Gut microbiota: Unseen conductor of polyherbal efficacy in diabetic neuropathy

Table 1 Key bioactive compounds in the polyherbal extract and their hypothesized microbiome-mediated mechanisms in diabetic neuropathy

Plant source	Key bioactive compounds	Direct action on microbiota	Microbiome-mediated systemic effects	Relevance to diabetic neuropathy
Curcuma longa (turmeric)	Curcuminoids (e.g., curcumin)	Prebiotic effect: Promotes growth of Bifidobacterium, Lactobacillus[49]. Antimicrobial: Inhibits growth of pathogenic taxa. Biotransformation: Gut microbes convert it to more bioactive metabolites (e.g., tetrahydrocurcumin)[49]	Anti-inflammatory: Reduced LPS translocation and microbial metabolism to anti-inflammatory compounds. Improved metabolism: Enhanced gut hormone secretion	Directly counters the chronic inflammation (TNF-α decrease, IL-1β decrease) and oxidative stress that drive nerve damage
Citrullus colocynthis (bitter apple)	Cucurbitacins, flavonoids, polysaccharides (fiber)	Selective fermentation: Serves as a primary substrate for SCFA-producing bacteria (e.g., Faecalibacterium, Roseburia)[52]. Diversity enhancer: Provides diverse nutrients for a wide range of commensal microbes	Barrier fortification: Increased butyrate production nourishes colonocytes, strengthening tight junctions. Metabolic regulation: Increased SCFAs improve glucose homeostasis and insulin sensitivity via GLP-1	Addresses metabolic dysregulation and restores intestinal barrier integrity, reducing the primary inflammatory trigger
Myristica fragrans (nutmeg)	Myristicin, eugenol, phenolic compounds	Selective antimicrobial: Suppresses the overgrowth of specific pathobionts without eliminating beneficial commensals[54]. Ecosystem remodeling: Creates an ecological niche for beneficial bacteria to repopulate and thrive	Reduced pathobiont load: Decreased production of pro-inflammatory bacterial products (e.g., hydrogen sulfide from sulfate-reducing bacteria). Neurotransmitter modulation: Influences microbial production of neuroactive compounds	Helps rebalance the dysbiotic ecosystem, potentially alleviating neuropathic pain through modulation of the gut-nerve axis

SCFA: Short-chain fatty acid; LPS: Lipopolysaccharide; GLP-1: Glucagon-like peptide-1; TNF: Tumor necrosis factor; IL: Interleukin.