Gut microbiota-multi-organ axis and neuroinflammatory network: A potential integrative hub in aging and age-related diseases

Table 1 Evidence grading of microbiota–multi-organ axis mechanisms in aging

Mechanism	Description	Evidence level	Evidence type
Gut-brain axis	Microbiota influences BBB and microglia	Strong	Animal + human
TMAO	Associated with cardiovascular risk	Moderate	Cohort + experimental
HADHB pathway	Microbiota-liver FAO link	Limited	Animal
TCM-microbiota	Multi-target modulation	Speculative	Preclinical

BBB: Blood-brain barrier; TMAO: Trimethylamine N-oxide; HADHB: Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; FAO: Fatty acid oxidation; TCM: Traditional Chinese medicine.

Table 2 Major microbial metabolites and their organ-level effects

Metabolite	Source	Target organ	Biological effect
SCFAs	Gut microbiota fermentation	Brain	Anti-inflammatory, BBB protection
TMAO	Choline metabolism	Cardiovascular	Pro-inflammatory, atherogenic
Bile acids	Liver-microbiota interaction	Liver/metabolism	Signaling regulation
LPS	Gram-negative bacteria	Systemic	Inflammation activation
Tryptophan metabolites	Microbial metabolism	Brain	Neurotransmitter modulation

SCFAs: Short-chain fatty acids; BBB: Blood-brain barrier; TMAO: Trimethylamine N-oxide; LPS: Lipopolysaccharide.

Table 3 Key unresolved questions and recommended experimental approaches in aging research

Unresolved question	Current limitation	Recommended approach
Which microbial taxa regulate hepatic HADHB	Lack of causal evidence	Germ-free models + microbiota transplantation
Is TMAO causally involved in aging	Mostly associative data	Longitudinal human studies + intervention trials
How does microbiota affect neuroinflammation	Mechanisms unclear	Multi-omics + BBB models
Can TCM effects be linked to microbiota causally	Limited mechanistic studies	Standardized formulations + microbiome sequencing
Are findings aging-specific or disease-driven	Evidence mainly from disease models	Dedicated aging cohorts

HADHB: Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; TMAO: Trimethylamine N-oxide; BBB: Blood-brain barrier; TCM: Traditional Chinese medicine.