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RESEARCH ARTICLE
Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence
upon Hepatic Encephalopathy
Rosângela Passos de Jesus1, Ramona Baqueiro Boulhosa2, Lucivalda
1 1
Magalhães Oliveira , Carla de Magalhães Cunha , Alexandre
Nogueira Matos3, Lourianne Nascimento Cavalcante4,5,6, Maria
7 8
Gabriela Fernandes Dezan , Allain Amador Bueno , André Castro
Lyra4,5,6
1.
Food, Nutrition and Health Postgraduate Programme, Federal
University of Bahia, Brazil
2.
Municipal Department of Health, Salvador, Brazil
3.
Municipal Hospital of Salvador, Brazil.
4.
D'Or Institute for Research and Education, Salvador, Bahia, Brazil
5.
Hospital São Rafael, Salvador, Bahia, Brazil
6.
OPEN ACCESS Gastro-Hepatology Service, Hospital Universitário Prof. Edgar
Santos, Department of Medicine, Federal University of Bahia, Brazil.
7.
Published: August 31, 2022 Medicine and Health Postgraduate Programme, Federal University
of Bahia, Brazil
8.
Citation: de Jesus RP, Boulhosa College of Health, Life and Environmental Sciences, University of
RB, et al., 2022. Diet, Gut Worcester
Dysbiosis and Liver Cirrhosis
and their Influence upon * ramonabaqueiro@hotmail.com
Hepatic Encephalopathy,
Medical Research Archives, ABSTRACT
[online] 10(8). Cirrhosis is the end stage of progressive liver fibrosis, resulted from
https://doi.org/10.18103/m chronic inflammation and liver injury. Early identification of risk factors
ra.v10i8.2915 and appropriate treatment for hepatic decompensation is paramount for
positive health outcomes. In this review study, we revisited mechanisms
Copyright: © 2022 European associated with gut dysbiosis and intestinal hyperpermeability in
Society of Medicine. This is an advanced liver disease, and further discussed nutritional strategies for
open- access article the management of dysbiosis in liver cirrhosis. In gut dysbiosis,
distributed under the terms of proportionally lower concentrations of bacteria belonging to beneficial
the Creative Commons taxa such as Lachnospiraceae, Clostridiales, Ruminococcaceae and
Attribution License, which Veillonellaceae and others are observed, in relation to pathogenic taxa
permits unrestricted use, such as Enterobacteriaceae, Bacteroidaceae and others. Cirrhotic
distribution, and reproduction patients present decreased bowel motility, bacterial overgrowth and
in any medium, provided the increased intestinal permeability. Dysbiosis may further exacerbate such
original author and source conditions due to the ability of pathogenic bacteria to adhere to the
are credited. epithelium, produce endotoxin, disrupt bile acid metabolism, activate the
DOI immune system and trigger inflammation, in a vicious cycle. The triad
https://doi.org/10.18103/m hepatic encephalopathy – cirrhosis – gut dysbiosis is an evident entity,
ra.v10i8.2915 and primary prevention as well as management strategies for those
three conditions aim strongly at improving intestinal health by focusing
ISSN: 2375-1924 on nutritional interventions. High-protein diets may be recommended for
cirrhosis patients, and the protein source is a key factor to consider, and
so are dietary fibre and carbohydrate compositions. Attention is given
to reduce saturated fat intake. Supplementation with branched-chain
amino acids, probiotics and prebiotics have also shown positive results.
Keywords: Diet; dysbiosis; microbiome; cirrhosis; hepatic
encephalopathy
Medical Research Archives |https://esmed.org/MRA/index.php/mra/article/view/2915
1
Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence upon Hepatic Encephalopathy
Introduction bacteria in relation to bifidogenic bacteria,
Cirrhosis, the leading cause of mortality by liver followed with narrower taxonomic diversity. In gut
diseases, is the end stage of progressive liver dysbiosis, proportionally lower concentrations of
fibrosis resulted from various mechanisms of liver bacteria belonging to beneficial taxa such as
injury that lead to inflammation¹. Recent data Lachnospiraceae, Clostridiales XIV,
demonstrated that cirrhosis contributed to 2.4% of Ruminococcaceae and Veillonellaceae are
total deaths globally in 2017. In that same year, observed, in relation to pathogenic taxa such as
10
the prevalence of cirrhosis was 10.6 million Enterobacteriaceae and Bacteroidaceae .
decompensated cases, and 112 million Dysbiosis may be particularly damaging to the host
compensated cases¹. due to the ability of segmented filamentous
The chronic progression of cirrhosis leads to severe bacteria to strongly adhere to the epithelium,
clinical manifestations including ascites, activating the immune system and triggering
8
oesophageal variceal bleeding, hepatic inflammation .
encephalopathy (HE), and jaundice. Once In this study we have reviewed the mechanisms
decompensation occurs, the morbidity attributed to associated with gut dysbiosis and intestinal
cirrhosis increases significantly, influencing quality hyperpermeability in advanced liver disease and
of life, elevated disability-adjusted life years, and further discussed nutritional strategies for the
years of life lost. The 1-year case-fatality rate management of dysbiosis in liver cirrhosis.
varies from 57 to 80%, depending on the cause of
2
decompensation . Western dietary patterns and their impact on
Considering the risk and relevance of obesity and global health
th
decompensation on mortality rate of cirrhotic From the second half of the 20 century,
populations, the early identification of possible risk advancements in food technology triggered
factors and appropriate treatment is of paramount changes in traditional dietary habits, making ultra-
importance for positive health outcomes. One of the processed foods (UPFs) more easily available and
11
several primary prevention strategies proposed affordable in westernised societies . Due to its
focuses on improving intestinal health, which often-poor nutritional composition, UPFs are not
12
considers not only the gut-liver axis as pivotal for recommended for prolonged consumption .
liver health but also the influence of gut microbiota The effects of westernised diets (WD) on weight
3
(GM) on spontaneous bacterial peritonitis . gain and development of metabolic diseases are
Cirrhotic patients present decreased bowel motility, often attributed to the nutritional composition of
bacterial overgrowth, and increased intestinal UPFs, typically characterised by their high content
4
permeability . Such manifestations increase the risk of free or added sugars, sodium, saturated fats,
of microbial translocation to mesenteric lymph trans fats and additives, and most importantly, high
5 11
nodes, which predisposes patients to infection . The energy density .
GM is also a source of endotoxin and other Both obesity and WD patterns are known risk
6
bacterial products that affect vascular function . factors for non-alcoholic fatty liver disease
The GM composition of patients suffering with (NAFLD). Obesity was associated with a modest
advanced chronic liver disease (CLD) and HE increase in the risk of incident severe liver disease
13
appears to be different from the one found in (adjusted HR 1.20, 95% CI 1.12-1.28) . A recent
7
healthy individuals . meta-analysis found that WD patterns increased
14
A healthy GM provides a range of beneficial the risk of NAFLD by 56% . Due to the marked
properties to its host, including the maintenance and connection between metabolic diseases and NAFLD,
integrity of the mucosal barrier, biotransformation the latter condition has been recently re-named as
and provision of key nutrients, and protection Metabolic (dysfunction)-Associated Fatty Liver
8 15
against pathogenic species . In healthy individuals, Disease .
bacteroid species are quantitatively amongst the
most prevalent genera in the intestine. It has also The impact of dietary patterns on gut health
been observed that the Enterobacteriaceae, The GM metabolic activity is fundamental for
Porphyromonadaceae and Alcaligeneacea genera nutrient digestion, biotransformation and
are mostly pathogenic and, therefore, occur in absorption, with the resulting bioavailability of
9
lesser amounts in the healthy GM . short-chain fatty acids (SCFAs), amines, phenols and
Gut dysbiosis is defined as an imbalance between indoles, sulphurous compounds, increased
the main phyla of bacteria residing in the intestine, bioavailability of minerals, and metabolism of bile
characterized by an increase in pathogenic acids. Additionally, GM further aids in gut health by
Medical Research Archives |https://esmed.org/MRA/index.php/mra/article/view/2915
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Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence upon Hepatic Encephalopathy
displacement of pathogenic species, production of (MUFA) and polyunsaturated fatty acid (PUFA)-rich
antimicrobial factors, regulation of enterocyte diet increases the Bacteroidetes / Firmicutes ratio,
exchange rate, differentiation of epithelial cells, as well as lactic acid-related species such as
strengthening of the intestinal barrier, and Bifidobacteria and Akkermansia muciniphila. On
maintaining the functioning of the intestinal mucosa the other hand, a SFA-rich diet facilitates the growth
16
immunity by inducing immunoglobulin A secretion . of Bilophila and Faecalibacterium prausnitzii, and
The maintenance of a healthy microbial composition at the same time reduces the counts of
is critical for protection against pathogens and Bifidobacterium, Bacteroidetes, Bacteroides,
17 21-22
overall immune response . Prevotella, and Lactobacillus ssp .
Alongside food, environmental microorganisms gain The effects of abundant SFA on GM also appear to
access to the gastrointestinal tract (GIT) and influence bile acid metabolism. The SFA stimulus for
compete with local microorganisms, posing a increased bile acid secretion appear to involve the
8
potential threat to gut integrity . Considering the overproduction of hydrophobic secondary bile
above, multiple factors dictate the composition of acids, including deoxycholic acid, leading to
9,23-24
the microbiota and its activity, but one of the most changes in microbial composition and function .
significant roles is played by nutrition, which Furthermore, SFA, as a component of the lipid
includes diet composition, dietary patterns, and portion of lipopolysaccharide (LPS) of pathogenic
17
long-term dietary habits . species, have been shown to activate inflammatory
17
Among macronutrients, carbohydrates (CHOs) play cascades via toll-like receptor 4 (TLR4) (Figure 1).
a pivotal role in GM remodelling. Simple CHOs can
rapidly deteriorate the GM, whilst complex CHOs Westernised diets, dysbiosis and gut
confer a more protective role upon GM hyperpermeability
18
composition . Complex carbohydrates are found Chronic exposure to WD is associated with negative
25
abundantly in vegetables but as the human GIT outcomes upon GM diversity and function . WD is
cannot digest plant cell wall polysaccharides and known to decrease not only the count of total
resistant starch, such nutrients become available for species but also the count of commensal
26
microbial fermentation, resulting in SCFAs Bifidobacterium and Eubacterium species . It has
production- acetate, propionate and butyrate. been suggested that chronic WD consumption may
Butyrate is involved in the maintenance of the be associated with irreversibly reduced microbial
intestinal barrier and, along with propionate, diversity and depletion of specific bacterial species
promotes intestinal gluconeogenesis. In hepatocytes due to its low content of microbiota-accessible
27
and adipocytes, SCFAs not only modulate the CHOs . Several studies emphasize that WD
activity of nuclear transcription factors, including the influences GM and potentially trigger chronic pro-
peroxisome proliferator-activated gamma inflammatory diseases28,29.
receptor, and G-protein-coupled receptors but Caesar and colleagues analysed the GM of mice
have also been implicated in the regulation of free fed high fat diets enriched with lard or fish oil, and
fatty acid metabolism, inflammation mediation and found higher counts of the commensal species
17
cancer risk. . Akkermansia muciniphila, Lactobacillus, and
Protein products metabolised by a diverse GM Bifidobacterium in the mice fed the fish oil diet. In
normally include indoles, amines, phenols, thiols, the opposite direction, the researchers found
hydrogen sulphide (H S), carbon dioxide (CO ), increased TRL4 activation and inflammation in the
2 2
30
methane (CH ) and Hydrogen gas (H ). However, white adipose tissue of lard-diet fed mice .
4 2
elevated production of acetic acid, CH and CO Interestingly, a systematic review appraising
4 2
19
suggest overgrowth of anaerobic bacteria . The interventional studies in humans found that high
effects of dietary protein on GM have been consumption of fat and SFA might unfavourably
associated with increased Proteobacteria, affect microbiota diversity, and also that MUFA-rich
Bifidobacterium and Lactobacillus and decreased diets might decrease total bacterial abundance,
Bacteroides fragilis and Clostridium perfringens. whereas PUFA-rich diets may not significantly
31
Protein consumption is also positively correlated modulate GM diversity .
with microbial diversity, and significant differences An experimental study investigated the effects of
in bacterial enterotypes have been observed various types of dietary protein upon GM
between diets with animal-derived protein versus composition of male rats20. The white meat-fed
20
plant-derived protein . group showed higher Lactobacillus count when
The amount and composition of dietary fats seem to compared to the red meat and non-protein-fed
influence GM composition. A monounsaturated groups, and higher Firmicutes count followed with
Medical Research Archives |https://esmed.org/MRA/index.php/mra/article/view/2915
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Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence upon Hepatic Encephalopathy
lower Bacteroidetes count when compared to intake of high fructose corn syrup (HFCS) and
casein-fed and soy-fed groups. The researchers sucrose. Chronic intake of HFCS induces insulin
also found that the soy-fed group showed higher resistance with a greater risk for metabolic
Bacteroidetes count, the beef-fed group showed syndrome and liver diseases such as steatosis and
37-39
higher Proteobacteria count, and the chicken-fed non-alcoholic steatohepatitis (NASH) .
group showed higher Actinobacteria count20. Furthermore, chronic intake of high-sucrose and
A small clinical trial investigated the effects of two HFCS foods has been associated with reduced
distinct diets, the first a plant-based diet and the diversity of bacteroids and Prevotella, alongside
second an animal-based diet rich in meats, eggs, elevated concentration of toxic molecules derived
and cheeses, upon GM composition. Nine subjects from the fermentation of tryptophan and tyrosine,
40
participated in both diet arms of the study, such as p-cresol and indoxyl sulphate . Excess
separated by 1 month period. The results showed fructose also increases intestinal translocation and
that the animal-based diet increased the plasma endotoxin levels, which associated with the
abundance of bile-tolerant microorganisms production of toxic metabolites in the intestine,
(Alistipes, Bilophila, and Bacteroides) and favours inflammation and the development of
41
decreased the levels of Firmicutes that metabolise NAFLD .
dietary plant polysaccharides (Roseburia,
26
Eubacterium rectale, and Ruminococcus bromii) . Dysbiosis and unfavourable clinical outcome for
Manifestations associated with dysbiosis induced by patients with advanced Chronic Liver Disease
WD chronic consumption include increased barrier The degree of dysbiosis in the patient with severe
permeability, which triggers low-grade liver disease worsens as the disease progresses,
32
inflammation and subsequent metabolic disorders . and often accelerates its evolution, causing a vicious
Additionally, exaggerated penetrability and cycle42-43. Cirrhosis patients in the more advanced
reduced growth rate of the inner mucus layer stages often show clinical decompensation, such as
33
facilitate the susceptibility to infections . upper digestive haemorrhage, obstructive jaundice,
42
Dysbiosis has the potential to negatively influence HE, ascites, and spontaneous bacterial peritonitis .
the activity of tight junction proteins, including Some cirrhosis complications are related to
34
zonula occludens-1 (ZO-1), claudin and occluding . imbalanced GM and intestinal hyperpermeability,
Additionally, upregulated zonulin facilitates usually caused by the presence of dysbiosis,
35
intestinal hyperpermeability . In combination, such intestinal dysmotility, portal hypertensive
disturbances increase intestinal permeability and vasculopathy, and overconsumption of alcoholic
44
the transfer of intraluminal molecules, including beverages . In addition to the aforementioned
dietary antigens and LPS, into the bloodstream, factors, alteration in the flow of bile acids, with a
further contributing to low-grade systemic consequent impairment of the bacteriostatic activity
45
inflammation. Reduced intestinal mucous layer of bile salts , also favours endotoxemia and
44
thickness is observed in mild chronic inflammation, increased risk of liver disease complications .
further feeding into a vicious cycle of increased Intestinal dysfunction in CLD patients, characterized
intestinal permeability and inflammation. In the by changes in intestinal motility and permeability,
lumen and across the intestinal barrier, LPS and bacterial overgrowth and bacterial translocation,
other bacterial-derived compounds such as lipoteic can further increase the risk of cirrhosis
acid, peptidoglycan, flagellin and bacterial DNA, complications such as bacterial peritonitis and
45,46
can further stimulate the immune system and induce HE .
18
inflammation via TL4R activation . Gastrointestinal motility and gastric emptying are
Low quantities of microbiota-accessible CHOs reduced in cirrhosis when compared to healthy
facilitate the erosion of the colonic mucus barrier as individuals, and is further delayed as the liver
48,49
a consequence of switched GM composition disease progresses . A clinical study assessing
towards species that utilize secreted mucins as cirrhosis patients found delayed gastric emptying
nutrient sources. A study conducted in experimental time in 24% of the patients, and delayed intestinal
models showed that dietary fibre deprivation, and transit in approximately 38%. The alterations in
subsequent erosion of the colonic mucus barrier, gastric emptying and delayed intestinal transit
promoted greater epithelial access, susceptibility to were also positively associated with feelings of
pathogens and enhanced expression of pro- postprandial fullness, early satiety, nausea,
36 49
inflammatory markers . diarrhoea, and abdominal pain .
A high consumption of sugary foods and beverages The dysbiosis commonly observed in cirrhosis
has been identified as contributor to the excessive patients is often characterised by quantitative
Medical Research Archives |https://esmed.org/MRA/index.php/mra/article/view/2915
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