Non-communicable diseases (NCDs) cause 74% of global deaths, driven by poor diets low in whole grains. Millets, nutrient-dense and climate-resilient grains, offer bioactive phytochemicals that may modulate gut microbiota to combat NCDs, yet evidence synthesis is lacking. This review synthesizes phytochemical diversity, gut microbiota modulation mechanisms, and multi-omics insights from millets to elucidate pathways reducing NCD risk. Narrative synthesis of> 100 studies (2020-2025) from PubMed, Google Scholar, and ScienceDirect on major/minor millets' composition, bioactivity, processing, microbiota effects, and omics data from in vitro, in vivo, and human studies. Millets provide resistant starch (53-81%), fiber (up to 38%), calcium (finger millet: 38%), polyphenols (ferulic/sinapic acids), and flavonoids, delivering antidiabetic (a-glucosidase inhibition), anticancer (miR-149 upregulation), anti-inflammatory (NF-KB suppression), and gut-protective effects. Phytochemicals boost SCFA producers (Bifidobacterium, Akkermansia), enhance barrier integrity via GABA/propionate, and curb dysbiosis-linked diabetes/colitis in rodent models; processing reduces antinutrients by 50-70%. Multi-omics reveals PHYTOENE SYNTHASE I-driven accumulation of phytonutrients for biofortification. Mil-lets emerge as microbiome-modulating functional foods for NCD prevention, especially in semi-arid regions. Large-scale human RCTs, standardized bioaccessibility protocols, synbiotics, and omics-guided breeding are needed to bridge preclini-cal to clinical translation.
Highlights
Millets are rich in phytochemicals, including polyphenols and flavonoids, which confer various therapeutic effects and make them functional foods.
Phytochemicals present in millets helps modulate gut microbiota and boost the production of short-chain fatty acids for better metabolic health.
Integrative Multi-omics approaches help understand the mechanisms by which phytochemicals present in millets influ-
ence gut microbiota and metabolism, and aid in the reduction of various non-communicable diseases. Various processing techniques that reduce antinutrients and increase the bioavailability of nutrients in millets.