Everyone already knows that a high-sugar and high-fat diet is closely related to metabolic diseases such as obesity and diabetes, but they did not expect that intestinal flora and immune cells will also participate in the love, hate and affection! The sugar in the diet will destr

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Milk tea, fried chicken, cola... More and more delicious foods occupy our recipes. But it can be said that eating is a good time, and it is a weight loss crematorium. Everyone already knows that high sugar and high fat diet is closely related to metabolic diseases such as obesity, diabetes , etc., but they did not expect that intestinal bacterial flora and immune cells will also participate in the love, hate, and hilarious !

Recently, the Ivaylo I. Ivanov team from Columbia University published important research results in the journal Cell. They found that Th17 cells can inhibit the absorption of seborrheic lipids in the intestinal region, thereby preventing the occurrence of metabolic diseases; and the sugar in the diet will destroy the balance of intestinal microbial flora in mice, resulting in a decrease in Th17 cells and increasing the risk of metabolic disease [1].

This discovery reveals the wonderful interaction between diet and immune cells, and provides new ideas for the prevention of metabolic diseases.

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As the interface between the host and the food antigen , in recent years, there has been increasing evidence that the intestinal immune system is an important regulator of maintaining metabolic homeostasis. High-fat diet is related to the increase in intestinal inflammation, but how does the diet affect intestinal immune cells, and can immune cells affect obesity and metabolic syndrome ? These issues need to be further studied.

To answer these questions, the researchers tested changes in intestinal immune homeostasis in mice for 4 weeks of high-fat diet feeding and before inflammatory changes in adipose tissue. Consistent with expectations, mice fed with high-fat diets developed characteristics of metabolic syndrome, including weight gain, insulin resistance, and glucose tolerance compared to normal diets. Analysis of intestinal immune cells by

found that in the small intestine lamina propria, the high-fat diet of resulted in a significant reduction in the proportion and total number of Th17 cells, and the RORγt expression level of Th17 cells decreased . RORγt is the key transcription factor for Th17 cells differentiation [2], and the decrease in RORγt level means the loss of Th17 cells' function. At the same time, the expression of IL-17 was also significantly reduced. However, a high-fat diet did not significantly affect other cells expressing RORγt or IL-17 (e.g., the overall level of RORγt⁺γδ T cells or ILC3 cells).

High-fat diet leads to a decrease in the proportion and function of Th17 cells

As early as 2009, Ivaylo I. Ivanov et al. discovered that in the intestinal tract of mice, Th17 cells can induce the production of by intestinal flora, especially the segmented filamentous bacteria (SFB). [3]. Therefore, the Ivaylo I. Ivanov team speculates whether a high-fat diet will affect SFB levels and thus Th17 cells?

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High-fat diet can lead to a decrease in Th17 cells and SFB. Further analysis found that after the knockout mouse model removed Th17 cells in the intestinal tract, the obesity and metabolic syndrome in mice worsened, indicating that Th17 cells have an important protective effect on resisting obesity and metabolic syndrome.

Based on these findings, the researchers further thought that if the SFB bacteria were transplanted when mice with high-fat diets could improve the maintenance of intestinal Th17 cells, thereby inhibiting obesity and metabolic diseases?

The researchers performed SFB gavage to mice fed with high-fat diets every other day for a total of four weeks. The results showed that SFB and Th17 cells in the control group mice decreased, and obesity and metabolic diseases also occurred; intestinal Th17 cells in the mice gavaged with SFB significantly recovered . What is more interesting is that compared with the control group, SFB gavage mice had significantly reduced weight gain on a high-fat diet, and avoided the occurrence of prediabetes manifestations such as insulin resistance and glucose tolerance .

Intestinal Th17 cells of mice gavaged with SFB were significantly restored, and their weight gain was significantly reduced under a high-fat diet, and the occurrence of prediabetes such as insulin resistance and glucose tolerance was avoided.

BW: weight change, ITT: insulin tolerance test, OGTT: oral glucose tolerance test

Next, the researchers analyzed the specific components that caused the decline in intestinal SFB and Th17 cells in a high-fat diet.

Two harmful characteristics of a high-fat diet are excessive fat and low dietary fiber. However, neither of these components affected SFB levels. In addition to fat, another ingredient that is high in high-fat diets is sugar. Add sucrose to drinking water from wild-type mice fed with normal diets, which can eliminate SFB in a dose-dependent manner and lead to a reduction in Th17 cells.

Sucrose can eliminate SFB in a dose-dependent manner and lead to a decrease in Th17 cells

So, how does sugar affect SFB and Th17 cells?

analysis of intestinal flora in mice found that compared with animals fed with normal diet, the intestinal flora of mice fed with high-fat feed and sugar had undergone great changes. Among them, Faecalibaculum rodentium (Frod) increased significantly in mice with high-fat diet and sugar-fed, and showed negative correlation with SFB levels.

Frod levels in high-fat diet and sugar-treated mice increased significantly, and showed a negative correlation with SFB

So, is the amplification of Frod the cause of the reduction of SFB in mice by sugar or high-fat diet?

To prove this, the Ivaylo I. Ivanov team directly tested whether Frod could replace SFB by sterile mice. They colonized SFB and Frod into the intestines of germ-free mice by gavage. It was found that Frod can significantly inhibit the colonization of SFB . If adds sugar to drinking water, it can promote the amplification of Frod and lead to a further decrease in SFB levels, which in turn leads to a decrease in intestinal Th17 cells.

Frod can significantly inhibit SFB colonization, and sugar can further lead to the decline of SFB

. Identify the mechanism by which diet affects intestinal Th17 cells. Next, we also need to know how Th17 cells prevent metabolic syndrome. IL-17 secreted by

Th17 cells play an important role in maintaining the integrity of intestinal epithelial cells. In the intestine, epithelial absorption of dietary lipids is a known regulator of metabolic syndrome [4]. Therefore, the Ivaylo I. Ivanov team studied the effect of Th17 cells on intestinal lipid absorption.

Researchers compared lipid concentrations in various tissues of Th17-deficient mice fed with high-fat diets (which develops metabolic syndrome) and Th17 normal mice (which are immune to metabolic syndrome). The results showed that the lipid content of intestinal epithelial cells and liver of normal mice in Th17 was significantly reduced, but the lipid level in feces increased . This shows that in the presence of Th17 cells, lipid absorption of intestinal epithelial cells decreased , while lipids accumulate in the intestinal cavity.

tested intestinal epithelial cells and found that in the intestinal epithelial cells of normal Th17 mice, the expression of several genes involved in lipid uptake and transport was downregulated, the most significant of which was Cd36, which encodes a transporter that dietary fatty acids enter the cells. Further analysis found that the downregulation of Cd36 was dependent on Th17 cell-derived IL-17. Compared with

and Th17-deficient mice (STOP), the lipid content of intestinal epithelial cells and liver in Th17 normal mice (STOP/CD4) was significantly reduced, but the lipid level in feces increased; in addition, the Cd36 expression level of intestinal epithelial cells was significantly reduced. In order to study whether Cd36 is needed for Th17 cells' protective effect, the researchers analyzed Cd36 knockout mice. We have known earlier that in wild-type mice, Th17 cells have a protective effect on high-fat diet-induced metabolic syndrome. However, Th17 cells did not further protect against , although Cd36-deficient mice had significantly reduced risk of metabolic syndrome compared with wild-type mice.

These results show that IL-17 secreted by Thh17 cells reduce lipid uptake and absorption by inhibiting the expression of fatty acid transporter Cd36 in epithelial cells, thereby providing protective effects for metabolic syndrome .

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Overall, this study found that Th17 cells induced by intestinal flora regulate lipid absorption of the intestinal epithelium through an IL-17-dependent method, thereby preventing the occurrence of obesity and metabolic syndrome . The sugar in the diet will affect the intestinal flora, which will lead to the loss of intestinal Th17 cells and function .

This study reveals a complex network of interactions between dietary ingredients, microbiota and intestinal immune cells. Although this study focuses mainly on mouse models, some previous studies have found that the Th17 cell-related bacterial population of may also be affected by metabolic diseases and sugar intake [5, 6]. If further confirmed, these findings may bring new hope for the prevention and treatment of metabolic diseases.

References

1. Kawano Y, Edwards M, Huang Y, Bilate AM, Araujo LP, Tanoue T, Atarashi K, Ladinsky MS, Reiner SL, Wang HH et al: Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell 2022.

2. Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR: The orphan nuclear receiver RORgammat directs the differentiation program of prototype IL-17+ T helper cells. Cell 2006, 126(6):1121-1133.

3. Ivanov, II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV et al: Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139(3):485-498.

4. Petersen C, Bell R, Klag KA, Lee SH, Soto R, Ghazaryan A, Buhrke K, Ekiz HA, Ost KS, Boudina S et al: T cell-mediated regulation of the microbiota protects against obesity. Science 2019, 365(6451).

5. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G et al: Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016, 535(7612):376-381.

6. Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T et al: Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 2015, 163(2):367-380.

Editor in charge丨Wang Xuening