Harnessing Sleep and Biological Rhythms to Improve Postoperative Recovery

PROJECT SUMMARY/ABSTRACT Up to one-third of older U.S. adults may not return to functional baseline six months after major surgery, with postoperative pain being one of the most significant contributors. At the same time, over a third of the adult population also suffer chronic sleep problems, which are even more prevalent in the 3.5 million adults who will require total knee arthroplasty (TKA) by 2030. Despite evidence-based treatment, perioperative sleep optimization represents a missed opportunity for improvement. One challenge is that the underlying mechanisms of how sleep impacts postoperative recovery remain a significant knowledge gap. Recent evidence suggests poor sleep health may impact pain via the nervous system and gut microbiome. Major surgery is a significant stressor, and habitual sleep disruption results in changes to metabolism, neuroinflammation, or the nervous system that increase the pro-nociceptive response to this stress. The gut microbiota influences host homeostasis for these processes, and insomnia can disrupt the gut-brain axis. Sleep health metrics of low sleep efficiency and poor daytime alertness were linked to increased blood homocysteine and IL-6 levels and decreases in the short-chain fatty acids-producing microbiota. At the same time, gut microbiome composition is altered in chronic pain conditions. Thus, the gut microbiome may mediate the influence of sleep on pain and serve as a target for adjuvant therapy for both pain and insomnia. My research program has built a unique translational perioperative sleep infrastructure for prospective studies and randomized efficacy trials. We focused on developing feasible and scalable at-home methods to estimate multi-dimensional sleep and circadian phenotypes before surgery using wearable actigraphy watches and other portable home devices. We have also collected blood to verify the circadian phase (internal time) using transcriptomic assays utilizing the circadian nature of transcriptomes. We propose using these preoperative sleep/rhythm phenotype measures to optimize surgical recovery. This is my area of expertise; I am an anesthesiologist with formal training in sleep/circadian biology, computational neuroscience, behavioral and psychosocial clinical trials, and translational studies in post-surgical pain and cognition outcomes. This research plan will aim to understand the mechanisms of how preoperative sleep/circadian disturbances may impact recovery outcomes through systemic changes in the gut microbiome and related metabolic factors. To address this, we propose 1) a longitudinal study (pre- to 1-year post-surgery) with rich phenotyping to understand the sleep-gut-pain relationships in TKA patients and 2) a randomized mechanistic trial with a well-known non-pharmacological intervention (CBT-I) to test whether intentionally altering real-world sleep conditions improves microbiome features. This may help us better risk stratify surgical patients and gain mechanistic inferences to novel mechanisms that inform therapeutic targets.