Metabolic memory in the gut: The microbiota-epigenetic crosstalk orchestrating obesity onset and novel therapeutic landscapes

Table 1 The persistent remodeling of gut microbiota induced by obesogenic diets

Commonality summary	Key microbial taxa/groups	Change in abundance	Key functional	Metabolic outcome	Evidence quality	Ref.
Metabolite- & epigenetics-driven “thrifty memory” (persists after HFD withdrawal; promotes lipid storage & energy conservation)	Odoribacter (e.g., O. splanchnicus)	Enriched/persistent (persists after HFD withdrawal)	Major short-chain fatty acid (butyrate) producer; possesses potent HDAC inhibitor activity	Maintains hypomethylation of hepatic lipid genes (e.g., Apoa4), facilitating lipid transport/storage upon HFD re-exposure	Review (covers in vitro, animal and human studies)	[8]
	Firmicutes/Bacteroidetes ratio	Elevated (residually high)	Broad indicator of energy harvest capacity	Sustained energy harvest, favoring positive energy balance despite caloric restriction	Animal study (rat model) + in vitro study (human microglia cells)	[105]
Impaired gut barrier & persistent low-grade inflammation (LPS/hydrogen sulfide, H2S/mucin degradation; metabolic set-point hard to reset)	Akkermansia muciniphila	Persistent depletion (slow or incomplete recovery)	Mucin degrader; critical for maintaining intestinal barrier integrity (Muc2; ZO-1 expression) and stimulating GLP-1 secretion	Weakens the mucus barrier, sustaining endotoxemia and inflammation, limiting metabolic reset	Animal study (rat model)	[106]
	Desulfovibrio	Persistent enrichment	SRB; produces H2S and highly endotoxic LPS	H2S/LPS impairs colonocyte oxidation and increases CD36-dependent lipid uptake, promoting weight regain	Review (covers animal and human studies)	[107]
	Ruminococcus gnavus	Enriched/persistent	Mucin-degrading specialist; produces inflammatory polysaccharides	Correlates with visceral adiposity and metabolic-syndrome traits despite intervention	Animal study (mouse model)	[108]
Gut-brain axis & behavior-related changes (appetite/mood/feeding behavior; harder weight maintenance)	Oscillibacter	Persistent enrichment	Strictly anaerobic; associated with HFD; produces specific metabolites (e.g., valeric acid) linked to barrier dysfunction	Linked to obesity susceptibility and weight-loss resistance via barrier dysfunction and hyperphagia	Animal study (mouse model)	[109]
	Lachnospiraceae (specific clades e.g., Muribaculaceae bacterium NK4A136, NK4A136)	Altered/variable (often depleted or slow to restore)	Major butyrate producers; pivotal in carbohydrate fermentation and glucose metabolism	Associated with impaired glucose tolerance, reduced metabolic flexibility, and addictive-like feeding, undermining maintenance	Review (covers human metagenomic studies, in vitro and animal studies)	[110]

HFD: High-fat diet; HDAC: Histone deacetylase; Apoa4: Apolipoprotein A-IV; LPS: Lipopolysaccharide; Muc2: Mucin 2; ZO-1: Zonula occludens-1; GLP-1: Glucagon-like peptide-1; SRB: Sulfate-reducing bacterium; CD36: Cluster of differentiation 36.