Hepatic encephalopathy (HE) is a brain disfunction caused by liver failure and/or by portal-systemic blood shunting that lead to neurological/psychiatric effects ranging from subclinical alteration to coma¹. Epidemiological investigations indicate that the prevalence of HE is 30-40% with an increase in mortality². Increasing evidences indicates that the dysfunction of the gut epitheluim, a major line of defense in the local immune system, can cause liver failure³, although the role of gut microbiota in pathogenesis of HE is still unclear. Some evidence shows that alteration in gut motility, the higher pH and the reduced bile concentrations in the colons of patients with cirrhosis may cause a failure to control gut bacterial overgrowth. Moreover, the bacterial composition in sigmoid colon in patients with HE was significantly altered, and it has been demonstrated that patients with HE treated with FMT (Fetal Microbiota Transplantation) showed an improvement in cognition, suggesting that a dysfunction of gut microbiota in involved in the development of HE^4, 5.

Gut microbiota is also affect by liver dysfunction. Infact, liver decomposed harmful substances produced by gut microbiota, and regulation of ammonia levels depend on the urea cycle in the liver. So, loss of normal function of the liver causes an increase level of ammonia in plasma leading to neuropsychiatric complications as HE^6, 7.

Based on the implication of the gut microbiota in the pathogenesis of HE different therapeutic strategies in use in order to promote the development of an effective therapy:

• Antibiotic therapy. Due to the correlation between gut microbiota and HE antibiotics are a feasible treatment. Rifaximin is a semisynthetic antibiotic that affect cognition in HE patients by regulating the state of gut microbiota, significantly reduce the production of gut ammonia that is correlated to gut dysfunction and reduced the presence of ammonia-producing bacteria^8, 9
• Prebiotics. It has been shown that they induced a strong inhibition of intestinal absorption of ammonia¹⁰. Lactulose, a prebiotic carbohydrate, is currently in used to treat HE¹¹ and can cause changes in fecal flora, which can explain its clincal efficacy¹² . However, further studies will be needed to investigate the relationship between gut microbiota and lactulose more deeply
• Probiotcs. Probiotcs have a significant impact on HE by preventing bacterial adhesion and traslocation, by reducing the number of pathogenic bacteria, ammonia production and absorption, and changing gut permeability¹³. Probiotic treatment cause a decreasein C-reactive protein (P=0,01), tumor necrosis factor (TNF) (P=0.01), FABP-6 (P=0.009), and claudin-3 (P=0.002) with a n increase in neutrophil oxidation (P=0.002)¹⁴. However, probiotics are not superior to lactulose or antibiotics in attaining remission in HE patients¹⁵.
• Dietary intervention. Since the composition of gut micriobiota in associated with diet, dietary change is recommended as a teatment to alleviate HE symptoms¹⁶. For example, lower protein and animal flat intakes in diets is associated with an increased risk of HE¹⁷.
• Fecal Micriobiota Transplantation (FTM). Due to the increase in microorganism resistance new therapies need to be identified. FTM refers to the transfer of feces from healthy donors to patients with dysfunction of gut microbiota. Different studies proved that FTM can improve cognitive function and the lenght of hospital stay in patients with HE¹⁸. This beneficial effects on gut microbiota are due to the increase in Ruminococcaceae and Bifidobacteriaceae and the decrease in Streptococcaceae and Veillonellaceae with an increase in E-cadherine (p=0.03), defensina alpha 5 (P= 0.03) and a decrease of interleukin-6 (P=0.02) and serum lipopolysaccharide binding protein (P=0.009)¹⁹. However, FTM is not a standard treatment yet.

Numerous studies are shedding light on the close correlation between gut microbiota and HE and reliable predictors and prognostic biomarkers. However, further research on the genetic background of HE related to the gut microbiota are necessary in order to deeply understand the pathogenesis of HE and, therefore, to find an effective treatment.

References

1. Montagnese S, Russo FP, Amodio P, et al. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2019;51(2):190-205. doi:10.1016/j.dld.2018.11.035
2. Patidar KR, Bajaj JS. Covert and Overt Hepatic Encephalopathy: Diagnosis and Management. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2015;13(12):2048-2061. doi:10.1016/j.cgh.2015.06.039
3. Arab JP, Martin-Mateos RM, Shah VH. Gut–liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int. 2018;12(Suppl 1):24-33. doi:10.1007/s12072-017-9798-x
4. Bajaj JS, Hylemon PB, Ridlon JM, et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol – Gastrointest Liver Physiol. 2012;303(6):G675-G685. doi:10.1152/ajpgi.00152.2012
5. Kao D, Roach B, Park H, et al. Fecal microbiota transplantation in the management of hepatic encephalopathy. Hepatology. 2016;63(1):339-340. doi:https://doi.org/10.1002/hep.28121
6. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol. 2017;67(5):1084-1103. doi:10.1016/j.jhep.2017.05.007
7. Milosevic I, Vujovic A, Barac A, et al. Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. Int J Mol Sci. 2019;20(2). doi:10.3390/ijms20020395
8. Ng KM, Aranda-Díaz A, Tropini C, et al. Recovery of the Gut Microbiota after Antibiotics Depends on Host Diet, Community Context, and Environmental Reservoirs. Cell Host Microbe. 2019;26(5):650-665.e4. doi:10.1016/j.chom.2019.10.011
9. Zuo Z, Fan H, Tang X-D, et al. Effect of different treatments and alcohol addiction on gut microbiota in minimal hepatic encephalopathy patients. Exp Ther Med. 2017;14(5):4887-4895. doi:10.3892/etm.2017.5141
10. Bosques-Padilla FJ, Flores-Rendón AR. [Treatment of hepatic encephalopathy with probiotics and prebiotics]. Rev Gastroenterol Mex. 2005;70(3):372-374.
11. Ruszkowski J, Witkowski JM. Lactulose: Patient- and dose-dependent prebiotic properties in humans. Anaerobe. 2019;59:100-106. doi:10.1016/j.anaerobe.2019.06.002
12. Ferreira M da F, Salavati Schmitz S, Schoenebeck JJ, et al. Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs. Sci Rep. 2019;9(1):13350. doi:10.1038/s41598-019-50090-7
13. Sharma BC, Singh J. Probiotics in management of hepatic encephalopathy. Metab Brain Dis. 2016;31(6):1295-1301. doi:10.1007/s11011-016-9826-x
14. Román E, Nieto JC, Gely C, et al. Effect of a Multistrain Probiotic on Cognitive Function and Risk of Falls in Patients With Cirrhosis: A Randomized Trial. Hepatol Commun. 2019;3(5):632-645. doi:10.1002/hep4.1325
15. Cao Q, Yu C-B, Yang S-G, et al. Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis. Hepatobiliary Pancreat Dis Int HBPD INT. 2018;17(1):9-16. doi:10.1016/j.hbpd.2018.01.005
16. Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol. 2019;11(6):489-512. doi:10.4254/wjh.v11.i6.489
17. Amodio P, Canesso F, Montagnese S. Dietary management of hepatic encephalopathy revisited. Curr Opin Clin Nutr Metab Care. 2014;17(5):448-452. doi:10.1097/MCO.0000000000000084
18. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatol Baltim Md. 2017;66(6):1727-1738. doi:10.1002/hep.29306
19. Bajaj JS, Salzman NH, Acharya C, et al. Fecal Microbial Transplant Capsules are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatol Baltim Md. 2019;70(5):1690-1703. doi:10.1002/hep.30690