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Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes
Ist Teil von
Cellular and molecular life sciences : CMLS, 2024-12, Vol.81 (1), p.77-77, Article 77
Ort / Verlag
Cham: Springer International Publishing
Erscheinungsjahr
2024
Link zum Volltext
Quelle
SpringerLink
Beschreibungen/Notizen
Background
Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic inflammation leading to the development of metabolic diseases. The inflammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the inflammasomes in the regulation of gut barrier dysfunction and metabolic inflammation in the context of obesity and type 2 diabetes (T2D).
Methods
Blood samples obtained from 80 volunteers (
n
= 20 normal weight,
n
= 21 OB without T2D,
n
= 39 OB with T2D) and a subgroup of jejunum samples were used in a case–control study. Circulating levels of intestinal damage markers and expression levels of inflammasomes as well as their main effectors (IL-1β and IL-18) and key inflammation-related genes were analyzed. The impact of inflammation-related factors, different metabolites and
Akkermansia muciniphila
in the regulation of inflammasomes and intestinal integrity genes was evaluated. The effect of blocking
NLRP6
by using siRNA in inflammation was also studied.
Results
Increased circulating levels (
P
< 0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (
P
< 0.05) after weight loss. Patients with obesity and T2D exhibited decreased (
P
< 0.05) jejunum gene expression levels of
NLRP6
and its main effector
IL18
together with increased (
P
< 0.05) mRNA levels of inflammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (
P
< 0.05) mRNA levels of
Nlrp1
,
Nlrp3
and
Nlrp6
in the small intestinal tract obtained from rats with diet-induced obesity were found.
NLRP6
expression was regulated by taurine, parthenolide and
A. muciniphila
in the human enterocyte cell line CCL-241. Finally, a significant decrease (
P
< 0.01) in the expression and release of
MUC2
after the knockdown of
NLRP6
was observed.
Conclusions
The increased levels of intestinal damage markers together with the downregulation of
NLRP6
and
IL18
in the jejunum in obesity-associated T2D suggest a defective inflammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.