Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

Figures & data

Figure 1. Common pathological factors and therapeutic strategies of cholestasis.

Table 1. Similarities and differences of various etiologies of cholestasis.

	Type	Disease population	Risk factors	Clinical features	Epidemiology	Diagnostic markers	Cholestasis trigger mechanism	References
DIC	Hepatocellular cholestasis, Bile duct cellular cholestasis	More common in the elderly	Individual, Drugs, Environment	Jaundice, pruritus; increased serum ALP, GGT, transaminase	China, 5265/25,927, 20.31% Sweden, 206/784, 26%	Recovery of abnormal liver parameters after drug discontinuation and positive reactions to re-dosing	Three major mechanisms: (i) transporter changes; (ii) hepatocellular changes; (iii) altered bile canalicular dynamics	^Citation3,Citation18–22
PBC	Bile duct cellular cholestasis	Women in their 5^th or 6^th decade of life	Heredity, Environment	Fatigue, pruritus, malabsorption syndrome, sicca syndrome, osteoporosis; increased serum ALP, GGT, transaminase	Asia Pacific(7 countries), 118.75/million China, Japan, 191.18 /million Korea, Australia, 39.09 /million	Elevated ALP, Positive AMA, Non-suppurative destructive cholangitis, Interlobular bile duct destruction	the interaction of immune and biliary pathways, which further leads to BEC damage	^Citation23–27
PSC	Bile duct cellular cholestasis	Men around the age of 40	Heredity, Environment	Pruritus, fatigue, right upper quadrant pain; increased serum ALP, GGT, transaminase	European Union, 5/10,000 Singapore, 0.13/10,000 Japan, 0.095/10,000	Elevated ALP, Elevated GGT, typical multifocal narrowing and segmental dilatation of the bile duct	Intestinal mucosal barrier disorder, bile duct mucosal barrier damage, flora imbalance, immune interaction	^Citation13,Citation28–32
ICP	Hepatocellular cholestasis	Pregnant woman	Phytohormone, Heredity, Environment	Pruritus; increased serum ALP, GGT, transaminase	Central, Western Europe, North America, Australia, 1% Chile, 5%	Elevated blood glycolic acid ≥10.75 μmol/L or Elevated TBAs ≥ 10 μmol/L	Abnormal BA transporter protein function; The increase of reproductive hormone estrogen and progesterone levels	^Citation14,Citation33–35
PFIC	Hepatocellular cholestasis	Infants and children	Heredity	Jaundice, pruritus; increased serum BA	1/50,000–100,000, exact prevalence is not know	Genes	Related to mutations in hepatocellular transport-system genes involved in bile formation(FIC1, BESP, MDR3)	^Citation36–40
PNAC	Hepatocellular cholestasis	Infants are more likely than adults	Heredity, Environment, Phytohormone,	Jaundice; elevated conjugated bilirubin, serum BA, transaminase	Britain, 924/3280, 28.2	two consecutive measurements of direct bilirubin >2 mg/dL	Altered enterohepatic circulation and flora translocation; PN itself or specific components of PN	^Citation41–45

Table 2. Therapeutic strategies.

		Mechanism	Dose	Applicable to		references
Existing therapies	UDCA	Reduce bile toxicity; Enhance hepatobiliary secretion; Protect hepatocytes from BA induced apoptosis; Change BA pool	13–15 mg/kg/D	PBC; PSC; ICP; DIC; PFIC; PNAC	^Citation9,Citation27,Citation85,Citation86
	SAMe	Form mixed micelles to protect hepatocyte membranes; Increase the fluidity of hepatocyte plasma membrane; Impel the activity of Na+/ K+ ATPase on the membrane; Increase the excretion of hormone metabolites	Intravenous injection: 0.5–1.0 g/D Oral SAMe tablets: 1.0–2.0 g/D	ICP; DIC; PNAC	^Citation68,Citation87–89
	FXR agonists (OCA)	Enhances secretion of BAs; Reduce the synthesis and import of BAs; Reduces the time hepatocytes are exposed to potentially toxic BAs	Start with the lowest recommended dose: 5 mg/day, increasing to 10 mg/day after 3 months	PBC	^Citation6,Citation27,Citation90
	PPAR agonists(fibrates)	Inhibition of BA synthesis; Stimulate phospholipid excretion; Anti-inflammatory effect (via inhibition of NF-κB signaling)	Bezafibrate (400 mg/D) Fenofibrate (160 mg/D)	PBC	^Citation91–95
Novel therapies	FXR agonists (LJN-45291, GS-967492, EDP-30593)	Same as OCA	Still in clinical trials	/	^Citation96–98
	FGF-19 analogues (NGM282)	Down regulating BAs synthesis; Prevent recapture of BAs in the ileum; Reducing BAs pool	Still in clinical trials	/	^Citation99,Citation100
	PXR agonists	Regulate the expression of genes involved in the detoxification and metabolism of BA	Still in clinical trials	/	^Citation9
	TGR5 agonists	Reduce bile acid synthesis; Reduces pro-inflammatory responses; Promotes BECs proliferation and inhibits BA-mediated cell damage	Still in clinical trials	/	^Citation101,Citation102

Figure 2. Enterohepatic circulation.

Figure 3. Possible mechanism of probiotics to relieve cholestasis.

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Data availability statement

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