High-fat diet induces antibiotic tolerance

High-fat diet affects the composition of the intestinal flora and the abundance of metabolites in mice
.

Recently, "Nature-Microbiology" published online research on the mechanism of the formation of antibiotic resistance induced by high-fat diet by Professor Wang Zhiqiang of the School of Veterinary Medicine of Yangzhou University
.

Neglected antibiotic resistance

The discovery and widespread application of antibiotics not only saved countless lives, but also played a vital role in the prevention and control of bacterial diseases in livestock and poultry breeding, ensuring the stable supply of animal-derived foods
.

According to Wang Zhiqiang, the co-corresponding author of the paper, antibiotic resistance means that bacteria have certain specific drug-resistant genes, which can express drug-resistant enzymes or activate efflux pumps, so that bacteria can resist antibiotics
.

The antibiotic resistance means that the bacteria do not carry any specific drug resistance genes, and they are sensitive bacteria in terms of genotype
.

The first author and co-corresponding author of the paper, Professor Liu Yuan of Yangzhou University, said in an interview with "China Science Daily" that antibiotic resistance can be determined by genomic analysis and minimum inhibitory concentration (MIC) test: antibiotic resistant bacteria Not only has the corresponding drug resistance gene, but also the MIC will increase significantly
.

Therefore, after the bacteria are isolated in the clinic, the antibiotic susceptibility test is mainly used to determine which antibiotics they are sensitive to and which antibiotics they are resistant to, so as to guide clinical medication
.

"The routine screening methods and medication strategies are almost entirely focused on antibiotic resistance
.

In the MIC test, antibiotic-resistant bacteria and susceptible bacteria will show the same lower MIC value; but in the sterilization experiment, the performance of antibiotic-resistant bacteria and susceptible bacteria will be completely different
.

Even so, antibiotic resistance has not received sufficient attention and attention in clinical practice
.

In 2017, "Science" magazine reported that antibiotic resistance will also promote the evolution and development of antibiotic resistance
.

Wang Zhiqiang explained that because resistant bacteria survive in an environment with high concentrations of antibiotics for a longer time, there is a greater chance of obtaining resistant mutations later
.

Therefore, “tolerance mutations paved the way for the subsequent rapid evolution of resistance
.
Preventing the evolution of tolerance may provide new strategies for delaying the emergence of resistance, and new drugs or drug combinations that reduce tolerance may help slow down The evolution of drug resistance
.
" Wang Zhiqiang said that the importance of tolerance is often ignored in clinical practice, and research on clinical bacterial drug resistance is far less common than bacterial drug resistance
.
In the future, it should be studied in depth, and the cure rate should be increased in a targeted manner, and the rate of acquired drug resistance should be reduced
.

The subtle role of intestinal flora

As early as 2011, "Science" magazine reported that rigorous reactions caused by starvation and hydrogen sulfide produced by certain bacteria mediate the formation of antibiotic resistance
.

However, "the reasons for the formation of antibiotic resistance and its inducing factors, especially the mechanism by which it occurs in the body, are still unclear
.
" Li Ruichao said
.

"With the improvement of people's living standards, high-fat diet has become an important daily diet, and it is also accompanied by the occurrence of obesity, type II diabetes and other related metabolic diseases
.
" Wang Zhiqiang told China Science Daily that high-fat diet is important for The impact of antibiotic treatment for bacterial infectious diseases is unclear
.
So they investigated the correlation between a high-fat diet and antibiotic tolerance
.

"Our research has found that compared with mice on a normal diet, mice on a high-fat diet are less sensitive to bactericidal antibiotic treatment after infection
.
" Liu Yuan introduced that they infected mice on a high-fat diet for 64 days.
Gavage antibiotics were administered 2 hours later, and the number of bacteria in the lung tissue was measured 24 hours after infection
.

It was found that the decrease in the number of bacteria in the lung tissue of mice on a normal diet was higher than that of mice on a high-fat diet, which indicated that mice on a high-fat diet were less sensitive to bactericidal antibiotic treatment after infection
.

"After discovering this phenomenon, we set out to investigate its underlying mechanism
.
" Li Ruichao said
.

Based on the results, they first compared the pharmacokinetic differences of antibiotics between normal diet and high-fat diet mice
.
The results show that the drug concentration-time curve of ciprofloxacin is similar between the two, which indicates that the difference in antibiotic activity is not due to the influence of pharmacokinetics
.

Next, they conducted experiments to eliminate the intestinal flora of mice on a high-fat diet and found that after the intestinal flora was eliminated, the effect of the high-fat diet on the antibiotic tolerance of the mice was also eliminated
.
Correspondingly, the effectiveness of antibiotics in normal diet mice transplanted with high-fat diet mouse feces was also significantly reduced
.
The above results indicate that the high-fat diet may change the abundance of metabolites by affecting the composition of the intestinal flora
.

"We found through experiments that the intestinal flora plays a key role in this process, and then we look for the changed intestinal flora
.
" Liu Yuan said
.

Discover an effective metabolic regulator

Through diversity analysis, they found that compared with mice on a normal diet, the number of Bacteroides and Ekman bacteria in the intestines of mice on a high-fat diet was significantly reduced, while the bacteria of the Lacetospirillaceae were significantly increased
.

Liu Yuan told reporters that the Bacteroides family is a symbiotic bacteria in the human intestine and provides essential nutrients for the body
.

Ekmania muciniphila, also known as Ekmania muciniphila, is the only probiotic bacteria in the human intestine that can store and decompose mucin to produce carbon and nitrogen factors
.
Mucin is a glycoprotein secreted by intestinal epithelial cells.
It is highly viscous and has a large amount of distribution on the inner surface of the gastrointestinal tract
.
It is worth noting that in recent years, it has been discovered that Ekmania can not only prevent diabetes, obesity and cardiovascular disease, but also enhance the effect of cancer immunotherapy
.

Laureus spirillum is an obligate anaerobic bacteria that is abundant in the intestine and participates in the metabolism of a variety of carbohydrates
.

Studies have shown that Bacteroides bacteria are the key strains for the biosynthesis of indole acetic acid
.
They speculated that in the intestinal flora of high-fat diet mice, the decrease in the number of Bacteroides bacteria may be an important reason for the decrease in indole acetic acid content
.

"Our research has found that indole acetic acid can activate bacterial metabolism
.
The main manifestation is that after the action of indole acetic acid, the levels of bacterial energy currency ATP and reactive oxygen species are significantly increased
.
This prevents the formation of resistant strains and helps antibiotics eliminate resistant bacteria.
Receiving bacteria
.
" Li Ruichao said
.

Inspired by the research conclusions, they used the bacterial metabolism regulator indoleacetic acid IAA and ciprofloxacin in the peritonitis protection model of high-fat diet mice, and achieved good therapeutic effects, significantly improving the mice’s Survival rate
.

However, Liu Yuan emphasized that the reduction of Ekman bacteria and the increase of Laevis in high-fat diets need to be further studied in the development of antibiotic resistance
.

In addition to indole acetic acid, what other metabolite changes will affect the occurrence and development of antibiotic resistance? What is its potential mechanism of action? Li Ruichao believes that these issues are the focus of their next research
.

Liu Yuan said that in order to combat stubborn infections caused by clinical bacteria, “we need to fully understand the possible reasons behind and find effective solutions in time
.
Our research not only reveals the potential of high-fat diets in the treatment of bacterial infectious diseases.
It is harmful and shows that bacterial metabolism regulators can be used as potential antibiotic synergists to fight resistant infections caused by pathogenic bacteria
.
"

"There is still a long way to go in
applying the conclusions from the mouse model to other mammals .
" Wang Zhiqiang added, "but a healthier and more balanced diet is bound to be of great benefit to our health.
"
.
(Source: China Science News Li Chensha Aihong)

Related paper information: https://doi.
org/10.
1038/s41564-021-00912-0