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This study aimed to determine whether  Bmi-1  deficiency leads to intestinal epithelial barrier destruction and microbiota dysfunction, which members of the microbial community alter barrier function with age, and whether  p16   INK4a   deletion could reverse the damage of intestinal epithelial barrier and microbial dysbiosis. Intestines from  Bmi-1 –deficient ( Bmi-1 –/–  ),  Bmi-1  and  p16   INK4a   double-knockout ( Bmi-1 –/– p16  INK4a –/–  ), and wild-type mice were observed for aging and inflammation. Duolink Proximity Ligation Assay, immunoprecipitation, and construction of  p16   INK4a   overexpressed adenovirus and the overexpressed plasmids of full-length, mutant, or truncated fragments for occludin were used for analyzing the interaction between p16  INK4a   and occludin. High-throughput sequencing of V4 region amplicon of 16S ribosomal RNA was conducted using intestinal microbiota. We found  Bmi-1  deficiency destructed barrier structure, barrier function, and tight junction (TJ) in intestinal epithelium; decreased the TJ proteins; increased tumor necrosis factor α (TNF-α)–dependent barrier permeability; and up-regulated proinflammatory level of macrophages induced by intestinal microbial dysbiosis. The transplantation of fecal microbiota from wild-type mice ameliorated TJ in intestinal epithelium of  Bmi-1 –/–   and  Bmi-1 –/– p16  INK4a –/–   mice. Harmful bacteria including  Desulfovibrio ,  Helicobacter , and  Oscillibacter  were at a higher level in  Bmi-1 –/–   mice. More harmful bacteria  Desulfovibrio  entered the epithelium and promoted macrophages-secreted TNF-α and caused TNF-α–dependent barrier permeability and aging. Accumulated p16  INK4a   combined with occludin at the 1st–160th residue in cytoplasm of intestinal epithelium cells from  Bmi-1 –/–   mice, which blocked formation of TJ and the repair of intestinal epithelium barrier.  P16   INK4a   deletion could maintain barrier function and microbiota balance in  Bmi-1 –/–   mice through strengthening formation of TJ and decreasing macrophages-secreted TNF-α induced by  Desulfovibrio  entering the intestinal epithelium. Thus, Bmi-1 maintained intestinal TJ, epithelial barrier function, and microbiota balance through preventing senescence characterized by p16  INK4a   accumulation. The clearance of p16  INK4a  -positive cells in aging intestinal epithelium would be a new method for maintaining barrier function and microbiota balance. The residues 1–160 of occludin could be a novel therapeutic target for identifying small molecular antagonistic peptides to prevent the combination of p16  INK4a   with occludin for protecting TJ.

frontiers in cell and developmental biology

P16INK4a Deletion Ameliorates Damage of Intestinal Epithelial Barrier and Microbial Dysbiosis in a Stress-Induced Premature Senescence Model of Bmi-1 Deficiency