Smoking Suppresses the Therapeutic Potential of Adipose Stem Cells in Crohn's Disease Patients through Epigenetic Changes.

Patients with Crohn's disease (CD) who smoke are known to have a worse prognosis than never-smokers and a higher risk for post-surgical recurrence, whereas patients who quit smoking after surgery have significantly lower post-operative recurrence. The hypothesis was that smoking induces epigenetic changes that impair the capacity of adipose stem cells (ASCs) to suppress the immune system. It was also questioned whether this impairment remains in ex-smokers with CD. ASCs were isolated from non-smokers, smokers and ex-smokers with CD and their interactions with immune cells were studied. The ASCs from both smokers and ex-smokers promoted macrophage polarization to an M1 pro-inflammatory phenotype, were not able to inhibit T- and B-cell proliferation in vitro and enhanced the gene and protein expression of inflammatory markers including interleukin-1b. Genome-wide epigenetic analysis using two different bioinformatic approaches revealed significant changes in the methylation patterns of genes that are critical for wound healing, immune and metabolic response and p53-mediated DNA damage response in ASCs from smokers and ex-smokers with CD. In conclusion, cigarette smoking induces a pro-inflammatory epigenetic signature in ASCs that likely compromises their therapeutic potential.

Simultaneous Treatment of Complex Incisional Hernia and Stoma Reversal.

Purpose: The simultaneous repair of incisional hernias (IH) and the reconstruction of the intestinal transit may pose a challenge for many surgeons. Collaboration between units specialized in abdominal wall and colorectal surgery can favor simultaneous treatment. Methods: Descriptive study of patients undergoing simultaneous surgery of complex IH repair and intestinal transit reconstruction from the start of treatment in a joint team. All interventions were performed electively and with the collaboration of surgeons experts in abdominal wall and colorectal surgery. Results: 23 patients are included. 11 end colostomies, 1 loop colostomy, 6 end ileostomies and 5 loop ileostomies. Seven (30%) patients presented with a medial laparotomy incisional hernia, 3 (13%) with a parastomal incisional hernia, and 13 (56%) with a medial and parastomal incisional hernia. Closure of the hernial defect was achieved in 100% of cases, and reconstruction of the intestinal tract was achieved in 22 (95%). Component separation was required in 17 patients (74%), which were 11 (48%) posterior and 6 (26%) anterior. In-hospital morbidity was 9%, and only two patients presented Clavien-Dindo morbidity > III when requiring reoperation, one due to hemorrhage of the surgical bed and another due to dehiscence of the coloproctostomy. The mean follow-up was 11 months, with 20 (87%) patients having no complications. Mesh had to be removed in one patient with anastomotic dehiscence, no mesh had to be removed due to surgical site infection.

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn's Disease.

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn's disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD.

The Gut Microbiota Metabolite Succinate Promotes Adipose Tissue Browning in Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease [CD] is associated with complex microbe-host interactions, involving changes in microbial communities, and gut barrier defects, leading to the translocation of microorganisms to surrounding adipose tissue [AT]. We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes. METHODS: Visceral [VAT] and subcutaneous [SAT] AT biopsies, serum and plasma were obtained from patients with active [n = 21] or inactive [n = 12] CD, and from healthy controls [n = 15]. Adipose-derived stem cells [ASCs] and AT macrophages [ATMs] were isolated from VAT biopsies. RESULTS: Plasma succinate levels were significantly higher in patients with active CD than in controls and were intermediate in those with inactive disease. Plasma succinate correlated with the inflammatory marker high-sensitivity C-reactive protein. Expression of the succinate receptor SUCNR1 was higher in VAT, ASCs and ATMs from the active CD group than from the inactive or control groups. Succinate treatment of ASCs elevated the expression of several beige AT markers from controls and from patients with inactive disease, including uncoupling protein-1 [UCP1]. Notably, beige AT markers were prominent in ASCs from patients with active CD. Secretome profiling revealed that ASCs from patients with active disease secrete beige AT-related proteins, and co-culture assays showed that bacteria also trigger the white-to-beige switch of ASCs from patients with CD. Finally, AT depots from patients with CD exhibited a conversion from white to beige AT together with high UCP1 expression, which was corroborated by in situ thermal imaging analysis. CONCLUSIONS: Succinate and bacteria trigger white-to-beige AT transition in CD. Understanding the role of beige AT in CD might aid in the development of therapeutic or diagnostic interventions.

Multicenter Controlled Study of Intracorporeal Mechanical Side-to-Side Isoperistaltic Anastomosis versus Extracorporeal Anastomosis in Laparoscopic Right Hemicolectomy: HEMI-D-TREND-Study.

Colorectal cancer is the second most frequent cancer in the Western world. A third of colorectal tumors are located in the right colon, and right hemicolectomy is the treatment in nondisseminated right colon cancer. The most serious complication of this procedure is anastomotic leak, which occurs in 8.4% of cases. At present, there is no standardized technique for laparoscopic ileo-colic anastomosis. In previous observational studies, intracorporeal side-to-side ileo-colic laparoscopic anastomosis has shown better results than extracorporeal anastomosis in terms of morbidity and mortality. It is known that randomized studies provide higher levels of evidence, but multicenter randomized controlled studies may imply a learning curve bias due to the differences in technical experience acquired at each hospital. As a result, we propose to carry out a prospective, controlled, nonrandomized TREND-study design (Transparent Reporting of Evaluations with Non-randomized Designs-TREND) in a large sample of 416 patients (208 per group) in order to assess the use of intracorporeal side-to-side ileo-colic laparoscopic anastomosis as the gold standard in right hemicolectomy.