PNAS: Butyrate enhances CPT1A activity and promotes fatty acid oxidation and iTreg differentiation

More and more evidences show that there is a link between iTreg differentiation and metabolic reprogramming, especially the reconnection in fatty acid oxidation (FAO)
.
In addition, ACSS2 inhibitors blocked the formation of BCoA, which affected the butyrate-mediated iTreg production and the alleviation of mouse colitis
.
Together, the authors revealed the previously unrecognized role of butyric acid in iTreg differentiation and clarified the regulation of the butyric acid-BCoA-CPT1A axis on immune homeostasis
.


Regulatory T cells (Treg) are CD4+ T cells that express Foxp3 and play a key role in immunosuppression
.
They can be divided into natural Treg (NTreg) cells and induced Treg (ITreg) cells
.
NTreg cells, usually called thymic Treg (TTreg), are produced during the differentiation of CD4+ T cells in the thymus under the influence of the relatively high affinity interaction of T cell receptors (TCR) with self-antigens
.
ITreg cells, also called peripherally induced Treg (PTreg), develop in secondary lymphoid tissues
.
In the presence of transforming growth factor β1, antigen-presenting cells (Apc) respond to non-self antigens (such as allergens, food, and symbiotic microbial flora), and induce the initial cd4+T into itreg through tcr linkage and costimulation Cell
.


Studies have shown that iTreg cells are abundant in intestinal-associated lymphoid tissues (GALT) and play an important role in maintaining the immune balance of the intestinal tract
.
Intestinal iTreg cells have been found to be important in the regulation of inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), which may affect any part of the gastrointestinal tract, with The passage of time can lead to many further complications, such as tissue fibrosis, stenosis, fistula and colon cancer
.
Enhancing the function of intestinal iTreg or adoptive transfer of iTreg can significantly reduce IBD in mice
.
Different types of T cells have different metabolic characteristics
.
Unlike the effector CD4+ T cells (including Th1, Th2, Th9 and Th17 cells) that mainly rely on aerobic glycolysis, iTreg cells mainly rely on fatty acid oxidation (FAO)
.
More and more evidence shows that T cell differentiation is always accompanied by metabolic reprogramming
.
For example, FAO needs to be established in the process of iTreg differentiation
.


FAO consists of a series of cyclic reactions that require different fatty acids (FA).
These fatty acids can be divided into long-chain fatty acids, medium-chain fatty acids, and short-chain fatty acids (LCFA, SCFA, and MCFA)
.
It mainly exists in mitochondria and produces Acetyl Coenzyme A (AcCoA), which can be consumed in the tricarboxylic acid (TCA) cycle
.
The oxidation of LCFA starts with the activation of LCFA in the cytoplasm to produce long-chain acyl-CoA
.
Subsequently, these molecules are converted into long-chain acylcarnitine by carnitine palmitoyltransferase 1 (CPT1) anchored on the outer membrane of the mitochondria
.
After shuttled into the mitochondria, the long-chain acylcarnitine undergoes a series of reactions to support FAO
.
Obviously, the transport of LCFA from the cytoplasm to the mitochondria is a prerequisite for FAO
.
Therefore, the rate-limiting enzyme CPT1, which controls this critical step, is considered to be the determinant of FAO
.
In contrast, SCFA and MCFA can diffuse across the mitochondrial membrane and drive FAO in a CPT1-independent manner
.
However, extensive research has shown that CPT1 plays an important role in iTreg differentiation
.


In the process of iTreg differentiation, butyric acid (BUT) can enhance CPT1-dependent fatty acid oxidation

In recent years, butyric acid is a special type of single-chain fatty acid, which is produced from fiber-rich feed through microbial fermentation.
It plays a key role in maintaining the homeostasis of the intestinal tract, so it is considered an effective ingredient in food
.
Butyrate helps to coordinate the delicate balance of the intestinal immune system by regulating different types of immune cells, including dendritic cells, macrophages, B cells and T cells
.
Rigorous studies have shown that butyric acid, as a histone deacetylase (Hdac) inhibitor, can promote iTreg differentiation by up-regulating the expression of foxp3
.
At the same time, as a metabolic fuel and energy source, butyric acid can also support FAO in colonic epithelial cells
.
However, it is unclear whether butyrate can regulate FAO to promote iTreg differentiation
.


In this study, the authors found that the increase in FAO helps to enhance the differentiation of iTreg cells in response to butyrate
.
Butyrate is processed by acyl-CoA synthase short-chain family member 2 (ACSS2) into butyryl-CoA (BCoA), which plays a key role in FAO's control by targeting CPT1A
.
The authors found that BCoA competes with malonyl-CoA (MCOA), the most famous metabolic intermediate that inhibits CPT1A, and releases FAO's CPT1A activity, thereby promoting the differentiation of iTregs
.
Inhibiting ACSS2 to block BCoA production will affect butyrate-mediated iTreg production and reduce mouse colitis
.
Overall, the authors describe a previously unrecognized mechanism, the butyrate-BCoA-CPT1A regulatory axis, for iTreg differentiation
.
(Bioon.
com) The authors found that the increase of FAO helps to enhance the differentiation of iTreg cells in response to butyrate
.
Butyrate is processed by acyl-CoA synthase short-chain family member 2 (ACSS2) into butyryl-CoA (BCoA), which plays a key role in FAO's control by targeting CPT1A

Reference

Fengqi Hao et al.
Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation.
PNAS.
2021 118 (22) e2014681118; https://doi.
org/10.
1073/pnas.
2014681118 Fengqi Hao et al.
Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation.
PNAS.
2021 118 (22) e2014681118; https://doi.
org/10.
1073/pnas.
2014681118