Immunity Jin Jin/Cao Qian collaborate to analyze the mechanism of selenium deficiency in Crohn’s disease that leads to T cell differentiation disorder

Editor | Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease that mainly affects the gastrointestinal tract.
It mainly includes two clinical subtypes, namely Crohn's disease (CD) And ulcerative colitis (Ulcerative colitis, UC)
.

IBD is a common digestive system disease in Western countries.
In recent years, the incidence in developing countries has shown a rapid increase trend.
It is estimated that the number of IBD patients in China will reach more than 1.
5 million by 2025 [1]
.

IBD is a chronic lifelong disease.
It is prone to adolescents and requires long-term treatment.
It has a variety of unfavorable prognosis, which greatly increases the social and economic burden
.

IBD is a complex disease involving multiple genes and multiple factors.
Its pathogenesis is not yet fully understood.
Immunity response disorders are considered to be the central link in the pathogenesis of IBD.
90% of current therapeutic targets target abnormal immune responses.
【2】
.

Past studies have mostly used samples from patients treated with different drugs.
There is still a lack of systematic research on the characteristic function or expression profile of intestinal immune cells in patients with CD or UC who are not treated in the early stage of the disease, such as these two types of bowel diseases.
What are the differences in immune cell subpopulations, whether there are new pathological-specific subpopulations, and what are their specific induction mechanisms? These issues have not been fully studied
.

The functional imbalance of T cells is one of the important pathogenic factors of IBD [3]
.

Previous studies have shown that there are differences in T cell response patterns between CD and UC patients [4, 5], which may involve different biological mechanisms, and our understanding of this is still very limited
.

The increase in the incidence of IBD in newly industrialized countries may be related to the process of urbanization and changes in diet [6], which suggests that local metabolic changes in our intestines may be related to the onset of IBD
.

Studies have shown that metabolites such as short-chain fatty acids, tryptophan and bile acids are involved in mucosal immune homeostasis and the pathogenesis of IBD [7]
.

The differentiation and function of T cells are regulated by many factors, including cytokines, chemokines, and microorganisms in the intestinal tract
.

The latest research shows that metabolites and reactive oxygen species (ROS) produced in the metabolic process also play an important role in the activation, proliferation and differentiation of T cells
.

Selenium is a trace element necessary for the human body.
A variety of selenoproteins such as Glutathione peroxidase (GPXs) and Thioredoxin reductase (TrxRs) are involved in ROS removal and redox Metabolic process
.

Some studies have reported that the level of selenium in IBD patients is lower than that of healthy people, and selenium deficiency in animal enteritis models can aggravate intestinal inflammation [8,9]
.

However, how selenoprotein regulates T cell function in the inflammatory state of IBD remains to be explored
.

On August 2, 2021, Jin Jin's research group from Zhejiang University's Life Sciences Research Institute and Cao Qian's research group from Run Run Run Run Shaw Hospital, Zhejiang University School of Medicine jointly published a titled Multiomic analyses reveal a critical role of selenium in controlling T cell differentiation in Immunity Crohn's disease article
.

The collaborative team first used single-cell transcriptome sequencing and metabolome analysis to analyze the colonic immune cell profile and metabolic microenvironment characteristics of newly diagnosed untreated IBD patients, and found that there are disease-specific immune cell subgroups and metabolite changes in CD or UC
.

Through in vitro experiments to screen the function of metabolites, we found metabolites that can regulate the differentiation of T cell subsets in specific diseases, especially the specific reduction of selenium-containing metabolites in the colon of patients with CD that can regulate a unique group of Th1- Like cell differentiation
.

In vivo and in vitro studies have confirmed that selenium supplementation can effectively inhibit the differentiation of Th1 and promote the alleviation of intestinal inflammation
.

Selenium mainly regulates one-carbon metabolism and purine salvage pathway through selenoprotein W (SELW) to mediate the removal of reactive oxygen species (ROS), thereby affecting the differentiation of Th1 cells
.

Fig.
1 Working model First, in order to analyze and compare the difference in the intestinal immune response pattern between CD and UC patients when they were first diagnosed and untreated, the author collected healthy people (n=3), CD (n=6), UC (n=6) patients The colon biopsy tissue was digested and sorted CD45-positive immune cells for single-cell transcriptome sequencing.
After data analysis, a total of 36 immune cell subgroups were obtained
.

The authors found that there is a unique group of Th1 (Th1-like) cells in the colon of CD patients, while there is a group of Th17-like cells (Th17-like) in UC patients
.

Cytokines derived from innate immune cells can regulate the differentiation of T cells.
In order to clarify the mechanisms that produce these two unique cell subpopulations in the two types of diseases, the author first compared the response patterns of innate immune cells in the two types of diseases, while regulating Th1 There is no significant difference in the expression of differentiated or Th17 differentiated cytokines in the innate immune cells of these two types of diseases
.

Interestingly, the authors found that these two T cell subgroups have differences in the expression of multiple metabolic enzymes, suggesting that the different metabolic modes of the two metabolic microenvironments may play an important role in shaping the T cell immune response of the two types of diseases
.

Therefore, the research team further performed non-targeted metabolome tests on the colon tissues of healthy volunteers, active CD and UC patients, and identified 92 and 275 metabolites with specific changes in CD and UC, respectively
.

In order to further clarify whether these metabolites regulate the differentiation of T cells, the authors conducted in vitro functional screening experiments and identified some metabolites that can regulate the differentiation of T cell subsets in specific disease subtypes
.

It is worth noting that a selenium-containing metabolite is specifically down-regulated in the colon tissue of CD patients, and the serum selenium level of CD patients is also negatively correlated with disease activity
.

In vitro differentiation experiments show that supplementation with selenium can significantly inhibit the differentiation of Th1 without affecting the polarization of Th17
.

In order to clarify the mechanism by which selenium regulates T cell differentiation, the author further analyzed the selenium-treated Th1 cells and control Th1 cells through transcriptome, metabolome, metabolic flow, flow cytometry and other technologies, and found the key transcription factors that regulate Th1 differentiation.
Not significantly affected, but after selenium treatment, the key enzymes and metabolic intermediates in the purine synthesis salvage pathway in Th1 cells were significantly increased, and the key enzymes and metabolites in the one-carbon metabolism folate cycle were significantly down-regulated
.

The activation of T cells requires the synthesis of a large amount of purines for nucleic acid synthesis, cell signal transduction and metabolic regulation [10].
Purines are mainly produced through two pathways: de novo synthesis and salvage pathways
.

The study showed that during the differentiation of Th1, selenium treatment can inhibit one-carbon metabolism, leading to a decrease in purine de novo synthesis and a compensatory up-regulation of the salvage pathway
.

The activation and differentiation of T cells are accompanied by the production of ROS, and the level of ROS in the cell is strictly regulated by antioxidant enzymes and other molecules
.

In-depth mechanism studies have shown that in Th1 cells, selenium mainly regulates one-carbon metabolism through selenoprotein W (SELW) and the purine salvage pathway mediates the removal of reactive oxygen species (ROS) in the cytoplasm, thereby affecting NF -Activation of κB signaling pathway inhibits the production of IFN-γ
.

In selenium-deficient mice, a T cell adoptive transfer enteritis model was established.
After supplementation with selenium preparations, the symptoms of enteritis can be significantly reduced, and the Th1 cells in the lamina propria of the colon are reduced
.

Clinical studies have also shown that selenium supplementation can promote the improvement of symptoms of selenium-deficient Crohn’s disease patients and the healing of colonic mucosa
.

This research system analyzed the composition and metabolic changes of the intestinal immune cells of newly diagnosed CD and UC, and clarified the mechanism of the unique metabolic changes in the CD colon to shape the local mucosal immune response pattern
.

Selenium supplementation is expected to promote the alleviation of CD intestinal inflammation by inhibiting Th1 cell differentiation
.

This work provides a new idea for the in-depth study of the immune-metabolic mechanism of IBD, and has important scientific significance and clinical value for the comprehensive understanding of the pathogenesis of CD and UC, and the development of treatment strategies targeting specific diseases
.

The double-appointed professor of the Department of Gastroenterology of the Run Run Run Run Run Shaw Hospital, Zhejiang University School of Medicine, Professor Jin Jin, a senior researcher at the Institute of Life Sciences, Zhejiang University, and the Director of the Department of Gastroenterology, Run Run Run Run Affiliated Hospital of Zhejiang University School of Medicine, and Professor Qian Cao of the Center for Inflammatory Bowel Disease, are co-authors of this article.
Corresponding authors, PhD students Huang Lingjie, Mao Xintao and Southeast University associate researcher Li Yiyuan are the co-first authors of this article
.

Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
07.
004 Platemaker: 11 References 1.
Kaplan, GG (2015).
The global burden of IBD: From 2015 to 2025.
Nat.
Rev.
Gastroenterol.
Hepatol.
12, 720–727.
2.
Bilsborough, J.
, Targan, SR, and Snapper, SB (2016).
Therapeutic Targets in Inflammatory Bowel Disease: Current and Future.
Am.
J.
Gastroenterol.
Suppl.
3 , 27–37.
3.
Xavier, RJ, and Podolsky, DK (2007).
Unravelling the pathogenesis of inflammatory bowel disease.
Nature 448, 427–434.
4.
Strober, W.
, and Fuss, IJ (2011).
Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases.
Gastroenterology.
5.
Rosen, MJ, Karns, R.
, Vallance, JE, Bezold, R.
, Waddell, A.
, Collins, MH, Haberman, Y.
, Minar, P.
, Baldassano, RN, Hyams, JS, et al.
(2017).
Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients.
Gastroenterology 152, 1345-1357.
e7.
6.
Zuo, T.
, Kamm, MA, Colombel, JF, and Ng, SC (2018).
Urbanization and the gut microbiota in health and inflammatory bowel disease.
Nat.
Rev.
Gastroenterol.
Hepatol.
15, 440–452.
7.
Franzosa, EA, Sirota-Madi, A.
, Avila- Pacheco, J.
, Fornelos, N.
, Haiser, HJ, Reinker, S.
, Vatanen, T.
, Hall, AB, Mallick, H.
, McIver, LJ, et al.
(2019).
Gut microbiome structure and metabolic activity in inflammatory bowel disease.
Nat.
Microbiol.
4, 293–305.
8.
Barrett, CW, Reddy, VK, Short, SP, Motley, AK, Lintel, MK, Bradley, AM, Freeman, T.
, Vallance, J.
, Ning, W.
, Parang, B.
, et al.
(2015).
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
J.
Clin.
Invest.
125, 2646–2660.
9.
Hinks, LJ, Inwards, KD, Lloyd, B.
, and Clayton, B.
(1988).
Reduced Concentrations of selenium in mild Crohn's disease.
J.
Clin.
Pathol.
41, 198–201.
10.
LINDEN, J.
, KOCH-NOLTE, F.
& DAHL, G.
2019.
Purine Release, Metabolism, and Signaling in the Inflammatory Response.
Annual Review of Immunology, 37, 325-347.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
and Signaling in the Inflammatory Response.
Annual Review of Immunology, 37, 325-347.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights.
Must investigateand Signaling in the Inflammatory Response.
Annual Review of Immunology, 37, 325-347.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights.
Must investigate
.