"Science": High-fat diet destroys intestines, intestinal bacteria, and blood vessels!

The key link of high-fat diet leading to cardiovascular disease has finally been found
.

Recently, the team of Professor Mariana X.
Byndloss from the Vanderbilt Medical University Center and the team of Professor Andreas J.
Bäumler from the University of California, Davis published an important research result in the journal Science[1]
.

They found that a high-fat diet can impair the function of mitochondria in colonic epithelial cells, increase the concentration of oxygen and nitrate in the intestine, promote the growth of E.
coli and the breakdown of choline, leading to an increase in trimethylamine (TMA) levels, which ultimately leads to circulation Elevated levels of the harmful metabolite trimethylamine oxide (TMAO)
.

This study not only opened up the chain of relationships between high-fat diet, gut microbes and cardiovascular disease, but also clarified the complex interaction between diet, gut physiology and gut microbes in the TMAO pathway for the first time
.

We all know that a Western->
.

However, in this process, whether a high-fat diet will affect the composition of intestinal microbes, and how it affects the composition of intestinal bacteria, is still poorly understood
.

In fact, previous studies have shown that a high-fat diet can increase the abundance of facultative anaerobic Enterobacteriaceae bacteria in the feces of mice, indicating that a high-fat diet can change the composition of the gut microbiota [4]
.

In addition, some studies have shown that a high-fat diet can also change the host’s intestinal physiology
.

For example, saturated fatty acids in the diet induce mitochondria to produce hydrogen peroxide, causing mitochondrial dysfunction [5] and impairing the physiological state of the intestinal epithelium
.

So, is the mitochondrial damage induced by a high-fat diet related to the increase in the abundance of Enterobacteriaceae? If relevant, is this a key part of the high-fat diet leading to the increase in TMAO levels? With these questions in mind, the researchers first constructed a high-fat diet-induced obesity mouse model, and found that the high-fat diet-induced mRNA levels of mitochondrial-related markers, adenosine triphosphate (ATP) levels, and pyruvate depletion in colon epithelial cells of mice Hydrogenase (PDH) activity was significantly reduced, suggesting that a high-fat diet can lead to a decrease in epithelial cell mitochondrial activity
.

The problem of detecting related indicators of mitochondrial damage in mouse colonic epithelial cells induced by high-fat diet is a big problem
.

We all know that under normal circumstances, the intestine is hypoxic, and anaerobic organisms dominate it [6]
.

This hypoxic state is of great significance for regulating intestinal barrier function and maintaining intestinal homeostasis
.

It is worth noting that in the colon, high mitochondrial activity is essential for maintaining the hypoxic state of epithelial cells.
Once mitochondrial activity decreases, the hypoxic state of epithelial cells will be destroyed, and the balance of intestinal microbes will definitely be disrupted
.

In order to prove the above speculation, the researchers inoculated mice with facultative anaerobic wild-type E.
coli Nissle 1917, and then fed them with high-fat food and low-fat food, and found that: compared with low-fat diet mice, high-fat The abundance of Escherichia coli in the feces of diet mice increased significantly
.

In order to further study the effect of high-fat diet on the hypoxic state of colonic epithelium, the researchers used the exogenous hypoxia marker Pimonidazole to stain the colonic epithelial cells of mice on low-fat and high-fat diets.
Mark
.

The results showed that the surface of the colonic epithelium of low-fat diet mice was hypoxic, while the hypoxic state of colonic epithelium of high-fat diet mice was eliminated
.

The above results indicate that a high-fat diet induces a decrease in mitochondrial activity, destroys the hypoxic state of the colonic epithelial surface, and promotes an increase in the abundance of Enterobacteriaceae
.

Pemonidazole staining of mouse colon sections How does a high-fat diet reduce mitochondrial activity and destroy the hypoxic state of the colonic epithelium? Previous studies have shown that in colonic epithelial cells, the decrease in mitochondrial activity is related to the up-regulation of Nos2 expression level [7]
.

The Nos2 gene encodes inducible nitric oxide synthase, which promotes the production of nitric oxide and converts it into nitrate in the intestinal mucosa [8]
.

It seems that the key to the problem may be Nos2
.

Sure enough, the researchers observed in both normal and sterile mice: After high-fat diet feeding, the expression level of Nos2 in colonic epithelial cells and the concentration of nitrate in the colonic mucus layer increased significantly
.

In addition, the researchers constructed a wild-type E.
coli Nissle 1917 cydAB mutant (aerobic respiration-deficient mutant), inoculated a mixture of Nissle 1917 and the mutant in normal mice at a ratio of 1:1, and then compared the two The growth status of the strain
.

The results showed that the wild-type strains had a more competitive advantage under the induction of high-fat diet and recovered faster growth
.

The researchers used the same method to compare the growth of wild-type E.
coli Nissle 1917 strain and napA narG narZ mutant (nitrate respiration-deficient mutant) and observed the same phenomenon
.

These results indicate that the high-fat diet provides growth advantages for the E.
coli strain Nissle 1917 that undergoes aerobic respiration and nitrate respiration, suggesting that the high-fat diet induces an increase in intestinal oxygen and nitrate concentrations and drives the growth of E.
coli
.

Normal mice were inoculated with wild-type and mutant E.
coli Nissle 1917 strains, CFU was detected at different time points, and the competition index (CI) was calculated.
Then, the high-fat diet induced the increase of host oxygen and nitrate and promoted the growth of E.
coli.
Will it also promote the catabolism of choline by Escherichia coli and produce TMA? To answer this question, the researchers used the E.
coli strain MS 200-1 for research, which carries the cutC gene (encoding the key protein that converts choline into TMA)
.

The cutC gene-mediated choline catabolic pathway in E.
coli MS 200-1.
Researchers have constructed the wild-type MS 200-1 strain and the cutC gene mutant MS 200-1 respectively, and cultured them in vitro to simulate the intestinal environment
.

The researchers chose a non-carbon source essential medium (NCE) to cultivate E.
coli, and added choline to the medium as a carbon source to observe the growth of E.
coli
.

As we mentioned earlier, the increase in nitrate concentration is also beneficial to the growth of E.
coli.
If nitrate is added to the NCE medium alone, will it affect the growth of wild-type and mutant MS 200-1? Surprisingly, in a hypoxic (1%) environment, when choline or nitrate is added to the culture medium alone, there is no significant difference in the growth status of the two strains, while the growth state of the two strains is not significantly different when choline and nitrate are added at the same time.
Among them, the wild-type strain has obvious growth advantages, and the expression level of its cutC gene has increased significantly
.

A similar phenomenon was observed in an anaerobic environment, that is, when the medium contains choline and nitrate at the same time, the wild-type strain has an obvious growth advantage and the cutC gene expression level is higher
.

Oxygen and nitrate are involved in the catabolism of choline by E.
coli.
In addition, compared with anaerobic conditions, both wild-type and mutant E.
coli under hypoxic (1%) conditions have more growth advantages
.

The above results indicate that the increase in oxygen and nitrate provides growth advantages for E.
coli and increases the expression of the cutC gene
.

As a result, the researchers predicted that the increase in host oxygen and nitrate concentrations induced by a high-fat diet would lead to increased catabolism of choline by E.
coli
.

This conjecture has also been confirmed in subsequent in vivo experiments
.

Based on the above results, the researchers intend to further explore whether the increased catabolism of choline by E.
coli will promote the level of TMAO in the circulation
.

The researchers inoculated the wild-type MS 200-1 strain and the cutC gene mutant MS 200-1 strain into sterile mice.
After induction with a high-fat diet, compared with the mutant strain, the blood of the wild-type strain was inoculated.
The level of TMAO increased significantly
.

These results confirmed that the high-fat diet induced an increase in host oxygen and nitrate, which promoted the catabolism of choline by E.
coli, which in turn led to an increase in the level of TMAO in mouse plasma
.

At this point in the research, we have clearly understood the specific mechanism by which a high-fat diet promotes the production of TMAO through the intestinal flora
.

However, the researchers also hope to develop a drug designed to reduce TMAO levels in mice on a high-fat diet
.

The researchers chose 5-aminosalicylic acid (5-ASA) as the test drug, which is currently approved for the treatment of inflammatory bowel disease
.

So, what role will it play in the high-fat-induced mouse model? They found that 5-ASA can target peroxisome proliferator-activated receptor γ (PPAR-γ), specifically activate mitochondria in intestinal epithelial cells, restore hypoxia in epithelial cells, and reduce the level of TMAO in the circulation
.

In general, this study found that high-fat diet affects the interaction between host physiology and intestinal flora, changes the metabolism of intestinal flora, promotes its catabolism of choline, and increases the level of TMAO in the circulation.
It provides new ideas for the treatment of cardiovascular diseases
.

In addition, this study also provides potential therapeutic drugs for preventing cardiovascular diseases caused by high-fat diet
.

Although this study has clarified the microbial metabolic pathway by which choline is converted into TMAO, the specific role of this metabolic pathway in cardiovascular diseases such as heart disease is still not very clear
.

Therefore, in future research, researchers may shift their horizons to the study of cardiovascular disease models and explore the role of complex interactions between host microorganisms in related diseases
.

Finally, let us develop healthy eating habits and say goodbye to all our worries! In the new course of Singularity, we used a 10-lecture system to sort out the 20-year history of advanced lung cancer treatment
.

A detailed inventory of the latest developments in targeted therapy has also fully demonstrated the vitality of rare target research
.

Of course, immunotherapy is also a top priority.
We will take you once again to insight into the in-depth mechanism of immunotherapy, go deep into the forefront of immunotherapy, explore treatment options for the era of chemotherapy-free, and witness the achievements of adjuvant and neoadjuvant therapy.

.

In addition, we will also gaze with you on the complex biomarker research and explore the unlimited potential of new targets for immunotherapy
.

Of course, depth does not mean obscurity, and complexity does not mean complicated
.

We have tried our best to integrate these complex knowledge points into superb audio courses, so that you can listen easily, smoothly, and not too big, so that this knowledge can be quickly integrated into our cognitive system and become the soil for the next step
.

After talking for a long time, the original price of such a good course is only 39.
9 yuan, and the certified purchase only costs 9.
9 yuan, which is only half a cup of milk tea! Now that you see this, scan the QR code below immediately, and the purchase sounds like it! References: [1].
Yoo W, Zieba JK, Foegeding NJ, et al.
High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide.
Science.
2021;373(6556):813-818.
doi :10.
1126/science.
aba3683.
[2].
Martínez-del Campo A, Bodea S, Hamer HA, et al.
Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria.
mBio.
2015;6 (2): e00042-15.
Published 2015 Apr 14.
doi:10.
1128/mBio.
00042-15.
[3].
Wang Z, Klipfell E, Bennett BJ, et al.
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
Nature.
2011;472(7341):57-63.
doi:10.
1038/nature09922.
[4].
Martinez-Medina M, Denizot J, Dreux N, et al.
Western diet induces dysbiosis with increased E coli in CEABAC10 mice,