Acute nickel exposure alters the gut microbiota-metabolite-immune axis in a route-dependent manner

Nickel is a widespread ubiquitous environmental contaminant whose short-term impacts on the gut microbiota-metabolite-immune axis remains poorly defined. In this study, mice were exposed to nickel chloride every alternate day for 15 days via gavage, intraperitoneal injection, or nasal drop. Subsequently, the microbial, metabolic, and immunological responses were assessed. Additionally, 16S rRNA sequencing revealed route-dependent dysbiosis, characterized by the depletion of commensal taxa such as Prevotellaceae UCG-001, Rikenellaceae_RC9, and Alistipes, as well as the enrichment of opportunistic bacteria, including Helicobacter, Enterobacter, and Alloprevotella, particularly in the gavage and intraperitoneal groups. Functional predictions (PICRUSt2) indicated enrichment of immune-related pathways-notably, NOD-like receptor signalling, Th17 cell differentiation, and MAPK (Mitogen-Activated Protein Kinase) signalling-thereby implicating innate and adaptive inflammatory responses. Targeted metabolomics revealed significant elevations of acetate and propionate in the gavage and intraperitoneal groups, whereas butyrate displayed a transient increase associated with Clostridium sensu stricto 1 enrichment. In contrast, administration of nasal drops reduced isobutyrate and isovalerate, suggesting impaired proteolytic fermentation. Despite the increase in short-chain fatty acids (SCFAs), serum tumour necrosis factor-α (TNF-α) levels were significantly elevated, which was consistent with an overriding pro-inflammatory drive. These findings demonstrate that acute nickel exposure perturbs the gut microbiota and alters SCFA metabolism in a route-dependent manner. Concurrently, functional predictions and inflammatory readouts suggest engagement of the NOD-MAPK-Th17 axes. Consequently, this study highlights the complex interplay between microbial adaptation and host inflammation under acute heavy metal stress.