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Page 6 of 14 Lu et al. Microbiome Res Rep 2024;3:17 https://dx.doi.org/10.20517/mrr.2023.44

and liver injury. Gut alkaline protease-producing bacteria, for example, Enterobacteriaceae that is increased
[40]
in HE patients , also metabolize proteins, urea, and glutamine, which are the main sources of blood
ammonia production.

Short-chain fatty acids
SCFAs are intestinal microbiota-derived metabolites, and have been reported to be decreased in cirrhotic
patients, including those with HE [53,54] . SCFAs have been reported to accelerate the release of hormones from
intestinal endocrine cells, such as serotonin from intestinal chromaffin cells, which can regulate emotional
[55]
activity in a paracrine manner . A study in mice showed that B. dentium and the SCFA acetate can regulate
key components of the serotonergic system to influence host behavior by increasing both the concentration
[56]
of 5-HT and the expression of its receptors, 4- and 5-HT transporters, in the intestine . High levels of LPS
and certain SCFAs, the acetate and valerate, in the blood were associated with increased deposition of
amyloid protein in the brain, which results in Alzheimer’s disease. On the contrary, high levels of another
[57]
type of SCFA, butyrate, were negatively associated with amyloidosis . Butyrate supplementation could
improve glucose homeostasis and beta-cell function in mice, which may reduce hepatic lipid accumulation
[58]
and inflammation . In addition, acetate, propionate, and butyrate reduced the production of
proinflammatory factors and NO, and inhibited inducible NO synthase, which is involved in the gut-liver-
[59]
brain axis . It has been shown that the abundance of gut SCFA-producing bacteria, such as
Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV, was decreased in cirrhotic patients, especially in
[40]
patients with HE .
Bile acids
BAs, a cluster of hydroxyl derivatives of cholanic acid, are critical to the microbiome-gut-liver-brain axis
due to their various physiological functions . Primary BAs are synthesized in the liver, discharged into the
[60]
intestine through the bile duct, and transformed into secondary BAs by enzymes produced by gut
bacteria . The synthesis, secretion, transformation, reabsorption, and processing of BAs are closely related
[61]
to the function of the host liver, gallbladder, intestine, and brain . The abnormal metabolism of BAs and
[62]
an imbalance of cholesterol metabolism inevitably affect the function of these organs because of their
influence on body energy metabolism and immunity. BA metabolism is mostly mediated by a nuclear
receptor Farnesoid X Receptor (FXR), the Takeda G-protein-coupled receptor 5 (TGR5), and sphingosine
1-phosphate receptor 2. TGR5 is involved in the regulation of energy metabolism and activation of the
[63]
[64]
immune response . Activation of the TGR5 signaling pathway can increase the expression of several
mitochondrial genes involved in energy consumption, trigger an induction in deiodinase 2 genes, and
promote the self-phosphorylation of the Sarcoma gene coding (SRC) protein-tyrosine kinases via the
[65]
TGR5-β-Arrestin-SRC pathway . Through phosphorylation, SRC activates various downstream immune
response-related proteins, including retinoic acid-inducible gene 1 (RIG-1) protein, virus-induced signaling
adapter (VISA) protein, stimulator of interferon gene protein (STING), TANK binding kinase 1 (TBK1)
gene protein, and interferon regulatory factor 3 (IRF-3). Binding of sphingosine 1-phosphate receptor 2 by
[66]
BAs can activate the extracellular signal-regulated kinase (ERK)1/2 and Akt-dependent pathways , which
subsequently affects blood-brain barrier permeability and may cause brain impairment by promoting
[67]
neuroinflammation associated with interleukin-1β and tumor necrosis factor-α . Aberrant BA signaling in
the gut-liver-brain axis may also be an important factor in the pathogenesis of neurodegenerative
diseases . Conjugated 12α-hydroxylated BAs (taurodeoxycholate and glycodeoxycholate) are reported to
[68]
have the ability to induce liver fibrogenesis via the ERK1/2 and p38 mitogen-activated protein kinases
(MAPK) signaling pathways . Microbiota dysbiosis and aberrant BA metabolism have been observed in
[69]
HE patients [70,71] .