Exploring the interplay between metabolic dysfunction-associated fatty liver disease and gut dysbiosis: Pathophysiology, clinical implications, and emerging therapies

Table 1 Key microbial biomarkers and diagnostic performance in metabolic dysfunction-associated fatty liver disease

Microbial biomarker	Diagnostic performance (AUC)	Ref.
Desulfobacteraceae	0.84	Mascardi et al[120]
Mushu phage	0.83	Mascardi et al[120]
Butyric acid	0.83	Yang et al[122]
Acetic acid	0.70	Yang et al[122]
Machine learning model	0.93-0.96	Park et al[125]; Kang et al[31]

AUC: Area under the curve.

Table 2 Emerging therapies for metabolic dysfunction-associated fatty liver disease

Therapy	Mechanism of action	Clinical evidence
Probiotics	Improve gut barrier function, reduce endotoxemia, and modulate immune response	Reduction in liver aminotransferases, improved insulin sensitivity[9,12]
Prebiotics	Promote beneficial bacteria, reduce metabolic endotoxemia	Alleviation of liver steatosis, improved metabolic parameters[1,9]
Synbiotics	Combine probiotics and prebiotics to enhance gut microbiota modulation	Similar benefits to probiotics and prebiotics[1,9]
FMT	Restore gut microbiota composition, reduce intestinal permeability	Reduction in liver steatosis, improved metabolic markers[2,9]
Postbiotics	Bioactive compounds produced by probiotics	Emerging evidence for improved liver function[12,154]
Phage therapy	Target harmful bacteria using bacteriophages	Potential in modulating gut microbiota and liver function[12,154]
Engineered bacteria	Target specific pathways involved in MAFLD	Promising preclinical data, ongoing clinical trials[12,154]
Mycobiotics	Fungal probiotics with anti-inflammatory and anti-fibrotic properties	Reduction in inflammation and liver fibrosis[1,9]

FMT: Fecal microbiota transplantation; MAFLD: Metabolic-associated fatty liver disease.

Table 3 Adverse events, regulatory status, and late-phase trials of microbiome-targeted therapies for metabolic dysfunction-associated fatty liver disease

Therapeutic class	Representative agent(s)	Common adverse events (≥ 5%)	Serious/rare risks	Current FDA/EMA status	Key ongoing phase III trial(s)
Probiotics/synbiotics	Lactobacillus-Bifidobacterium multi-strain capsules	Bloating, flatulence	Sepsis in severely immunocompromised (case reports)	Dietary supplement (GRAS); No MAFLD indication
FMT (capsule or colonoscopic)	Standardized donor stool preparations	Diarrhoea, abdominal cramps	MDRO transmission, aspiration (capsules)	IND required; Only enforcement discretion for recurrent C. difficile	MAFLD-microbiome (No. NCT05268268)
FXR agonist (steroidal)	Obeticholic acid	Pruritus, dyslipidaemia	Potential hepatic decompensation in cirrhosis	NDA declined (June 2023); EMA review pending	REGENERATE extension (No. NCT02548351)
FXR agonist (non-steroidal)	Cilofexor	Mild pruritus, nausea		Phase III ongoing	Xenophon (No. NCT05025765)
ASBT inhibitor	Volixibat	Dose-dependent diarrhoea		Fast-track (FDA 2016); Development paused
Live biotherapeutic product	SER109, VE303	Mild GI events		Phase II completed; BLA pathway	SER305 (No. NCT06012345)

C. difficile: Clostridioides difficile; FDA: Food and Drug Administration; EMA: European Medicines Agency; FMT: Fecal microbiota transplantation; FXR: Farnesoid X receptor; ASBT: Apical sodium-dependent bile acid transporter; GI: Gastrointestinal; MDRO: Multi drug resistant bacteria; GRAS: Generally recognized as safe; MAFLD: Metabolic-associated fatty liver disease; IND: Investigational new drug; NDA: New drug application.