Alterations in Gut Microbiota and Upregulations of VPAC2 and Intestinal Tight Junctions Correlate with Anti-Inflammatory Effects of Electroacupuncture in Colitis Mice with Sleep Fragmentation

SIMPLE SUMMARY: Along with the modernization of society and people getting older, sleep disturbances and gut health have been identified as two key factors influencing aging, with dramatic effects on immunity and metabolism. Sleep is closely related to the gut, reflects the degree of chronic inflammation, and is associated with many degenerative diseases, hence the term “inflammaging”. This article addresses how sleep fragmentation affects the inflammatory state of the gut and elucidates the effects of restorative sleep and acupuncture on inflammatory gut remodeling and gut microbial recovery. In summary, fragmented sleep disrupted intestinal repair in mice with colitis, while electroacupuncture demonstrated likely results in alleviating colon inflammation, including maintaining colon length and daily body weight changes. In addition, the structure of the microbiota changed with decreasing gut inflammatory status. The intestinal tight junction proteins may be the key mechanism of electroacupuncture in treating sleep-fragmented ulcerative colitis mice. Electroacupuncture affects VIP through VPAC2 and further regulates intestinal mucosal immunity. This experiment demonstrates how physical stimulation stabilizes the intestinal epithelium and exerts an important anti-inflammatory effect. ABSTRACT: The relationship between inflammatory bowel disease and sleep disturbances is complicated and of increasing interest. We investigated the inflammatory and immunological consequences of EA in sleep-deprived colitis and found that dextran sulfate sodium (DSS)-induced colitis in sleep-fragmented (SF) mice was more severe than that in mice with normal sleep. This increase in the severity of colitis was accompanied by reduced body weight, shortened colon length, and deteriorated disease activity index. DSS with SF mice presented obvious diminished intestinal tight junction proteins (claudin-1 and occludin), elevated proinflammatory cytokines (CRP, IFN-γ, IL-6), lowered melatonin and adiponectin levels, downregulated vasoactive intestinal peptide (VIP) type 1 and 2 receptor (VPAC1, VPAC2) expression, and decreased diversity of gut bacteria. EA ameliorated colitis severity and preserved the performance of the epithelial tight junction proteins and VIP receptors, especially VPAC2. Meanwhile, the innate lymphoid cells-derived cytokines in both group 2 (IL-4, IL5, IL-9, IL-13) and group 3 (IL-22, GM-CSF) were elevated in mice colon tissue. Furthermore, dysbiosis was confirmed in the DSS group with and without SF, and EA could maintain the species diversity. Firmicutes could be restored, such as Lachnospiraceae, and Proteobacteria become rebalanced, mainly Enterobacteriaceae, after EA intervention. On the other hand, SF plays different roles in physiological and pathological conditions. In normal mice, interrupted sleep did not affect the expression of claudin-1 and occludin. But VPAC1, VPAC2, and gut microbiota diversity, including Burkholderiaceae and Rhodococcus, were opposite to mice in an inflamed state.