates a close inter-
action between the liver and gut microbiome, it is possible
that gut microbial metabolites and circulating byproducts
influence liver function. Indeed, it is known that slow blood
flow and fenestrated endothelium in the sinusoids lead to
the interaction between substances derived from the gut
and hepatocytes, parenchymal cells, and hepatic immune
cells (11). Similarly, dietary antigens are known to affect
liver function, and because dietary components are among
the strongest factors that predict the ecosystem that makes
up the gut microbiome (12, 13), both diet and the micro-
biome need to be considered in the pathogenesis of NAFLD.
In the present review, we summarize the current evidence
that supports the association between NAFLD, the gut
microbiome, and dietary factors.
Current Status of Knowledge
NAFLD and the gut microbiome. The gut harbors
;1013–1014 bacteria, which is predicted to encode genes
>100 times as in the human genome (14). Despite the
wide microbial diversity in humans, only 4 main phyla dom-
inate: Firmicutes, Bacteroidetes, Actinobacteria, and Proteo-
bacteria. Approximately 90% of the microbes come from the
Firmicutes and Bacteroidetes phyla (14) and each has unique

240 ã2017 American Society for Nutrition. Adv Nutr 2017;8:240–52; doi:10.3945/an.116.013151.
functions. Major contributors of Firmicutes are as follows:
Lachnospiraceae, which are composed mostly of microbes
from the genera Blautia, Clostridium, Coprococcus, Eubac-
terium, Roseburia, and Ruminococcaceae, which are com-
posed mostly of the genera Faecalibacterium, Oscillospira,
and Ruminococcus. Major contributors of the Bacteroidetes
phylum are Bacteroides, Parabacteroides, Porphyromonas,
Prevotellaceae (Prevotella), and Rikenellaceae (Alistipes).
The most prominent Actinobacteria are Bifidobacteriaceae
(Bifidobacterium), and the most abundant Proteobacteria
are the Enterobacteriaceae (Escherichia) (15, 16). Although
the functions of most Firmicutes are not yet clear, there is
some evidence that indicates that some members of this
phylum are among the butyrate-producing bacteria that
increase energy extraction from the diet (17–19). On the
other hand, members of the phylum Bacteroidetes
participate in carbohydrate metabolism and accomplish
this by expressing enzymes similar to glycosyl transferases,
glycoside hydrolases, and polysaccharide lyases (20).
Understanding the functions associated with the microbial
community is important, because alterations in the
intestinal microbiota have been associated with host
diseases, including obesity, type 2 diabetes, and NAFLD
(8, 21, 22). In patients with NAFLD, the microbiome’s
abundance (23) and community structure is altered (also
called dysbiosis) (15, 24). The importance of the gut
microbiome in the prevention and treatment of NAFLD is
highlighted by the fact that fecal transplantation from
mice with NAFLD into wild-type mice caused NAFLD in
mice that received the microbiota (25). In addition, the
alteration of microbiota can change the disease severity
(26–30). Overall, these results suggest that the microbiome
is important in NAFLD.
Several lines of evidence have shown that NAFLD can be
affected by the gut microbiome through various proposed
mechanisms. The contribution of increased intestinal per-
meability (20), overgrowth of bacteria (15), and elevated se-
rum LPS (31, 32) has been shown in patients with NAFLD.
Overgrowth of bacteria, in particular gram-negative bacte-
ria, increases the production of hepatotoxic products such
as LPS (23). The disruption of the intestinal integrity in-
creases intestinal permeability, which leads to bacterial
translocation, and bacterial endotoxins penetrate into the
portal vein, which increases the risk of NAFLD development
through the activation of hepatic inflammatory cells (23,
33). Bacterial endotoxins are recognized by toll-like recep-
tors (TLRs) on hepatocytes, which recognize several compo-
nents of microbes and initiate immunologic responses (32).
When bacterial LPS signals through TLR4, signaling ulti-
mately activates NF-kB and proinflammatory cytokines
(32, 34). Moreover, dysbiosis is associated with reduced syn-
thesis and secretion of fasting-induced adipocyte factor
[(FIAF) also known as angiopoietin-like 4] in enterocytes,
which results in increased activity of lipoprotein lipase
(LPL) and the accumulation of TGs in the liver (35, 36).
Dysbiosis and inflammasome deficiency may be important
in the development of hepatic steatosis and inflammation (37,
38). Inflammasomes are cytoplasmic multiprotein complexes
that sense endogenous or exogenous stress- or damage-
associated molecular patterns (39, 40). Upon sensing the rel-
evant signal, they assemble, typically together with the adaptor
protein, apoptosis-associated speck-like protein (ASC), into a
multiprotein complex that governs caspase-1 activation and
subsequent cleavage of effector proinflammatory cytokines,
including pro–IL-1b and pro–IL-18, which ultimately leads
to apoptosis (38). In inflammasome deficiency, large amounts
of bacterial endotoxins enter the portal vein, and the liver then
has to process high amounts of endotoxins, which leads to ab-
errant and damaging inflammatory responses that promote
progression to NASH (37). Another mechanism by which
the gut microbiota contributes to the development of NAFLD
may be through increasing the number of ethanol-producing
bacteria (e.g., Escherichia coli) (15). These bacteria produce al-
cohol, which could participate in the disruption of gut per-
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meability, the generation of ROS, and consequently, liver
inflammation (41, 42). However, the specific mechanisms
of this hypothesis require further investigation.
The characterization of the gut microbial composition
and comparing it between patients and healthy individuals
is regarded as one way of identifying a healthy microbial ec-
osystem (43). Indeed, a few studies have examined dysbiosis
in NAFLD (Table 1). Patients with NASH harbor a lower abun-
dance of Faecalibacterium and Firmicutes (Clostridiales
family, Anaerosporobacter) but a higher abundance of Para-
bacteroides and Allisonella in their fecal microbiome (45).
Importantly, it has been reported that improved intrahepatic
TG content is related to a lower abundance of Firmicutes
and a higher abundance of Bacteroidetes (45). In support
of this, obese individuals with NAFLD have increased mem-
bers of the phylum Firmicutes [Lachnospiraceae (Dorea,
Robinsoniella, and Roseburia)] (46). Yet, children and adoles-
cents with NASH do not show similar patterns and instead
have increased Bacteriodetes [Prevotellaceae (Prevotella,
Porphyromonas)] and Proteobacteria [Enterobacteriaceae
(Escherichia), Alcaligenaceae] and a decrease in Firmicutes
[Lachnospiraceae (Blautia, Coproccus, Eubacterium, Roseburia),
Ruminococcaceae (Faecalibacterium, Oscillospira, Ruminococcus)]
and Actinobacteria [Bifidobacteriaceae (Bifidobacterium)]
in their fecal microbiomes (15). In support of these stud-
ies, pediatric patients with NAFLD showed an increase in
Bradyrhizobium, Anaerococcus, Peptoniphilus, Propionibacterium
acnes, Dorea, and Ruminococcus and a decrease in Oscillospira
and Rikenellaceae (44). Although it is clear that there may
be some discrepancies in what defines dysbiosis in liver dis-
ease, the frequency of disease also occurs in association with
obesity and is considered a manifestation of metabolic syn-
drome. Thus, the dysbiosis may be related to these metabolic
disturbances, considering that several studies suggested
that increased Firmicutes and reduced Bacteroidetes
may be a cause of obesity (17, 47). However, the reduction
in Bacteroidetes is not simply a cause of obesity in patients
with NASH, considering that Bacteroidetes abundance is re-
duced in these patients even after adjusting for BMI and fat
intake (24).
Gut microbiome and NAFLD: role of nutrition 241
TABLE 1 Intestinal microbiota composition in patients with NAFLD1
Study, year
(ref) Subjects
Del Chierico et al., 2016 Pediatric NAFLD, NASH, or obesity (n = 61); 16S rRNA pyrosequencing NAFLD vs. healthy controls:
(44) healthy subjects (n = 54)
Mouzaki et al., 2013 (24) NASH (n = 22); SS (n = 11); healthy
controls (n = 17)
Wong et al., 2013 (45) NASH (n = 16); healthy controls (n = 22)
Raman et al., 2013 (46) Obese NAFLD patients (n = 30); healthy
controls (n = 30)
Zhu et al., 2013 (15) NASH children (n = 22); obese children
(n = 25); healthy children (n = 16)
Wigg et al., 2001 (23) Healthy controls (n = 23)
1
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ref, reference; rRNA, ribosomal RNA; SS, simple steatosis; [, increased; Y, decreased.
Overall, the evidence suggests that the gut microbiome
may have an important role in NAFLD pathology, but
the studies have not identified a particular microbe in-
volved due to the heterogeneous results. Similar to other
microbiome studies, discrepancies can be due to variations
in the study designs. Some of the studies, such as the study
conducted by Zhu et al. (15), used patients with no history
of antibiotics, probiotics, proton pump inhibitors, and his-
tamine receptor antagonists within 3 mo before examining
the fecal microbiota; however, others did not consider all of
these precautions. In addition, the collection and process-
ing of fecal samples have been shown to produce large var-
iances and inaccuracies in the interpretation of the taxa
present in the microbiota (48), which may be a contribut-
ing factor to the conflicting data found in NAFLD micro-
biome studies. Even so, all of these studies have evaluated
the association, and well-designed studies are needed to
unravel any causal relation between the gut microbes and
NAFLD.
242 Mokhtari et al.
Change in
Method microbiota
[Bradyrhizobium, Anaerococcus, Peptoniphilus,
Propionibacterium acnes, Dorea, Ruminococcus
YOscillospira and Rikenellaceae
qPCR NASH vs. both SS and healthy controls:
YPercentage of Bacteroidetes (Bacteroidetes to
total bacteria counts)
NASH vs. SS:
[Clostridium coccoides
16S rRNA pyrosequencing NASH vs. healthy controls:
YFaecalibacterium, YAnaerosporobacter
[Parabacteroides, [Allisonella
Improvement in intrahepatic TG content was
associated with a reduction in the abundance of
Firmicutes (R2 = 0.4820, P = 0.0028) and an
increase in Bacteroidetes (R2 = 0.4366,
P = 0.0053)
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16S rRNA pyrosequencing Obese NAFLD vs. healthy controls:
[Lactobacillus species
[Firmicutes (Lachnospiraceae; genera: Dorea,
Robinsoniella, and Roseburia)
YOne member of phylum Firmicutes
(Ruminococcaceae; genus, Oscillibacter)
YA member of phylum Bacteroidetes
(Porphyromonadaceae)
16S rRNA pyrosequencing NASH vs. healthy controls:
[Proteobacteria [Enterobacteriaceae (Escherichia),
Alcaligenaceae]
[Bacteroidetes [Prevotellaceae (Prevotella),
Porphyromonas], YRikenellaceae (Alistipes)
YActinobacteria [Bifidobacteriaceae
(Bifidobacterium)]
YFirmicutes [Lachnospiraceae (Blautia, Coproccus,
Eubacterium, Roseburia), Ruminococcaceae
(Faecalibacterium, Oscillospira, Ruminococcus)],
[Peptoniphilus
C-D-xylose and lactulose Small intestinal bacterial overgrowth was present in
breath test 50% of patients with nonalcoholic steatosis and
in 22% of control subjects (P = 0.048)
Diet and the gut microbiome. Dietary factors are strong
predictors of the gut microbiota composition (49–51). In
fact, it has been projected that dietary factors play a more im-
portant role in shaping the gut microbiota composition than
do genetic factors (52). To understand the role of nutrition,
the gut microbiome, and NAFLD, we summarized the exper-
imental studies that evaluated this potential relation (Table 2).
Energy homeostasis and the gut microbiota. An imbal-
ance between energy intake and expenditure is regarded as
the main cause of increased hepatic lipogenesis. Increased
lipogenesis and reduced FA oxidation result in increased sus-
ceptibility to hepatic steatosis and the subsequent conse-
quences (63). Several studies indicated that an increase in
the relative abundance of the members of Firmicutes, and
especially of some Clostridium clusters, is involved in har-
vesting energy from the diet (17, 18, 64), and this contrib-
utes to the development of excessive weight gain and
hepatic lipogenesis.
TABLE 2 Studies evaluating the effects of dietary factors on the gut microbiota in animal models of NAFLD1
Study, year Animal Main
(ref) model Treatment Method(s) results
Saha and Reimer, Wistar rats HF or HP diet from 3 to 15 wk of qPCR HF vs. control group:
2014 (53) age; a high-fat, high-sucrose diet [Total bacteria, [Bifidobacteria,
from 15 to 21 wk; the respective and [Bacteroides:Prevotella
HF or HP diets from 21 to 25 wk HF vs. HP:
YFirmicutes, YFirmicutes:
Bacteroidetes, Yhepatic
cholesterol content
Negative correlation between
liver weight and Bacteroides:
Prevotella (r = 20.415, P = 0.044)
Bomhof et al., 2014 (54) Sprague-Dawley rats Initiate with a high-fat, high-sucrose qPCR Prebiotic oligofructose vs control:
diet for 8 wk and then prebiotic YEnergy intake, Y weight gain,
OFSs vs. the probiotic BB-12 Yfat mass, [PYY, [Bifidobacteria,
for 8 wk [Lactobacilli
Improved glycemia and
Yinsulin concentrations,
Yliver TGs in OFSs and BB-12

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Ritze et al., 2014 (55) C57BL/6 mice High-fructose diet with LGG vs.
high-fructose diet over 8 wk
Zeng et al., 2013 (56) C57BL/6 mice HFD vs. LFD for 10 wk
Park et al., 2013 (57) C57BL/6J mice HFD + probiotic (Lactobacillus
curvatus HY7601 and Lactobacillus
plantarum KY1032) vs.
HFD + placebo for 10 wk.
Pachikian et al., C57BL/6J mice n–3 PUFA–depleted diet for 3 mo
2013 (58) supplemented with FOSs during the
last 10 d of treatment
Cano et al., 2013 (59) C57BL/6 mice HFD supplemented with Bifidobacterium
pseudocatenulatum CECT 7765 vs.
HFD for 7 wk
[GLP-1 in OFSs
[GLP-2 in probiotic BB-12
No differences in plasma LPS,
TNF-a, IL-6, IL-1β
qPCR High-fructose diet with LGG vs.
high-fructose diet:
YALT, Yfat, Yaccumulation in liver,
YChREBP, YACC1, YFAS,
YTNF-a, YIL-1β, [occludin,
YLPS, [total bacterial numbers
Sequencing 16S rRNA HFD vs. LFD:
[Hepatic lipid accumulation,
[inflammatory cell infiltration,
[leptin, [TNF-a
[Lactobacillus gasseri and/or
[Lactobacillus taiwanensis
Positive correlation of L. gasseri
and/or L. taiwanensis DNA and
lipid droplets in liver
Sequencing 16S rRNA HFD + probiotic vs. HFD + placebo:
YALT, [FA oxidation–related
genes, Yproinflammatory
genes (TNFa, IL6, IL1b), Ygut
microbiota diversity,
[Bifidobacterium Pseudolongum
DGGE, qPCR n-3 PUFA-depleted diet
supplemented with FOSs
vs. n-3 PUFA-depleted diet:
[Bifidobacterium spp.
YRoseburia spp., YSREBP2,
[PPAR-a, YLDL, YHDL, [GLP-1
qPCR HFD supplemented with
B. pseudocatenulatum CECT
7765 vs. HFD:
YSerum cholesterol, Yserum TGs,
Yserum glucose, Yinsulin
resistance, Yhepatocytes with
grade 3 steatosis,
Yfat absorption, Yleptin,
YIL-6, YMCP-1, [IL-4, [IL-10,
[Bifidobacteria,
YEnterobacteriaceae,
Ybody weight gain,
Yfood intake

(Continued)

Gut microbiome and NAFLD: role of nutrition 243

TABLE 2 (Continued )

Study, year Animal Main

(ref) model Treatment Method(s) results
Axling et al., 2012 (60) C57BL/6J mice HFD with or without a supplement GT Sequencing 16S Lp + GT vs. control:
and supplemented with Lp or the rRNA, qPCR [Lactobacillus, [diversity
combination of both (Lp + GT) of bacteria, Yliver weights,
for 22 wk Yliver size, YTGs, YALT
Akkermansia correlated negatively
with body fat content
(r = 20.43, P = 0.04), plasma
insulin (r = 20.47, P = 0.03),
and liver TGs (r = 20.44,
P = 0.03).
Neyrinck et al., 2011 (61) C57BL/6J mice HFD supplemented with arabinoxylans DGGE, qPCR HFD supplemented with
from wheat vs. HFD for 4 wk arabinoxylans from
wheat vs. HFD:
[Bifidobacteria, Yadipocyte
size, Yserum and hepatic
cholesterol accumulation

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and insulin resistance,
[tight junction proteins
(ZO-1 and occludin),
Yinflammatory markers
(IL-6 and MCP-1)
Cani et al., 2009 (62) C57BL/6mice Prebiotic (oligofructose) vs. nonprebiotic DGGE, qPCR analysis Prebiotic vs. nonprebiotic:
carbohydrates (microcrystalline [Total bacteria count,
cellulose) for 4 wk [Lactobacillus spp.,
[Bifidobacterium spp.,
[Clostridium coccoides–
Eubacterium rectale cluster,
YLPS, [ZO-1 and occludin,
YPAI-1, YNADPHox, YiNOS,
YTLR4, YTNF-a, [GLP-2,
Yhepatic expression of
inflammatory and oxidative
stress markers
Cani et al., 2007 (33) C57BL/6J mice High-fat and carbohydrate-free diet vs. FISH High-fat and carbohydrate-free
normal-diet group for 4 wk diet vs. normal-diet group:
[Liver weight, [Liver TGs,
[TNF-a, [IL-1, [IL-6, [LPS,
YBifidobacterium spp.,
E. rectale/C. coccoides
1
ACC1, acetyl-CoA carboxylase 1; ALT, alanin transferase; BB-12, Bifidobacterium animalis subsp. lactis BB-12; ChREBP, transcription factor carbohydrate-responsive element-
binding protein; DGGE, denaturing gradient gel electrophoresis; FAS, fatty acid synthase; FISH, Fuorescent in situ hybridization; FOS, fructo-oligosaccharide; GLP,
glucagon-like peptide; GT, green tea powder; HF, high prebiotic fiber; HFD, high-fat diet; HP, high protein; iNOS, inducible nitric oxide synthase; LFD, low-fat diet; LGG,
Lactobacillus rhamnosus GG; Lp, Lactobacillus plantarum DSM 15313; MCP-1, monocyte chemoattractant protein-1; NADPHox, NAD(P)H oxidase; NAFLD, nonalcoholic fatty
liver disease; OFS, oligofructosaccharide; PAI-1, plasminogen activator inhibitor 1; PYY, peptide YY; ref, reference; rRNA, ribosomal RNA; SREBP2, sterol regulatory element
binding protein 2; TLR4, Toll-like receptor 4; TNFa, tumor necrosis factor a (gene); ZO-1, zonula occludens-1; [, increased; Y, decreased.

With the use of germ-free animal models, it has been
shown that the gut microbiota increases energy harvested
from dietary polysaccharides and augments key enzymes in
hepatic de novo FA biosynthesis, including acetyl-CoA car-
boxylase (ACC) and FA synthase (FAS), and consequently,
hepatic TG accumulation. On the other hand, the gut
microbiota drives the host to increase LPL activity and hepatic
production of TGs by the inhibition of FIAF (an LPL inhib-
itor) in intestinal epithelium cells (35). In addition, germ-
free mice showed increased AMP-activated protein kinase
(AMPK) activity, which is an intracellular energy sensor in
the liver and skeletal muscle, leading to increased FA oxida-
tion and insulin sensitivity and reduced glycogen concentra-
tions. This would protect germ-free mice against diet-induced
obesity. In normal mice with normal gut microbiota, inac-
tive AMPK is associated with decreased FA oxidation in
skeletal muscle (36). In addition, gut satiety hormones are
affected by the gut microbiome through the gut-brain axis
(65). Therefore, the gut microbiome influences energy in-
take in addition to energy expenditure. Any changes in the
gut microbial taxa can increase gastrointestinal satiety hor-
mones, hence influencing energy hemostasis (66–68).
Another key function of the intestinal bacteria is to hy-
drolyze polysaccharides and oligosaccharides that are not
completely catabolized by the host enzymes. Although
much is still to be learned about which microbes synthesize
and/or metabolize the SCFAs and the roles of these potent
metabolites, saccharolytic fermentations are major players

244 Mokhtari et al.

in metabolic disorders (69). A wide range of bacterial groups
are able to produce acetate, whereas the production of pro-
pionate and butyrate seems to be more specific. Akkermansia
municiphila has been known as a major propionate-producing
bacterium (70) and Eubacterium hallii, Eubacterium rectale,
Roseburia inulinivorans, Faecalibacterium prausnitzii, Clostridium
lavalense, Bacteroides uniformis, and Ruminococcus bromii
appear to be responsible for most of butyrate production
(70–72). Butyrate and propionate at low amounts exert mul-
tiple advantageous effects on the host, including the preven-
tion of colonic carcinogenesis, inflammation, and oxidative
stress; improvement in intestinal barrier function; and stim-
ulation of satiety and lipid oxidation in hepatocytes (73, 74).
Acetate may be more important for modulating insulin sen-
sitivity and metabolic disease (75) and the development of
diabetes (76). However, more studies are required to under-
stand which microbes produce each SCFA and the relation
this has on liver health and disease.
SCFAs are ligands for G-protein–coupled receptor (GPR)
43 expressed on intestinal epithelial cells. The stimulation of
GPR43 by SCFAs is necessary during immune responses
(77). GPR41 is another SCFA receptor. Binding to GPR41
is associated with upregulation of peptide YY (PYY) and
glucagon-like peptide 1 [(GLP1), anorectic hormones] that
have effects on appetite control; therefore, SCFAs are linked
to food intake by activating these receptors (78, 79). Current
evidence indicates that SCFAs have paradoxical effects on
hepatic health. SCFAs have been identified as rich sources
of energy for the host and act as intestinotrophic agents to
promote intestinal absorption of nutrients. On the other
hand, through their receptor GPR43 and other pathways,
they reduce gut permeability and invasion of bacterial pro-
ducts through the portal vein and liver, and thus protect
the liver from the ensuing damaging inflammation, which
then results in downregulation of insulin signaling in adi-
pose tissue, thereby decreasing fat accumulation (80).
Thus, it seems that SCFAs are beneficial for hepatic health
if the body is receiving a balanced diet, whereas they exag-
gerate steatosis when extra calories are consumed. However,
more mechanistic studies are required to understand the
role of each of the SCFAs on NAFLD.
Macronutrient intakes and the gut microbiome in
NAFLD. Several studies have shown that high-fat diets
(HFDs) participate in the development of dysbiosis through
diet-induced reductions in Bacteroidetes, Lactobacilli, and
Bifidobacteria and increases in Firmicutes (81, 82). Thus,
an HFD may contribute to the development of NAFLD at least
partially through dysbiosis, which may increase intestinal
permeability. Furthermore, HFD exposure impairs choline
metabolism via dysbiosis. Choline is converted to methylamines
(dimethylamine, trimethylamine, and trimethylamine-N-oxide)
by intestinal microbes with consumption of an HFD. It is
associated with a reduction in plasma phosphatidylcholine
and increases in urinary methylamines. Indeed, changes in
the gut microbiota mimic the effect of a choline-deficient
diet, which leads to accumulation of TGs in hepatocytes and
reduced VLDL secretion (83). Maintenance of mice fed an
HFD for 4 wk resulted in a significant increase in
Bifidobacterium spp. and the E. rectale/Clostridium
coccoides group, while decreasing the C. coccoides group
and Bifidobacteria E. rectale. Moreover, fat consumption
can produce a wide amount of chylomicrons, which
translocate LPS toward other organs, especially the liver
(84), which can bind to TLR4 on hepatic immune cells
and initiate the inflammatory process. It has been shown
that plasma inflammatory cytokines are positively
correlated with plasma LPS concentrations and negatively
correlated with intestinal Bifidobacteria count (85). An
HFD not only changes the gut microbiota but also
plays a role in the development of steatohepatitis in mice
(56). It has been shown that Lactobacillus gasseri and
Lactobacillus taiwanensis increase after consumption of an
HFD. These bacteria are bile acid–resistant and probably
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contribute to bile acid deconjugation and reduction in fat
absorption. There was a positive significant association
between L. gasseri and/or L. taiwanensis DNA and lipid
droplets in the liver (R2 = 0.3, P = 0.02). Increased fat
intake simultaneously increases bile acid secretion and
bile acid–resistant bacteria. Increased Lactobacillus in HFD
may affect lipid metabolism through bile acids (86, 87).
A high-protein diet also affects the gut microbiome,
favoring a potentially pathogenic and proinflammatory mi-
crobiota profile with increased ammonia, phenols, and hy-
drogen sulfide concentrations, which induce mucosal
inflammation and alter the enteric nervous system and in-
testinal motility (88). In addition, the dietary source of pro-
teins plays a critical role in shaping the gut microbiota and
their ability to produce secondary metabolites, so that
meat protein–fed rats showed a higher relative abundance
of the beneficial genus Lactobacillus but lower amounts of
SCFAs and SCFA-producing bacteria, including Fusobacte-
rium, Bacteroides, and Prevotella spp. compared with the
soy protein–fed group (89). Overall, studies evaluating the
effects of different dietary patterns on the human gut micro-
biome are limited; further studies are needed to elucidate
more details in this area.
Probiotics and the gut microbiome in NAFLD. Current
studies hypothesize the use of probiotics for modulating
dysbiosis in many diseases, including NAFLD. Probiotics
are beneficial microorganisms when ingested in specified
dosages. Several studies showed that gut microbiota manip-
ulation by probiotic supplements is associated with reduced
liver damage, decreased concentrations of LPS, as well as im-
proved aminotransferase concentrations (90–93). A recent
review summarized the studies that show that probiotic sup-
plementation in animal models and human studies improve
inflammatory status and clinical manifestations in NAFLD
(94). Manipulating the gut microbiota with probiotics
may improve dysbiosis associated with an HFD. In support
of this, consumption of an HFD upregulates the expression
of genes involved in hepatic lipid biosynthesis, and supple-
mentation with Lactobacillus curvatus HY7601 and
Gut microbiome and NAFLD: role of nutrition 245
Lactobacillus plantarum KY1032 upregulates the expression
of genes involved in hepatic FA oxidation (57). Another study
showed that increasing tissue n–3 PUFAs in the gut alters the
gut bacterial composition, which is associated with a decrease
in LPS and gut permeability and eventually results in meta-
bolic endotoxemia and inflammation (95). Overall, although
there are some exciting possibilities with regard to the use of
probiotics as a treatment for NAFLD, experimental studies are
still required to test the mechanisms of action and clinical
trials are still required to test their efficacy.
Prebiotics and intestinal microbiota in NAFLD. In addi-
tion to probiotics being potentially protective in NAFLD, ac-
cumulating data also suggest that there are beneficial effects
of prebiotics in NAFLD. A prebiotic is defined as “a selec-
tively fermented ingredient that results in specific changes,
in the composition and/or activity of the gastrointestinal mi-
crobiota, thus conferring benefit(s) upon host health” (96).
Prebiotics are naturally found in foods such as onions, as-
paragus, garlic, and leeks and resistant starch (RS) sources
such as legumes, potatoes, and cereals. Prebiotics could
modulate the intestinal microbiota, because they would in-
crease beneficial bacteria for the host, in particular the
indigenous Bifidobacteria and Lactobacilli, and inhibit
bacterial activities harmful to host health (97). Furthermore,
in the large intestine, inulin-type fructans and RS are
completely catabolized by the microbiota into SCFAs,
bacterial biomass, and organic acids such as lactic acid and
gases (carbon dioxide, hydrogen, methane).
Prebiotics have beneficial effects on the gut microbiota,
serum lipids, and the prevention of hepatic steatosis (61,
62, 98, 99). In fact, the addition of RS to rodent feed pellets
increases Bacteriodetes, Actinobacteria (Bifidobacteria spp.),
and Verrucomicrobia (A. muciniphilia) while decreasing
Firmicutes (100–102). Also, in humans, the administration
of RS has been shown to induce phylum-level changes, selec-
tively increasing numbers of Actinobacteria and Bacteroidetes
and reducing Firmicutes; at the species level, an increase
in Bifidobacterium adolescentis, E. rectale, Roseburia spp.,
and R. bromii have been reported (103–107). These var-
ious bacteria differ significantly in the production of
metabolic byproducts and potential interactions with the
host. It has been well established that Bifidobacteria spp., a
source of lactate and acetate and low amounts of ethanol
and formate, are broadly used as probiotics and have
health-promoting properties because of their potential
modulating effects on the immune system, metabolism,
and elimination of pathogenic bacteria of the host (108).
Members of E. rectale, Roseburia, and R. bromii are main
producers of butyrate in the colon (71, 107, 109). It has
been shown that increasing butyrate-producing bacteria
and butyrate production is closely linked with prevention
of the progression from steatosis to hepatocarcinogenesis
and improving hepatic inflammatory and oxidative stress in-
dexes and gut integrity (74, 110, 111). This would appear to
indicate that there is a mutualistic relation between the gut
microbiota and the host; dietary ingredients such as RS
246 Mokhtari et al.
could induce special species of bacteria that produce meta-
bolic products such as butyrate. Butyrate could act as a sig-
naling molecule in the host that participates in various
signaling pathways (110); thus, products of the gut micro-
biota could explain part of the role of nutritional factors
in the gut liver axis and their relation with NAFLD.
It has been reported that prebiotic supplementation can
modulate the effects of HFDs. Prebiotic consumption leads
to increased Bifidobacteria and total bacteria Bacteroides:
Prevotella spp. and decreased Firmicutes (53). Cano et al.
(59) reported that Bifidobacterium pseudocatenulatum con-
sumption improved glucose tolerance and inflammatory
status while decreasing serum LPS and hepatic steatosis in
HFD-fed mice. Another study showed that prebiotic oligo-
fructose in combination with probiotic Bifidobacterium
animalis subsp. lactis BB-12 decreased the ratio of Firmicutes
to Bacteroidetes and improved glycemia. This decrease in
Downloaded from advances.nutrition.org at Fudan University on March 15, 2017
the Firmicutes-to-Bacteroidetes ratio is hypothesized to de-
crease obesity-inducing effects of the microbiome (54). In
addition, oligofructose decreases energy intake, weight
gain, and fat mass (54). In this study, prebiotics and pro-
biotics had no effect on increased LPS and inflammatory
factors induced by high-fat and high-sucrose diets (54). A
significant increase in the abundance of Bifidobacterium
spp. and Lactobacillus spp. by the administration of inulin-
type fructo-oligosaccharides (FOSs) has been documented
(112). Increasing total bacteria counts of Lactobacillus spp.
and Bifidobacterium spp. by prebiotics improved intestinal
barrier function and hepatic inflammation and oxidation.
Furthermore, stimulating the proliferation of these bacteria
was associated with a reduction in intestinal endotoxin and
modulated gut mucosal function (113, 114). Lactobacillus
spp. inhibit proinflammatory responses that result from
endotoxins by suppressing NF-kB (115).
Inulin-type fructans or FOSs are also able to modify
groups of bacteria other than Bifidobacteria or Lactobacilli.
Inulin-containing diets result in an increase in bacteria be-
longing to C. coccoides and E. rectale cluster in animal models
(116). In addition, inulin can stimulate the metabolic activity
of Roseburia spp. and E. rectale genera of the Firmicutes phy-
lum (117, 118). Roseburia spp. and E. rectale belong to the
butyrate-producing bacteria; therefore, they may mediate
some of the advantageous properties of prebiotics. Further-
more, the consumption of inulin, galacto-oligosaccharides,
and raffinose stimulates F. prausnitzii (119–121). F. prausnitzii,
which belong to the butyrate-producing bacteria, could be
crucial to gut barrier function and could modulate systemic
inflammation (common to NAFLD) (79, 122). All of these
proposed actions may play a role in the beneficial effects of
prebiotics in NAFLD prevention and/or treatment. How-
ever, well-designed clinical trials are required to support
the efficacy of prebiotics during NAFLD.
Choline and other nutrients and the gut microbiome in
NAFLD. Choline deficiency is related to NAFLD pathogen-
esis. Although choline is synthesized in the body, it is con-
sidered to be an essential nutrient and dietary intake is
required to fulfill its roles in the body (123). Choline plays a
role in brain function, acetylcholine and neurotransmitter
synthesis, cell signaling, lipid transport, and lipid metabo-
lism (124, 125). Several studies have shown that choline is
critical for the development of hepatic steatosis due to its
contribution to lipid metabolism (125–127). When hepatic
de novo lipogenesis or TG synthesis from diacylglycerol is
greater than the lipid secretion from the liver and/or fat ox-
idation, hepatic steatosis occurs. Choline is one of the methyl
group donors in the body that contributes to hepatic synthe-
sis of phosphatidylcholine (125). Phosphatidylcholine is
required for VLDL synthesis and secretion. Reduced
phosphatidylcholine contributes to TG accumulation in
the liver and NAFLD (128). Choline-deficient diets disturb
the mitochondrial function, resulting in increased hepatic
lipid accumulation that contributes to NAFLD pathogenesis
(129). Gut bacteria can convert choline to trimethylamine
and reduce choline bioavailability, mimicking choline de-
ficiency side effects (130). A reduction in choline bio-
availability is associated with increased reactive oxygen
species resulting from FFA oxidation, more hepatic lipid
accumulation, and reduced hepatic VLDL excretion, all of
which contribute to the development of hepatic steatosis
(125, 126). Choline metabolism is mainly disrupted by 3
main bacterial phyla in the gut microbiota: Proteobacteria,
Firmicutes, and Actinobacteria (130). Spencer et al. (131),
in a longitudinal experimental study in healthy women who
consumed a rigorously controlled diet, showed that choline
deficiency led to hepatic lipid accumulation. In addition,
decreased amounts of Gammaproteobacteria and increased
Erysipelotrichi were directly associated with elevated
accumulation of hepatic fat. This study was the only study, to
our knowledge, that examined gut microbiota composition
in relation to diet and development of NAFLD in humans.
In addition to the evidence of gut dysbiosis in NAFLD,
patients with NASH also have dysbiosis, including small in-
testinal bacterial overgrowth (23). Bacterial overgrowth en-
hances the number of bacteria metabolizing choline and
influences hepatic lipid accumulation (125). Pyruvate pro-
duced by the gut microbiota from carbohydrate increases
metabolites such as acetaldehyde and ethanol. These metab-
olites are toxic and associated with gut permeability (132,
133). Overall, although better designed studies are needed,
there are sufficient data to support that choline and the
gut microbiome together play a role in liver disease.
High-fructose dietary intake is also considered to be a sig-
nificant risk factor in the development of NAFLD (134,
135). Some studies have indicated that antibiotics, prebi-
otics, and probiotics are protective factors in fructose-
induced liver damage (136–139). These studies suggested
that gut microbe manipulation may protect from the side ef-
fects of high-fructose diets on the liver. The chronic intake
of fructose is associated with bacterial overgrowth, which
causes increases in endotoxins in the portal vein, develop-
ment of inflammatory responses in the liver, and insulin re-
sistance in hepatocytes, resulting in increased hepatic lipid
accumulation (140, 141). Ritze et al. (55) reported that the
use of Lactobacillus rhamnosus GG protects against NAFLD
in animals fed a high-fructose diet through increasing the
proteins involved in gut integrity and decreasing inflamma-
tory factors and endotoxins. The authors suggested that
L. rhamnosus GG may increase occludin and claudin-1 (ef-
fective proteins in gut integrity), which lead to reductions
in LPS and other toxins translocated to the liver.
Several recent studies reported that polyphenol com-
pounds attenuate inflammatory markers and hepatic steato-
sis grade in patients with NAFLD (142–145). Some of these
act through the amelioration of insulin resistance, whereas
some act through the modulation of the gut microbiome
(146, 147). These compounds can reduce pathogen bacteria
and increase lactic acid bacteria, such as some strains of Bi-
fidobacteria (148). The manipulation of the gut microbiota
may be 1 of the mechanisms of action involved in the ben-
eficial effects of polyphenols on NAFLD. Axling et al. (60)
Downloaded from advances.nutrition.org at Fudan University on March 15, 2017
reported that green tea in combination with Lactobacillus
plantarum (which metabolizes phenolic acids) in HFD-fed
mice was able to promote growth of Lactobacillus in the in-
testine and to attenuate HFD-induced inflammation and he-
patic TG and cholesterol accumulation. Furthermore, there
was a significant inverse association between the amount of
Akkermansia and hepatic TG accumulation. A. muciniphila is a
mucus-degrading bacterium that contributes to the regulation
of immune responses through upregulation of the expression
of some genes involved in intestinal mucus integrity (149).
n–3 FAs and the intestinal microbiota in NAFLD. A low
intake of n–3 PUFAs is associated with hepatic steatosis
(150). n–3 PUFAs play an important role in lipid metabo-
lism because they can induce FA oxidation by activating
PPAR-a and inhibition of lipogenesis by suppressing sterol
regulatory element binding protein 1 (SREBP-1) (151). It
has been shown that n–3 PUFA supplementation, and not
total calories from fat, alters the gut microbial composition
by enhancing numbers of Lactobacillus and Bifidobacteria
spp. in adult mice (152) as well as in aged mice, which
modulated both gut immunity and oxidative stress (153). In
support of these data, other studies have shown that changes
in gut microbiota composition by n–3 PUFA deficiency can
be modulated by prebiotics such as FOS. FOS consumption
was associated with increased cecal Bifidobacterium spp. and
reduced Roseburia spp. in n–3 PUFA–depleted mice (58).
Moreover, it has been shown that an increase in lactic acid
bacteria, such as Bifidobacterium spp., is related to a reduc-
tion in cholesterol absorption (154) and an increase in
bile acid deconjugation, which leads to more excretion of
bile acids and elimination of hepatic cholesterol (155).
Conclusions
In summary, intestinal pathogenic bacteria contribute to
NAFLD pathogenesis through the following ways: 1) by in-
creasing LPS, which binds to TLR4 in hepatic immune cells,
resulting in the activation of the NF-kB pathway and its re-
lated inflammatory pathways, leading to hepatic injury, ne-
crosis, and finally fibrosis; 2) inhibition of FIAF, which
Gut microbiome and NAFLD: role of nutrition 247
increases the activity of LPL and lipogenesis; 3) enhance-
ment in polysaccharide digestion and absorption, which in-
creases the production of SCFAs and hepatic lipogenesis;
and 4) conversion of choline into methylamines, which re-
duces choline availability and induces fat accumulation
and reactive oxygen species production in the liver.
Nutritional factors and the gut microbiota have bilat-
eral interactions that contribute to the development and/or
protection from NAFLD. High-fat, high-protein, and high-
fructose diets and diets that are low in n–3 FAs (Western di-
etary pattern) may contribute to the development of NAFLD
by dysbiosis in the intestinal microbiota. On the other hand,
gut microbiota manipulation by nutritional factors such as
prebiotics, probiotics, and polyphenols can improve charac-
teristics of NAFLD. Few studies have investigated the effects
of nutritional factors on the gut microbiota in patients with
NAFLD, and in particular, human studies are scarce. Further
studies are needed to elucidate the exact mechanism(s) of
action and probable therapeutic options.
Acknowledgments
ZM and AH contributed to the conception of the article, the
literature search and interpretation, writing the article, and
the critical revisions related to important intellectual con-
tent of the manuscript and approved the final manuscript;
and DLG contributed to the final revisions of the manu-
script. All authors read and approved the final manuscript.
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