The imbalance of gut microbiota, such as dysbiotic expansion of Enterobacteriaceae, is strongly associated with the progress of inflammatory bowel disease (IBD) via exacerbating gut inflammation and disturbing intestinal mucosal barrier. Recently, a microbiota-based strategy is an attractive paradigm for IBD therapy. Here, we explored the therapeutic potential of tungsten oxide nanoparticles (WO3NPs) against DSS-induced acute colitis mice. WO3NPs (47.9 nm in diameter) significantly reduced intestinal inflammation, attenuated bacterial translocation, restored the colonic epithelium barriers, and remodeled gut microbiota homeostasis in inflamed colon, compared with the free tungsten (sodium tungstate). The element quantification and mapping results showed WO3NPs could increase the adherence of tungsten with Enterobacteriaceae in colonic mucus layer, which inhibited Enterobacteriaceae growth by microbial metabolic reprogramming and ameliorate colitis. This nano-enabled approach for tungsten reduced its deposition in the main organ except for the colon thereby improve the therapeutic efficacy with good biosafety. Together, our results provide insights into the potential nanotherapeutics of WO3NPs against the invasion processes of microbiota in the treatment of IBD. Display omitted •Reprogramming of microbial metabolism by tungsten oxide nanoparticles contributes to ameliorate IBD.•Tungsten oxide nanoparticles target intestinal microbial respiration and blunt the dysbiotic bloom of Enterobacteriaceae in acute colitis mice.•Tungsten oxide nanoparticles act as a microbe-based therapy against IBD by remodeling gut microbiota homeostasis and recovering intestinal mucosal immune barrier.