Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune-mediated IBD.

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Median nerve stimulation (MNS) at 10-12 Hz was recently proposed as a potential treatment for tics in Tourette syndrome and other chronic tic disorders (TS/CTD). Here we report on 31 people ages 15-64 with TS/CTD who participated in a 4-week open label study of MNS, 27 of whom completed the final survey. They reported tic frequency and intensity each time they began or ended stimulation, and twice daily at random times between 09:00 and 21:00 when prompted by a text message. They also reported tolerability of stimulation when the device was on. Reported MNS use was 50 minutes per day used (median; interquartile range [IQR] =93 minutes) with the average participant using the device 1.5 days per week (median, IQR=1.4). Tic frequency improved during MNS (1.0 mean difference on a 0-5 scale, p <0.001), as did tic severity (0.9 mean difference, p <0.001). Mean discomfort during stimulation was 1.2, signifying mild discomfort. 78% of participants reported they planned to continue using the device after the study ended. Participants’ results in this study did not correlate significantly with their results in the preceding blinded, randomized, controlled trial. However, improvement in tic frequency on ratings performed during the study period did correlate with participants’ perception of overall therapeutic benefit at the conclusion of the study (R=−0.58, p=0.005). Symptom improvement did not clearly persist after a stimulation session ended. We did not detect significant differences between participants who reported overall therapeutic benefit during the study period and those who did not. One of the most common suggestions by participants was for a more unobtrusive form factor. We provide individual participant data.

Much of the research regarding Tourette’s syndrome (TS) has focused on why certain individuals develop tics while others do not. However, a separate line of research focuses on the momentary influences that cause tics to increase or decrease in patients who are already known to have TS or another chronic tic disorder (CTD). Environmental and internal variables such as fatigue, anxiety, and certain types of thoughts all have been shown to worsen tic severity and may even overcome the positive effects of treatment. Other influences such as stress, distraction, and being observed have had mixed effects in the various studies that have examined them. Still, other variables such as social media exposure and dietary habits have received only minimal research attention and would benefit from additional study. Understanding the impact of these environmental and internal influences provides an opportunity to improve behavioral treatments for TS/CTD and to improve the lives of those living with these conditions. This review will examine the current literature on how these moment-to-moment influences impact tic expression in those with TS/CTD.