Microbiome Army Medical University Fan Xiaotang / Soochow University Xu Xingshun et al. have discovered possible mechanisms of anxiety-like behavior induced by inflammatory bowel disease

iNature

Although the deficiency of estrogen receptor β (ERβ) is a risk factor for the development of inflammatory bowel disease (IBD) and psychiatric disorders, its underlying cellular and molecular mechanisms are not fully understood
.

On September 29, 2022, Fan Xiaotang of the Army Medical University, Xu Xingshun of Soochow University, and Jan-Ake Gustafsson of the Karolinska Institute in Sweden jointly published a joint newsletter in Microbiome (IF=17) titled "Estrogen receptor β deficiency impairs gut microbiota: a possible mechanism of IBD-induced anxiety-like behavior" research paper that sheds light on the role
of intestinal flora in IBD development and associated anxiety-like behaviors in ERβ-deficient mice.
In response to dextran sodium sulfate (DSS), ERβ-knockout mice exhibit significant changes in the diversity of α and β in fecal flora composition and exacerbate
colitis and anxiety-like behavior.
In addition, DSS-induced colitis also induces hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ERβ-deficient mice, which is associated
with colitis and anxiety-like behavior.
RNA sequencing data suggest that ErbB4 may be a target for ERβ involved in regulating HPA axis overactivity caused by DSS damage
.
Intestinal microbiota remodeling in common-room wild-type mice worsened colitis and anxiety-like behavior compared with single-room wild-type mice
.
These findings suggest that the gut microbiota plays a key role
in mediating colitis disease activity and anxiety-like behavior through abnormal neural processing within the gut-brain axis.
The potential for ERβ to inhibit the development of colitis and anxiety-like behavior by reshaping the intestinal flora suggests that ERβ is a promising therapeutic target for the treatment of IBD and associated anxiety-like
behaviors.
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a group of chronically disabling diseases
that cause symptoms in the gastrointestinal tract.
Psychiatric complications, such as anxiety and depression, are common in patients with IBD, with up to one-third of patients affected by anxiety and a quarter affected by depression, posing a major challenge
to optimal physical and mental health for patients.
IBD and related psychiatric complications are considered diseases of the intestinal-brain axis, and through the nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and the immune response, the intestine can regulate brain function
through the nervous system.
In addition to the effects of disease activity on anxiety and depression severity in patients with IBD, gender differences also affect the prevalence of psychiatric symptoms
.
Women with IBD are more likely than men to experience anxiety, depression and decreased quality of
life.
However, the interaction between the gut-brain axis, psychiatric complications, and sex differences in IBD is unclear
.
ERβ-^/-Mouse DSS-induced imbalance of the hypothalamic-pituitary-adrenal axis in colitis (Figure derived from Microbiome) The intestinal flora can directly regulate the intestinal-brain axis
.
Abnormal intestinal flora is called intestinal dysregulation and affects host physiology
by regulating homeostasis within the intestinal barrier and intestinal inflammation.
Intestinal microbiota disorder is one of the main causative factors in the development of
IBD.
There is growing evidence that intestinal microbiota disorders occur frequently in patients with IBD
.
Notably, gut microbiota disorders are associated with a wide range of mental health conditions, such as anxiety and depression
, through the microbiome-gut-brain axis.
After receiving fecal flora from patients with irritable bowel syndrome, mice exhibited faster bowel movements, intestinal barrier dysfunction, colon inflammation, and anxiety-like behavior
.
Kilinçarslan et al.
showed that transplanting fecal flora from healthy age-matched donors into the intestines of IBD patients reduced the severity of anxiety, depression and obsessive-compulsive disorder, as well as gastrointestinal symptoms
.
It was further found that manipulation of the microbiota, such as the use of prebiotics or probiotics, could improve intestinal abnormalities and neurobehavioral deficits in
animals and humans.
Therefore, intestinal microbiota disorders are closely related to intestinal dysfunction and related
mood disorders in gastrointestinal diseases.
The composition of the intestinal flora remains relatively constant throughout adult life and may change
in subsequent cases that affect the health of the host.
Interestingly, different levels of sex hormones, including testosterone and estradiol, are associated with the diversity and composition of the human gut flora, suggesting an association
between sex hormones and the gut microbiome.
The estrogen receptor (ER) β is an important ligand-activated nuclear transcription factor involved in estrogen signaling and is the primary ER subtype in colon tissue that plays an important role
in colonic mucosal homeostasis by maintaining the integrity of tight connections and barrier function.
Intestinal epithelial cell-specific deletion of ERβ alters the composition of the intestinal flora in
mice.
This is further confirmed by the significant decrease in the expression of ERβ in active ulcerative colitis and Crohn's disease, suggesting that ERβ plays an important role
in the development of IBD.
In addition, there is growing evidence that ERβ has anxiolytic effects on rodents
.
In addition, selective ERβ agonists may reduce anxiety-like behavior
in mice.
It appears that ERβ is important for maintaining homeostasis
and mental health.
However, the mechanisms by which ERβ is involved in microbiome-mediated IBD development and behavioral change remain to be determined
.
In this study, the authors found that ERβ knockout (ERβ^−/−) mice exhibited anxiety-like behavior
in dextran sodium sulfate (DSS)-induced acute colitis.
At the same time, the deficiency of ERβ in mice caused changes in the composition of the intestinal flora, increasing the susceptibility
to colitis.
The HPA axis is hyperactive (not neuroinflammatory), and IBD-associated anxiety-like disorders
are involved after mice lose ERβ.
Co-feeding of wild-type (WT) mice with ERβ^−/− mice further suggests that intestinal microbiota disorders are associated with anxiety-like behaviors associated
with IBD.
The authors' findings emphasize that the gut microbiota plays a role
in triggering events in IBD and associated anxiety-like behaviors in ERβ-deficient mice.

Original link: https://microbiomejournal.
biomedcentral.
com/articles/10.
1186/s40168-022-01356-2

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