Role of Microbiome in the Outcomes Following Surgical Repair of Perianal Fistula: Prospective Cohort Study Design and Preliminary Results.

BACKGROUND: Anal fistulae are common, predominantly cryptoglandular, and almost invariably require surgical treatment. Recurrences are common for procedures other than fistulotomy regardless of technique and adequacy of repair. Growing evidence supports the pivotal role of specific intestinal bacteria in anastomotic failures after bowel resection. Anal crypts harbor colonic microbiota suggesting that similar mechanisms to anastomotic healing might prevail after anal fistula repair and hence influence healing. This study aims at assessing the potential role of the intestinal microbiome in the clinical outcomes after surgical repair of cryptoglandular anal fistula. METHODS: This is a pilot prospective cohort study enrolling patients with anal fistula undergoing endoanal advancement flap. For microbiome analysis, stool samples are taken via rectal swab before the procedure; additionally, a portion of the fistula is collected intraoperatively after fistulectomy. Samples from groups with treatment failure are compared to samples from patients who healed after surgical repair. Alpha and beta diversities and differential abundance of microbial taxa are determined and compared between groups with DADA2 analytical pipeline. RESULTS: Five patients have been enrolled to date (one female, four male). At median follow-up of 6 months (2-11), one patient experienced disease recurrence at 3 months. DNA from the 5 rectal swab and tissue samples was extracted, showing increased relative abundance of Enterococcus faecalis in samples from the patient who developed a recurrent fistula but not in those without recurrence. CONCLUSION: These very preliminary data suggest that intestinal microbiome may represent a crucial determinant of the surgical outcomes after anal fistula surgery.

Synaptopodin Deficiency Ameliorates Symptoms in the 3xTg Mouse Model of Alzheimer's Disease.

Disruption in calcium homeostasis is linked to several pathologies and is suggested to play a pivotal role in the cascade of events leading to Alzheimer's disease (AD). Synaptopodin (SP) residing in dendritic spines has been associated with ryanodine receptor (RyR), such that spines lacking SP release less calcium from stores. In this work, we mated SPKO with 3xTg mice (3xTg/SPKO) to test the effect of SP deficiency in the AD mouse. We found that 6-month-old male 3xTg/SPKO mice restored normal spatial learning in the Barns maze, LTP in hippocampal slices, and expression levels of RyR in the hippocampus that were altered in the 3xTg mice. In addition, there was a marked reduction in 3xTg-associated phosphorylated tau, amyloid ß plaques, and activated microglia in 3xTg/SPKO male and female mice. These experiments indicate that a reduction in the expression of SP ameliorates AD-associated phenotype in 3xTg mice.SIGNIFICANCE STATEMENT This study strengthens the proposed role of calcium stores in the development of AD-associated phenotype in the 3xTg mouse model, in that a genetic reduction of the functioning of ryanodine receptors using synaptopodin-knock-out mice ameliorates AD symptoms at the behavioral, electrophysiological, and morphological levels of analysis.