Microbiota and the gut-liver axis: Bacterial translocation, inflammation and infection in cirrhosis

Table 1 Changes in intestinal microbiota and clinical consequence in cirrhosis

	Ref.	Implicated dysbiosis	Potential biological functions
Cirrhosis vs healthy people	Stool samples, Bajaj et al[5]	Overgrowth of (family):	There is a reduction in autochthonous taxa that can be disruptive given that they produce short-chain fatty acids that reduce colonic inflammation and nourish colonocytes improving the intestinal barrier
		Leuconostocaceae ↑
		Enterobacteriaceae ↑↑↑
		Fusobacteriaceae ↑
		Alcaligenaceae ↑
		Reduction of (family):
		Clostridium Incertae sedis XIV ↓↓↓
		Lachnospiraceae ↓
		Ruminococcaceae ↓
	Mucosal samples, Bajaj et al[5]	Overgrowth of (family - genus):	There was a significantly lower abundance of autochthonous genera (Clostridium Incertae Sedis XIV) and a higher abundance of potentially pathogenic ones (Enterococcus, Proteus, Clostridium) in cirrhotic patients compared with the mucosa of healthy controls
		Clostridiaceae - Clostridium ↑
		Enterococcaceae - Enterococcus ↑↑
		Enterobacteriaceae - Proteus ↑
		Reduction of (family - genus):
		Clostridium Incertae sedis XIV ↓↓
		Ruminococcaceae - Subdoligranulum ↓
		Lachnospiraceae ↓
Cirrhotics with vs without infection	Stool samples, Bajaj et al[18]	Overgrowth of (family):	There is an increase in abundance of pathogenic taxa, reduction in autochthonous taxa and higher endotoxemia compared to uninfected patients despite matching for MELD-score and medication confounders
		Enterobacteriaceae ↑
		Reduction of (family):
		Clostridium Incertae sedis XIV ↓↓
		Lachnospiraceae ↓↓
		Ruminococcaeae ↓↓
		Veillonellaceae ↓
Cirrhotics with vs without inflammation	Stool samples, Bajaj et al[18]	Overgrowth of (family):	This relative overgrowth of Enterobacteriaceae can result in endotoxemia due to increased production with worsening intestinal permeability, which has been associated with worsening disease severity and complications in cirrhosis. The lower abundance of butyrate producing genera (such as Roseburia and Ruminococcaceae) might represent a trophic injury to colonocytes
		Bacteroidaceae
		Enterobacteriaceae
		Reduction of (family):
		Clostridium Incertae sedis XIV
		Lachnospiraceae
		Ruminococcaeae
		Roseburia
Cirrhotics with vs without hepatic encephalopathy	Mucosal samples, Bajaj et al[23]	Overgrowth of (family - genus):	Firmicutes such as members of genera Veillonella, Megasphaera, Bifidobacterium, and Enterococcus were higher in HE whereas Roseburia was more abundant in the no-HE group
		Enterococcaceae - Enterococcus ↑
		Veillonellaceae - Megasphaera ↑
		Bifidobacteriaceae - Bifidobacterium ↑↑
		Veillonellaceae - Veillonella ↑
		Reduction of (family - genus):
		Lachnospiraceae - Roseburia ↓↓
Higher MELD score	Stool samples, Bajaj et al[18]	Overgrowth of (family):	With the increase in cirrhosis severity, there was a significant increase in potentially pathogenic and decrease in autochthonous taxa
		Staphylococcae
		Enterococceae
		Enterobacteriaceae
		Reduction of (family):
		Clostridium Incertae sedis XIV
		Lachnospiraceae
		Ruminococcaeae
		Rikenellaceae
Cirrhotics with vs without decompensated disease	Stool samples, Bajaj et al[18]	Overgrowth of (family):	With the increase in cirrhosis severity, there was a significant increase in potentially pathogenic and decrease in autochthonous taxa
		Enterobacteriaceae ↑
		Alcaligenaceae ↑
		Reduction of (family):
		Clostridium Incertae sedis XIV ↓
		Lachnospiraceae ↓
		Ruminococcaceae ↓
		Veillonellaceae ↓
Aetiology of cirrhosis
Alcoholic aetiology vs others	Stool samples, Bajaj et al[18]	Overgrowth of (family):	Alcoholic cirrhotics had a significantly higher abundance of Enterobacteriaceae and Halomonadaceae, lower Lachnospiraceae, Ruminococcaceae, and Clostridialies XIV, despite statistically similar MELD score and BMI compared to those without alcoholic etiology
		Enterobacteriaceae ↑
		Halomonadaeace ↑
		Reduction of (family):
		Clostridiales Incertae sedis XIV ↓
		Lachnospiraceae ↓
		Ruminococcaceae ↓
NASH aetiology vs others		Overgrowth of (family):	There is a higher abundance of Porphyromonadaceae, Bacterioidaceae, and lower Veillonellaceae in NASH patients than the non-NASH counterparts
		Bacteroidaceae ↑
		Porphyromonadaceae ↑
		Reduction of (family):
		Veillonellaceae ↓

Normalized relative abundance: ↑/↓: 1-2 fold of increase/reduction vs control; ↑↑/↓↓: 3-6 fold of increase/reduction vs control; ↑↑↑/ ↓↓↓ > 7 fold of increasereduction vs control. NASH: Nonalcoholic steatohepatitis; MELD score: Model for end-stage liver disease score; BMI: Body mass index.

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

Ref.	Type of study	Category of patients	Therapy	Clinical outcome	Microbiota changing
Albillos et al[68]	RCT	102 Cirrhotics/ 30 controls	Norfloxacin 400 mg orally TD vs Placebo	Norfloxacin improved cardiac index in patients with elevated LBP, no improvement in portal pressure in the rest of patients	NA
Bass et al[100]	RCT	299 cirrhotics	Rifaximin 550 mg twice daily (140 patients) vs placebo (159 patients)	Rifaximin group maintained remission from hepatic encephalopathy more effectively than did placebo	NA
Rayes et al[104]	RCT	66 cirrhotics underwent LT	Pediacoccus pentosaceus + Leuconostoc mesenteroides + Lactobacillus paracasei and L. plantarum vs Placebo	Significant reduction of post-operative bacterial infections (3% vs 48% of controlls)	NA
Lata et al[105]	RCT	39 cirrhotics	Cirrhotics were randomly allocated to treatment with E. coli Nissle or placebo for 42 d	In probiotic group , the authors found a trend of significant lowering of the endotoxemia (P = 0.07) and improvement of Child-Pugh score (P = 0.06)	Restoration of normal colonic colonization in pts treated with E. coli Nissle
Gupta et al[106]	RCT	94 cirrhotic patients with large oesophageal varices without history of variceal bleeding	Patients were randomized to three treatment Groups: (1) propranolol plus placebo (2) propranolol Plus norfloxacin 400 mg BD (3) propranolol plus VSL#3, 900 billion/d	Group 2 and 3 showed a greater reduction in HVPG than Group 1. In addition, in Group 2 and 3 the TNF-a levels were significantly lower than Group 1	NA
Bajaj et al[107]	RCT	25 nonalcoholic MHE cirrhotics (defined by a standard psychometric battery)	Cirrhotics were randomized to Receive yogurt contained Lactobacillus bulgaricus and Streptococcus Thermophilus or no treatment for 60 d in a 2:1 ratio	Twelve of 17 yogurt patients reversed MHE (71% on intention-to-treat and 86% on per-protocol analysis) compared to 0% in the no-treatment group (P = 0.0030) Levels of citokyne were similar between groups	NA
Bajaj et al[56]	PS	20 nonalcoholic MHE cirrhotics (defined by a standard psychometric battery)	Patients received rifaximin 550 mg BID for 8 wk and the psychometric tests, stool analysis and blood test were repeated at the end of the study	There was a significant improvement in cognition test performance and a reduction of endotoxemia after rifaximin	After rifaximin there was a significant reduction in the abundance of faecal Veillonellaceae (P = 0.025) and increase in the abundance of Eubacteriaceae (P = 0.042)
Bergheim et al[101]	Animal model	Mice with induced NAFLD	For 8 wk, C57BL/ J6 mice had free access to solutions containing 30% glucose, fructose, sucrose, or water sweetened with artificial sweetener or plain water	The group treated with polymixin B and Neomycin were protected against the fructose-induced NAFLD and had a lower level of endotoxin	NA

RCT: Randomized controlled study; PS: Pilot study; LT: Liver translanted; NA: Not applicable (the study did not provide microbiota characterization); BD: Bis in die; HVPG: Hepatic venus pressure gradient; NAFLD: Non-alcoholic fatty liver disease.