Gut microbiota and host metabolism in liver cirrhosis

Table 1 Metabolite, gut microbiota, and potential biologic functions

Metabolites	Related bacteria	Potential biological functions	Ref.
Short-chain fatty acids	Clostridial clusters IV and XIVa of Firmicutes, including species of Eubacterium, Roseburia, Faecalibacterium, and Coprococcus	Decreased colonic pH, inhibit the growth of pathogens; stimulate water and sodium absorption; participate in cholesterol synthesis; provide energy to the colonic epithelial cells; GI hormones secretion via enteroendocrine cells, implicated in human obesity, insulin resistance and type 2 diabetes, colorectal cancer. Immunological homeostasis in the gut	[14-18]
Bile acids	Lactobacillus, Bifidobacteria, Enterobacter, Bacteroides, Clostridium	Absorb dietary fats and lipid-soluble vitamins, facilitate lipid absorption, maintain intestinal barrier function, signal systemic endocrine functions to regulate triglycerides, cholesterol, glucose and energy homeostasis	[19-21]
Choline metabolites	Faecalibacterium prausnitzii, Bifidobacterium	Modulate lipid metabolism and glucose homeostasis. Involved in nonalcoholic fatty liver disease, dietary induced obesity, diabetes, and cardiovascular disease	[22,23]
Phenolic, benzoyl, and phenyl derivatives	Clostridium difficile, F. prausnitzii, Bifidobacterium, Subdoligranulum, Lactobacillus	Detoxification of xenobiotics; indicate gut microbial composition and activity; utilize polyphenols. Urinary hippuric acid may be a biomarker of hypertension and obesity in humans. Urinary 4-hydroxyphenylacetate, 4-cresol, and phenylacetate are elevated in colorectal cancer. Urinary 4-cresyl sulfate is elevated in children with severe autism	[24,25]
Indole derivatives	Clostridium sporogenes, E. coli	Protect against stress-induced lesions in the GI tract; modulate expression of proinflammatory genes, increase expression of anti-inflammatory genes, strengthen epithelial cell barrier properties. Implicated in GI pathologies, brain-gut axis, and a few neurological conditions	[26-28]
Vitamins	Bifidobacterium	Provide complementary endogenous sources of vitamins, strengthen immune function, exert epigenetic effects to regulate cell proliferation	[29,30]
Polyamines	Campylobacter jejuni, Clostridium saccharolyticum	Exert genotoxic effects on the host, anti-inflammatory and antitumoral effects. Potential tumor markers	[31,32]
Lipids	Bifidobacterium, Roseburia, Lactobacillus, Klebsiella, Enterobacter, Citrobacter, Clostridium	Impact intestinal permeability, activate intestine-brain-liver neural axis to regulate glucose homeostasis; LPS induces chronic systemic inflammation; conjugated fatty acids improve hyperinsulinemia, enhance the immune system and alter lipoprotein profiles. Cholesterol is the basis for sterol and bile acid production	[33,34]
Neurotransmitters and neuroactive compounds:serotonin, tryptophan, kynurenine. dopamine, noradrenaline, GABA	Lactobacillus ,Bifidobacterium, Escherichia, Bacillus, Saccharomyces, Candida, Streptococcus, Enterococcus	Neurofunction related as mood, emotion, cognition, reward (CNS), motility/secretion and behavior	[35-39]
HPA hormones: cortisol	Lactobacillus, Bifidobacterium	Indirect regulation of HPA. Regulation of stress response, host metabolism, anti-inflammation, wound healing, endocrine abnormalities prominent in stress related psychiatric disorders	[40]

GI: Gastrointestinal; LPS: Lipopolysaccharide; GABA: γ-aminobutyric acid; CNS: Central nervous system; HPA: Hypothalamic-pituitary-adrenal. Adapted from Ref. [12, 13] and revised by the authors.

Table 2 Effects of the probiotics intervention on gut microbiota composition and its clinical and/or biochemical consequences

Type of study	Category of patients/duration of treatment	Probiotics	Clinical outcome	Ref.
RCT	36 cirrhotics/6 mo	Lactobacillus.acidophilus, Lactobacillus bulgaricus, Bifidobacterium lactis and S. thermophiles	Blood ammonia levels	[88]
RCT	65 cirrhotics/6 mo	Lactobacilli	Incidence of HE, hospital admission, plasma-ammonia level, serum bilirubin level	[83]
R	50 cirrhotics/14 d	Bifidobacterium, L. acidophilus and Enterococcus vs Bacillus subtilis and Enterococcus faecium	Bifidobacterium count, fecal pH, fecal and blood ammonia in both groups, endotoxin level only with B. subtilis and E. faecium	[89]
RCT	17 cirrhotics with HVPG > 10 mmHg/2 mo	VSL # 3®	Plasma aldosterone	[81]
RCT	41 chronic liver disease/14 d	Bifidobacterium bifidus, L. acidophilus, Lactobacillus bulgaricus, and S. thermophilus	E. coli count, intestinal flora imbalance, improvement in debilitation, food intake, abdominal distension, and ascitic fluid	[90]
RCT	66 cirrhotics underwent liver transplantation/2 wk after the operation	Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei and Lactobacillus plantarum	Infectious complication	[78]
RCT	39 cirrhotics/42 d	E. coli Nissle	Endotoxemia, Child-Pugh score, Restoration of normal colonic colonization	[91]
RCT	63 cirrhotics patients with large oesophageal varices without history of variceal bleeding/2 mo	Propranolol plus VSL # 3®	HVPG, plasma TNF-α levels.	[92]
RCT	25 nonalcoholic minimal HE cirrhotics (defined by a standard psychometric battery)/60 d	Yogurt contained L. bulgaricus and S. thermophilus	Minimal HE	[93]
RCT	61 cirrhotics underwent hepatic surgery/2 wk before and after surgery	Lactobacillus casei strain Shirota, Bifidobacterium breve strain Yakult, and galactooligosaccharides	Intestinal integrity, infectious complication	[79]
RCT	63 cirrhotics underwent liver transplantation/12 d after the operation	L. plantarum 299 and oat fiber	Infectious complication	[77]
RCT	50 cirrhotics underwent living donor liver transplantation/2 d and 2 wk before and after the operation, respectively	L. casei strain Shirota, B. breve strain Yakult, and galactooligosaccharides	Infectious complication	[94]
RCT	30 cirrhotics with minimal HE/4 wk	Lactobacillus GG	Endotoxemia, gut dysbiosis, gut microbiome-metabolome linkages	[69]
RCT	138 cirrhotics/3 mo	VSL # 3®	HE, small intestinal bacterial overgrowth	[84]

HE: Hepatic encephalopathy; HVPG: Hepatic venous pressure gradient; RCT: Randomized controlled trial; R: Randomized.