Table 1 The current clinical scenario involving the use of agents that focus on the gut microbiota for the treatment of NAFLD
Target | Drug | Clinical Status | Disease | Impact |
|---|---|---|---|---|
FXR-agonist | Obeticholic acid (OCA) | Approved | NAFLD | It regulates glucose, lipid metabolism, oxidative stress, and inflammation [54, 55] |
PX-104 | Phase IIa | Non-diabetic NAFLD | Improve insulin sensitivity, a key regulator of bile acid glucose and lipid homeostasis [56] | |
Nidufexor (LMB-763) | Phase II | NASH and diabetic nephropathy | Diminish NAFLD activity scores, lower triglyceride levels, and mitigate liver fibrosis [57] | |
Cilofexor (GS-9674) | Phase III | Reduce levels of serum g-glutamyl transferase, C4, and primary bile acids [61] | ||
Tropifexor | Phase II | Cholestatic liver diseases and NASH | Inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion [62] | |
EDP-305 | Phase II | NASH, cholangiopathies, renal fibrosis | Reduce alanine aminotransferase ALT levels and liver fat content [63] | |
Chenodeoxycholic acid (CDCA) | Approved | NAFLD | Enhance liver functionality while reducing the synthesis of endogenous bile acids [64] | |
FXR-antagonist | Ursodeoxycholic Acid (UDCA) | Approved | NASH | Reduce serum levels of ALT and GGT in patients with NASH [65] |
Glycine-β-muricholic Acid (Gly-MCA) | Approved | NAFLD | Reduction of plasma ceramide levels by decreasing the intestinal production of ceramide [66] | |
Glucagon like peptide-1 agonist | Semaglutide | Approved | NAFLD | Semaglutide exhibits the capacity to lower blood glucose levels, mitigate the buildup of liver fat, and exert anti-inflammatory effects in advanced NAFLD attributed to the impacts of a high-fat diet [67] |
Fibroblast growth factor 19 mimetics | Aldafermin | Phase IIb | NASH | Functioning as an FGF19 analogue, curbs CYP7A1 activity via the FGFR4-βKlotho receptor complex on hepatocytes. This, in turn, leads to diminished levels of hydrophobic and glycine-conjugated bile acids in patients with NASH [68] |
Fibroblast growth factor 21 mimetics | Pegbelfermin | Clinical investigation | NAFLD | Pegbelfermin decreased DCA levels, suppressed gene expression, and influenced microbiome-driven secondary BA synthesis in NASH [69] |
Efruxifermin | Phase IIa | NASH cirrhosis | Efruxifermin decreases liver fat and markers of liver injury, reduces fibrosis, improves glucose and lipid metabolism, and lowers hyperuricemia. Furthermore, a weight loss trend is observed [70] | |
Peroxisome proliferator-activated receptor (PPAR) | Seladelpar (MBX‐8025) PPARδ | Clinical investigation | Diabetic NAFLD, NASH | Seladelpar enhanced multiple aspects of glucose regulation and liver tissue structure, addressing issues like inflammation and fat buildup [71] |
Saroglitazar (PPARα and PPARγ agonist) | Clinical investigation | NASH | Improves hepatic steatosis, and decreases plasma ALT levels. In addition, it positively affected all histologic characteristics associated with NASH [72, 73] | |
Thyroid hormone receptor beta (THR-B) agonist | VK2809 | Clinical investigation | NAFLD | Reduction in hepatic TAG content in NAFLD [74] |
ASC41 | Advancing to phase II | NAFLD, NASH | Hypolipidemic activity in healthy volunteers [75] | |
TERN-501 | Phase I | Hyperlipidemia and NASH | Reduced serum cholesterol levels and attenuated liver steatosis and fibrosis [76] | |
Resmetrirom (MGL -3196) | Phase III | TRβ agonist reduces hepatic fat and markers of inflammation and fibrosis and reduces elevated liver enzymes [77] | ||
Clostridium butyricum combined with Rosuvastatin | Clinical investigation | NAFLD | Gut microbiota and HMG-CoA reductase Inhibitor [78] |