**3.3 Microbiota**

*Liver Disease and Surgery*

**6**

**3.2 Inflammation**

*thus producing intracellular swelling and edema.*

**Figure 2.**

thereby contributing to the cerebral dysfunction seen in HE [17]. The high-energy consumption by this process leads to oxidative stress which is accompanied by cellular dysfunction and disruption of neurotransmission predominantly of glutamate and γ-aminobutyric acid [24]. In the brain, NH3 produces inactivation of neuronal chloride extrusion pumps; these processes result in inhibition of both axonal conduction and excitatory postsynaptic potentials, subsequently suppressing inhibitory postsynaptic potential formation and depolarizing neurons [25, 26].

*Pathogenesis of hepatic encephalopathy. In normal conditions, gut release of ammonia results in high portal vein ammonia levels. Microbiota is also responsible for the formation of ammonia, endotoxins. In liver cirrhosis, the liver extracts portal venous ammonia poorly. The subsequent increase of arterial ammonia levels leads to increased disposition of ammonia in other tissues. Both the brain and muscle lack a complete urea cycle and rely on the formation of glutamine. Thus, the brain and muscle become ammonia-uptake and glutaminereleasing organs. In the brain, astrocytes metabolize ammonia through glutamine synthetase, converting glutamate and ammonia to glutamine which is osmotically active and promotes water shift into the astrocyte,* 

Studies demonstrated that, severity of MHE might not correlate with severity of liver disease or the level of ammonia, proposing the existence of other pathogenic

Studies suggested that, many interactions with gut microbiota can play an active role in MHE (**Figure 2**). Microbiota changes have been linked with impaired cognition, endotoxemia, and inflammation. With the progression of cirrhosis, there is dysbiosis (unfavorable change in the composition of the microbiome) with decreased levels of autochthonous taxa (native Firmicutes) bacteria and increased levels of other taxa (Bacteroidetes, Actinobacteria). The native bacteria are important for the harmony of the gastrointestinal flora and for the well-being of the entire body. The autochthonous bacteria produce short-chain fatty acids that feed the colonic mucosal cells and reduce local colonic inflammation, and produce anti-bacterial peptides [32]. In patients with minimal HE, stool microbiota studies demonstrated an increase in *Streptococcus salivarius* [33]. Zhang et al. found worse dysbiosis in all cirrhotic patients versus healthy controls and also found overrepresentation of two bacterial families, Streptococcaceae and Veillonellaceae, in cirrhotic patients with and without MHE as compared with controls. Moreover, patients with MHE had an overabundance of *Streptococcus salivarius*. This dysbiosis could increase ammonia production due to its urease activity, and its count positively correlated with ammonia levels and cognitive testing in patients with MHE [34]. The cirrhosis dysbiosis ratio (CDR) is the ratio of autochthonous to nonautochthonous taxa in cirrhosis. The lower the CDR the more the endotoxemia and more decompensated the cirrhosis [35].
