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Cui et al. Microbiome Res Rep. 2025;4:31 https://dx.doi.org/10.20517/mrr.2025.25 Page 9 of 14

NAFLD
NAFLD pathogenesis is tightly linked to gut-liver axis perturbations. Dysbiosis elevates gut permeability
and LPS translocation, activating hepatic TLR4-mediated inflammation and impairing mitochondrial β-
oxidation . Altered microbial metabolism of choline produces toxic intermediates (e.g., δ-valerobetaine)
[82]
[83]
that inhibit the carnitine shuttle and exacerbate triglyceride accumulation in hepatocytes . Conversely,
SCFA-enhancing prebiotics expand myeloid-derived suppressor cells that mitigate hepatic steatosis and
oxidative stress in rodent NAFLD models . Immune crosstalk also plays a crucial role: gut-derived type 3
[84]
innate lymphoid cells migrate to the liver and secrete IL-22, promoting hepatocyte lipid oxidation and
reducing fibrosis; strategies that boost the ILC3-IL-22 axis via washed microbiota transplantation have
achieved up to 43% reduction in liver fat in early trials [85,86] . Collectively, these insights provide a mechanistic
framework for microbiota-based therapies in NAFLD, including probiotics, synbiotics, and targeted
microbial metabolite analogs.

Other disorders
In addition to obesity, T2D, and NAFLD, several other well-recognized microbiota-mediated metabolic
disorders have been identified, including metabolic syndrome, hypertension, and polycystic ovary
syndrome (PCOS). Metabolic syndrome is associated with gut dysbiosis, reduced microbial diversity,
impaired metabolism of SCFAs and bile acids, and increased levels of LPS. These alterations contribute to
systemic inflammation, insulin resistance, dyslipidemia, and elevated blood pressure . Clinical
[87]
interventions using prebiotics, probiotics, synbiotics, and postbiotics have shown improvements in
metabolic parameters. However, the outcomes remain variable and highlight the importance of personalized
therapeutic strategies . In hypertension, gut microbiota dysbiosis is marked by reduced microbial diversity,
[88]
enrichment of mucin-degrading taxa (Muribaculaceae, Alistipes), and depletion of SCFA-producing genera
(Ruminococcus, Eubacterium eligens), as observed in hypertensive cohorts. These changes correlate with
altered microbial metabolic pathways (e.g., increased acetate-CoA ligase activity, decreased GPR43
signaling) and contribute to elevated blood pressure via impaired vascular and inflammatory regulation.
FMT from hypertensive humans into germ-free mice has causally linked dysbiosis to hypertension
development [89,90] . PCOS also displays characteristic features of gut dysbiosis, including lower microbial
diversity, a disturbed Firmicutes to Bacteroidetes ratio, increased abundance of Escherichia-Shigella, and
reduced levels of Akkermansia. These changes are correlated with insulin resistance, hormonal imbalance,
and chronic inflammation [11,91] . Microbiota-targeted interventions, including probiotics, prebiotics, and
precision microbiome-based therapies such as designer microbial consortia, have shown potential to
improve both metabolic and reproductive outcomes in individuals with PCOS [92,93] . Table 2 summarizes
these therapeutic strategies, highlighting the range of microbiota-targeted approaches being investigated for
metabolic disorders.

CONCLUSION
The gut microbiota plays a central role in regulating lipid metabolism through its metabolites and
interactions with host signaling pathways. SCFAs, produced by microbial fermentation of dietary fiber,
suppress hepatic lipogenesis by inhibiting SREBP-1c and activate GPR41/43 receptors to enhance
mitochondrial β-oxidation. Microbial enzymes convert primary bile acids into secondary bile acids, which
activate FXR to inhibit hepatic triglyceride synthesis and stimulate TGR5 receptors to promote adipose
thermogenesis. LPS translocated from dysbiotic microbiota triggers TLR4-NF-κB signaling, driving insulin
resistance and adipose tissue inflammation. BCAAs, metabolized by gut microbes, activate the mTORC1-
PPARγ axis to promote adipogenesis, with elevated circulating BCAA levels strongly linked to obesity and
metabolic dysfunction. In livestock, microbiota-targeted strategies optimize fat deposition for meat quality.
For instance, probiotic supplementation in pigs enriches Lactobacillus and BCAA metabolic pathways,
enhancing IMF, while dietary succinate or coated sodium propionate reshapes cecal microbiota in chickens