Neurons in the gut help explain why chronic stress can cause IBD flare-ups

Authors: Kai Markus Schneider, Niklas Blank, Yelina Alvarez, …, Robert O. Heuckeroth, Maayan Levy, Christoph A. Thaiss

Full Article: The enteric nervous system relays psychological stress to intestinal inflammation: Cell

Media Release: Neurons in the gut help explain why chronic stress can cause IBD flare-ups | Journal Club | PNAS



Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.


Psychological stress exerts a profound impact on inflammatory processes throughout the body,1,2,3 suggesting that improving a patient’s mental state might be a powerful yet underutilized strategy for the management of numerous diseases. The effect of psychological stress on disease severity is particularly striking in inflammatory bowel disease (IBD),4 with numerous epidemiological studies supporting the hypothesis that stressful life events can exacerbate IBD flares.5,6,7,8 However, the mechanistic basis for aggravated, stress-associated IBD flares is not fully understood.

In this study, we uncover several mechanisms by which psychological stress influences bowel inflammation via the enteric nervous system (ENS). Unlike the central nervous system (CNS), where responses to psychological stress have been deeply characterized,9 ENS responses to stress and their consequences are less well understood. We provide insights into how the ENS may serve as a relay between brain-derived stress signals and the priming of inflammatory responses in the intestine. Our findings highlight enteric neurons and glia as possible therapeutic targets to ameliorate inflammatory sequelae of mental health impairment.


Chronic psychological stress is strongly associated with the severity of IBD flares,6,8,35 but the underlying mechanisms remain largely unclear. In this study, we identify a cascade of cellular and molecular events that link stress perception to exacerbation of enteric inflammation, elements of which may apply to other inflammatory diseases of the gut, as well as extraintestinal disorders associated with psychological stress.

Our findings have several important implications. First, we provide important insights into the biology of enteric glial cells. Our results demonstrate that the molecular state of enteric glia and their impact on the intestinal microenvironment are influenced by CNS-derived signals. As such, enteric glia may perform previously unrecognized functions in CNS-ENS communication. Of note, the molecular profile of stress-associated astrocytes shares several features with eGAPS, including high expression levels of Nur family transcription factors,36,37 suggesting that this stress-associated glial expression profile may emerge via common signaling mechanisms in different tissues.

Second, our study addresses a conundrum that arises from the fact that stress worsens inflammatory disease, whereas the canonical systemic mediators of psychological stress, catecholamines and glucocorticoids, are generally considered anti-inflammatory.16 The induction of inflammatory enteric glia and exacerbated colitis by glucocorticoid signaling was particularly perplexing, given that the glucocorticoid receptor agonist prednisone is used to treat colitis in IBD patients. There are several possible explanations for this paradox. For instance, prolonged stress or dexamethasone treatment may induce inadequate adrenal production of corticosterone due to negative-feedback-mediated suppression of the hypothalamic-pituitary-adrenal axis.38,39 However, the beneficial effects of acute GR inhibition (Figures 2B–2D) are not consistent with “adrenal suppression.” Alternatively, the balance between anti- and pro-inflammatory effects of glucocorticoids might be a temporal phenomenon.40,41,42 Although acute glucocorticoid treatment ameliorates DSS-induced colitis,43 we find that persistently elevated levels of corticosterone contribute to the appearance of eGAPS and accumulation of TNF-producing monocytes. Similarly, clinical observations have documented that only short-term steroid treatment leads to beneficial outcomes in IBD.44,45

Third, our study emphasizes the importance of considering a patient’s mental health in the clinical management of inflammatory diseases. Given that we found opposing roles of two common IBD treatment regimens (corticosteroids and monoclonal antibodies against TNF) on the severity of stress-mediated colitis in mice, it is possible that treatment effects vary depending on the psychological state of affected individuals. The evaluation of mental state, in conjunction with strategies to reduce stress, anxiety, and depression, could thus be a powerful and underutilized tool to enhance treatment success.46

Limitations of the study

Our model implies that glia are the critical source of CSF1 and neurons the critical source of TGF-β2 in stress-exacerbated colitis. Although several lines of evidence support this model, the generation of new conditional knockout mice for cell-type-specific ablation of these cytokines will be required for unequivocal evidence. Additionally, our findings do not clarify the temporal sequence of events underlying TGF-β2-mediated neuronal alterations in response to stress. Is TGF-β2 induced by GR signaling and subsequently reprograms neurons to express precursor genes rather than differentiation genes? Alternatively, does GR signaling induce an immature state in neurons that is then propagated by TGF-β2? Similar questions regarding the induction of the eGAPS phenotype remain to be clarified.

Our model suggests that the downstream effect of glial and neuronal perturbation by psychological stress are largely distinct, with glia affecting TNF-driven inflammation and neuronal changes driving dysmotility. However, inhibition of TGF-β signaling also provides a certain degree of protection from severe inflammation, albeit only partially. This either suggests that our dichotomous model is oversimplified, or that the rescue of motility itself helps to ameliorate bowel inflammation.

Finally, our study does not address the evolutionary purpose of exacerbated inflammatory responses to chronic stress. Systemic stress responses likely serve the function of resource allocation during times of high energy demand. Notably, the relative benefits of a heightened inflammatory and alert state versus an immunosuppressed state that allows for reallocation of energy within the organism may depend on the source and nature of the stressful trigger.47 We speculate that glucocorticoids thus serve a dual function, with acute immunosuppression purposed to centralize resources for survival of essential organs, followed by inflammatory states in the periphery in case the trigger persists. Understanding the impact of stress on intestinal inflammation in more detail may ultimately facilitate harnessing the power of brain-derived signals in the treatment of IBD.48