A recent study by Cell The journal reports on the mechanisms by which psychological stress affects intestinal inflammation.
Research: The enteric nervous system transmits psychological stress to intestinal inflammation. Image credit: sdecoret/Shutterstock.com
Psychological stress has a significant impact on risk responses. The effect of psychological stress on the severity of the disease is particularly prominent in inflammatory bowel disease (IBD).
Various epidemiological studies support that stressful events exacerbate IBD flares. Still, the mechanistic basis of stress-related exacerbations of IBD is poorly understood.
The study and its findings
In this study, researchers investigated the main mechanisms of the effect of psychological stress on internal inflammation.
First, they induced colitis in a mouse model of chronic stress (restraint stress) and observed an exacerbation of intestinal inflammation. Dramatic gene expression changes uncovered by RNA sequencing.
Genes associated with type 2 immunity and antimicrobial peptides were up-regulated, while genes associated with IBD and pro-inflammatory cytokines were up-regulated.
In particular, the stress experienced before the onset of colitis had a significant impact on the exacerbation of inflammation. This suggests that when stress interacts with a collitogenic trigger, the gut is primed for a more inflammatory response.
Single cell RNA with more than 23,000 clusters is differentially expressed 45-positive (CD45).+) identified 13 specific immune cells in leukocytes from colonized control and stressed mice.
In stressed rats, T cells, innately lymphoid cells and monocytes or macrophages had significantly different genes. The team also found that neither endogenous nor adaptive lymphocytes drove the intestinal inflammatory response to stress.
Therefore, the researchers focused on myeloid cells, especially macrophages and monocytes. Subclustering of the data revealed three monocytes (Mono 1–3) and two macrophages (Mac 1–2) subsets.
Pseudo-time trend analysis reveals monocyte accumulation in stressed rats. Depletion of CC motif chemokine receptor 2-positive (CCR2.) mice+) monocytes protected against stress-mediated exacerbation of colitis.
In addition, tumor necrosis factor (TNF)-producing monocytes were significantly increased in stressed rats. Neutralization of mice with monoclonal antibodies (MAB) protected against stress-mediated effects.
Next, the researchers followed the transmission of psychological stress from the brain to the gut. Restraint stress significantly increased serum levels of corticosterone and noradrenaline in rats.
The team inhibited the brain-mediated release of adrenal corticosterone, which reduced corticosterone levels and made the mice resistant to the restraint stress of colitis.
Similarly, adrenalectomy or inhibition of glucocorticoid receptor (GR) signaling prevents exacerbation of stress-induced colitis.
The researchers hypothesized that GR signaling in myeloid cells is responsible for stress-mediated effects on IBD. However, mice lacking the GR gene, nuclear receptor subfamily 3 group C member 1 (Nr3c1), in myeloid cells are susceptible to stress effects similar to their littermates, suggesting an indirect effect of glucocorticoids on monocytes.
Next, the team investigated the effects of chronic psychological stress on ENS cells. sorry, Nr3c1 It is deleted from intestinal neurons and glia. This protected the mice from stress-mediated colitis and prevented monocyte accumulation.
Together, these findings suggest that the ENS may be a mediator between glucocorticoids and the intestinal inflammatory response.
Next, single-nuclear RNA sequencing of enteric neurons and glia was performed, and uniform manifold approximation and projection (UMAP) clusters were identified.
Subcluster analysis revealed four distinct transcriptional states. One state, called enteric glia, which is associated with psychological stress (eGAPS) was only for stressful situations.
Mice depleted of enteric glia are resistant to stress-induced colitis. Moreover, glia depletion prevented monocyte accumulation in the colon. Next, the team created and analyzed a pairwise interaction map based on single nuclei and single-cell transcriptomes, which revealed several hypothesized interactions between colonial myeloid cells and eGAPS.
The group is highly focused on the interactions between the Mono1 cluster and eGAPS. Tnf expression in these monocytes. Colony Stimulation Factor 1 (Csf1) was one of the mediators of this interaction.
Moreover, in the year Csf1 Expression is elevated in the intrinsic glia upon stress. High colony Csf1 Expression depends on the ENS GR signal because Nr3c1 Cancellation is numb. Csf1 Inspiration on stress.
Neutralization of CSF1 protein with mAb conferred resistance to stress effects on colitis. Next, the researchers studied the neuron section of the single-nuclei ENS data set.
Nitrergic and cholinergic subunits of mature neurons were underrepresented in the depressed group, whereas precursors were enriched. This suggests that stress increases progenitor neurons and decreases mature neurons.
Further experiments showed that stress induced a shift to a slightly different phenotype and decreased cholinergic and nitrergic neurons, leading to dysmotility.
Expression profiles of immature and mature enteric neurons were compared. Transformative Development Mode Beta 2 (Tgfb2) gene is significantly associated with the predisposing factor.
Using TGF-β-neutralizing antibodies prevents the transition and restores intestinal motility in depressed mice. Finally, the researchers examined the relationship between psychological stress, intestinal inflammation and dementia in human IBD patients.
Patients with high levels of chronic psychological stress have a higher risk of developing IBD than those without stress.
Psychological stress has been associated with more severe post-diagnosis IBD. Leukocytes, including monocytes, are increased in congested patients. Patients with stress have discomfort with bowel habits and bloating, the development of ileus and require surgery. The team investigated whether these changes were general or specific to IBD patients.
They studied people in the United Kingdom (UK) Biobank who were disease-free or had irritable bowel syndrome or extra-intestinal disease (rheumatoid arthritis).
They identified that dysmotility was associated with stress in all populations, but elevated inflammatory markers and monocyte concentrations were only observed in the context of intestinal disease.
The authors identified cellular and molecular events that link stress perception to the exacerbation of intestinal inflammation.
Overall, the study provided a mechanistic basis for the effects of psychological inflammation and identified the ENS as a mediator between psychological stress and intestinal inflammation, suggesting that stress management is beneficial in IBD care.