Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis

Table 1 Therapeutic strategies in hepatic encephalopathy

Therapeutic approach	Mechanism of action				Gut microbiota modulation	Level of evidence according to EASL/AASLD guidelines
Non absorbable disaccharides (lactulose and lactilol)	Decrease serum ammonia levels by:		- Accelerating intestinal transit		Yes	- Treatment: GRADE II-1, B, 1 [3]
			- Reducing ammonia synthesis in the gut			- Secondary prophylaxis: GRADE II-1, A, 1 [3]
Rifaximin	Decreases serum ammonia levels and proinflammatory cytokines release by:		- Modifying intestinal bacterial metabolism and abundance		Yes	Secondary prophylaxis:
						GRADE I, A, 1 [3]
			- Inhibiting bacterial translocation
Adequate protein intake (1.2-1.5 g/kg per day)	Decrease serum ammonia levels by:		- Balancing nitrogen metabolism		-	Treatment:
						- GRADE I, A, 1 [3]
						- GRADE II-2, B, 1 [136]
			- Preventing sarcopenia
Dairy proteins	Decrease serum ammonia levels (process unclear)				Yes	Treatment:
						- GRADE II-3, B, 1 [136]
Vegetable proteins	Decrease serum ammonia levels by:		- Increasing ammonia detoxification (urea cycle)		Yes	Treatment:
			- Accelerating intestinal transit (high fiber content)
						- GRADE II-3, B, 1 [136]
	Reduce circulating mercaptans and indoles
Oral branched-chain amino acids (BCAA)	Unclear. Postulated:		- Increasing ammonia detoxification (glutamine synthesis)		-	Treatment:
						- GRADE I, B, 2 [3]
	Decrease serum ammonia levels by:
						- GRADE I-1, A, 1 [136]
	Rebalance of CNS system neurotransmitters synthesis
L-ornithine-L-aspartate (LOLA)	Decreases serum ammonia levels by:		- Increasing ammonia detoxification (urea cycle and glutamine synthesis)		-	Treatment:
						- GRADE I, B, 2 [3]
Zinc	Decrease serum ammonia levels by:		- Increasing ammonia detoxification (urea cycle and glutamine synthesis)		-	No recommendations
Prebiotics	Decrease proinflammatory cytokines release and serum ammonia levels by:		- Reducing intestinal permeability		Yes	No recommendations
			- Reducing luminal pH
			- Reducing ammonia absorption
			- Accelerating intestinal transit
Probiotics	Decrease proinflammatory cytokines release and serum ammonia levels by:		- Reducing intestinal permeability		Yes	No recommendations
			- Reducing luminal pH
			- Reducing ammonia absorption
Gluten-casein free diet	Unclear. Postulated:	- reducing absorption of gluten- and casein-derived peptides			Yes	No recommendations
	Rebalance of CNS dysfunction by:
		- decreasing proinflammatory cytokines production
Fecal microbiota transplantation	Rebalance of gut microbiota				Yes	No recommendations

Criteria used to classify recommendations (EASL/AASLD guidelines)[3,136]: Level of evidence: I: Randomized, controlled trials, II-1 controlled trials without randomization, II-2) cohort or case-control analytical studies, II-3 multiple time series, dramatic uncontrolled experiments, III opinions of respected authorities, descriptive epidemiology. Quality of evidence: A: High: further research is very unlikely to change our confidence in the estimated effect; B: Moderate: further research is likely to have an important impact on our confidence in the estimated effect and may change the estimate; C: Low: further research is likely to have an important impact on our confidence in the estimated effect and is likely to change the estimate. Any change of estimate is uncertain. Grade of recommendation: 1: Strong: factors influencing the strength of recommendation included the quality of evidence, presumed patient-important outcomes, and costs, 2: Weak: variability in preferences and values or more uncertainty. Recommendation is made with less certainty, higher costs, or resource consumption. CNS: Central nervous system.