Objective: The aim of the study was to assess feasibility and outcomes of a multicenter training program in laparoscopic pancreatoduodenectomy (LPD). Background: Whereas expert centers have reported promising outcomes of LPD, nationwide analyses have raised concerns on its safety, especially during the learning curve. Multicenter, structured LPD training programs reporting outcomes including the first procedures are lacking. No LPD had been performed in the Netherlands before this study. Methods: During 2014–2016, 8 surgeons from 4 high-volume centers completed the Longitudinal Assessment and Realization of Laparoscopic Pancreatic Surgery (LAELAPS-2) training program in LPD, including detailed technique description, video training, and proctoring. In all centers, LPD was performed by 2 surgeons with extensive experience in pancreatic and laparoscopic surgery. Outcomes of all LPDs were prospectively collected. Results: In total, 114 patients underwent LPD. Median pancreatic duct diameter was 3 mm [interquartile range (IQR = 2–4)] and pancreatic texture was soft in 74% of patients. The conversion rate was 11% (n = 12), median blood loss 350 mL (IQR = 200–700), and operative time 375 minutes (IQR = 320–431). Grade B/C postoperative pancreatic fistula occurred in 34% of patients, requiring catheter drainage in 22% and re-operation in 2%. A Clavien-Dindo grade ≥ III complication occurred in 43% of patients. Median length of hospital stay was 15 days (IQR = 9–25). Overall, 30-day and 90-day mortality were both 3.5%. Outcomes were similar for the first and second part of procedures. Conclusions: This LPD training program was feasible and ensured acceptable outcomes during the learning curve in all centers. Future studies should determine whether such a training program is applicable in other settings and assess the added value of LPD.

Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.

Clinical trials suggest that vagus nerve stimulation presents an alternative approach to classical immune suppression in Crohn's disease. T cells capable of producing acetylcholine (ChAT(+) T cells) in the spleen are essential mediators of the anti-inflammatory effect of vagus nerve stimulation. Besides the spleen, ChAT(+) T cells are found abundantly in Peyer's patches of the small intestine. However, the role of ChAT(+) T cells in colitis pathogenesis is unknown. Here, we made use of CD4(cre)ChAT(fl/fl) mice (CD(4)ChAT(-/-) mice) lacking ChAT expression specifically in CD4(+) T cells. Littermates (ChAT(fl/fl )mice) served as controls. In acute dextran sulfate sodium (DSS)-induced colitis (7 days of 2% DSS in drinking water), CD4ChAT(-/-) mice showed attenuated colitis and lower intestinal inflammatory cytokine levels compared with ChAT(fl/fl )mice. In contrast, in a resolution model of DSS-induced colitis (5 days of 2% DSS followed by 7 days without DSS), CD4ChAT(-/-) mice demonstrated a worsened colitis recovery and augmented colonic histological inflammation scores and inflammatory cytokine levels as compared with ChAT(fl/fl) mice. In a transfer colitis model using CD4(+)CD45RB(high) T cells, T cells from CD4ChAT(-/-) mice induced a similar level of colitis compared with ChAT(fl/fl) T cells. Together, our results indicate that ChAT(+) T cells aggravate the acute innate immune response upon mucosal barrier disruption in an acute DSS-induced colitis model, whereas they are supporting the later resolution process of this innate immune-driven colitis. Surprisingly, ChAT expression in T cells seems redundant in the context of T cell-driven colitis. NEW & NOTEWORTHY By using different mouse models of experimental colitis, we provide evidence that in dextran sulfate sodium-induced colitis, ChAT(+) T cells capable of producing acetylcholine worsen the acute immune response, whereas they support the later healing phase of this innate immune-driven colitis.

Background: Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis. Methods: Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of β-adrenergic receptors (β-ARs). Results: Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of β-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes. Conclusions: Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.