Multi-omics uncovers the critical role of ceramide-mediated Acinetobacter growth suppression in pressure injury healing under aging and malnutrition

The epidemiology of tolerance and susceptibility in an individual suggests that aging and malnutrition (MN) should be critically regarded as a common clinical combination in the pathomechanism of pressure ulcer/injury (PU). However, the influence of these two factors on wound healing has not been fully elucidated. In this study, we used a random forest (RF) to screen macro and laboratory indicators to compare the characteristic variables of single versus dual interventions for aging or MN. The 16S ribosomal RNA (16S rRNA) microbiome sequencing as well as serum and skin metabolomics studies were conducted, along with the integration of bulk and single-cell RNA sequencing (scRNA-seq) data using bioinformatics. MetOrigin, MIMOSA2, and MetaNet were used to identify the molecular driving factors. The main findings demonstrated that the dual intervention played an essential role in inflammatory infiltration, suppressing Acinetobacter colonization, affecting the activity of arachidonic acid (AA) and sphingolipid metabolic pathways, and simulating the metabolic profile of natural skin aging. The results of multi-omics association analysis, molecular biology, and antibacterial experiments in vitro indicated that the dual intervention affected keratinocytes through the cascading changes of the ceramide- Acinetobacter -AA-autophagy/wingless/integrated (WNT) axis to influence the healing process of PU wounds. In summary, this study has identified previously unknown links among skin microbiota, metabolites, and genomics in MN and aging, demonstrating that ceramide supplementation promotes wound healing in the older adults. • Malnutrition-aging double hit disrupts healing via Acinetobacter /ceramide deficit. • Ceramide- Acinetobacter -AA-autophagy/WNT axis occurs in epidermis. • Ceramide deficit initiates inflammation/autophagy-WNT suppression. • Ceramide supplement inhibits Acinetobacter colonization, promoting wound healing.