Article is from WeChat public account: Back to Park (ID: fanpu2019) , author: Gushu Chen (Institute of life Science, Zhejiang University young Investigator), from the title figure: IC photo

No one is an island and you have been inseparable from the microbial community since your birth. There are trillions of microbial communities in our body, including bacteria, fungi and viruses, which parasitize our skin, genitals, mouth and digestive tract. In fact, human cells are not the most abundant cells in the human body. The number of commensal microorganisms far exceeds the number of human cells, weighing more than 1.27 kilograms. [ 1 ] , in which intestinal microorganisms account for about 80% of the total weight of human microorganisms.

They are a complex ecosystem, a huge society that helps the human body shape the body parts of the digestive system, immune system, nervous system, etc., for the benefit of mankind. But symbiotic microorganisms can still stand on their own. In order to expand their own interests, they cooperate and compete with each other on the battlefield of survival and evolution. They can be our partners, but they are not always our friends. Even in the most harmonious symbiotic relationship, there will be conflict, selfishness, and betrayal.

Figure 1.The microbial universe we are in. Image source: Nature

In the gut with the most commensal bacteria, microorganisms can easily switch roles between probiotic and pathogenic. Many diseases are now considered to be affected by the gut microbiota, such as cancer, autoimmune diseases, multiple sclerosis, and autism spectrum disorders. In addition, some intestinal microorganisms can affect the effects of some drugs. [3 ] .

Researchers analyzed 768 samples from 96 parts of 29 different organs of mice, which were from 4 sterile mice and 4 with normal microorganisms (SPF) . Using mass spectral informatics, researchers labeled inactive molecules in the organs of each mouse, and compared the obtained data with the GNPS database (by Dorrestein and co-authors The authors developed a mass spectrometry library) for comparison.

Ultimately, researchersMolecular maps were obtained in mice with microorganisms. After comparing the maps, it was found that up to 70% of the intestinal chemical composition of mice is determined by their intestinal microbiome. Even in distant organs, such as the uterus or brain, about 20% of the molecules in mice with gut microbes are different from sterile mice. ( Figure 2) .

Figure 2. Meta-mass-shift chemical analysis showing spectral counts of known mass differences in different segments of the digestive tract in sterile or SPF mice

Researchers have further discovered a specific family of molecules from the differences in the maps. There is a significant difference between mice with and without microorganisms, which is bile acid. Bile acids are mainly produced by the livers of mice or humans, which aid in the digestion of oils and fats, and can transmit information throughout the body as signal molecules. The research team found previously unknown bile acid-modified structures in mice with normal microbiomes, but not in sterile mice.

Usually, host liver enzymes add amino acids to bile acids, especially glycine and taurine. However, in mice with normal microbial communities, the research team found other amino acids (phenylalanine, tyrosine, and leucine) Labeled bile acids were not found in sterile mice, suggesting that the microbes determined novel amino acid modifications of bile acids. This opens up more possibilities for the impact of microorganisms on human health.

Researchers are also curious whether the same types of microbially modified bile acids are also present in the human body, so they created a mass search tool (MASST) And searched 1004 human samples analyzed by mass spectrometry in the public sample data set. They also analyzed about 3,000 stool samples by mass spectrometry from California.The American Gut Project, a large citizen science project at the University of San Diego School of Medicine. The researchers found that the unique microbially modified bile acid observed in mice was also present in 25.3% of human samples, and that this modified bile acid was higher in infants and patients with inflammatory bowel disease or cystic fibrosis.

Bile acid plays a very important role in fat metabolism. It can transfer information from the intestine to other parts of the body by activating bile acid receptors in the intestine. Bile acid receptors can also be negative when activated Feedback inhibits bile acid secretion. At the same time, it also helps to regulate triglyceride levels in the liver and body fluids in the intestine, so it plays an important role in liver disease and obesity. Many of the several drugs that are currently being developed are [4 ] for activating liver diseases by activating bile acid receptors . The study found that microbially modified bile acids strongly stimulate receptors, thereby inhibiting the expression of genes that produce bile acids in the liver. This discovery opens up more possibilities for the role of microbes in driving liver and other diseases, as well as affecting the activity of therapeutic drugs, and also points a new direction for the future design of drugs targeting receptors.

Another article published on February 27th in Nature , Mutational signature in colorectal cancer caused by genotoxic pks + E. coli, Utrecht, Netherlands The institute’s Ruben van Boxtel and Hans Clevers research group used organoid models to present evidence that pathogenic intestinal bacteria can cause mutations in human cell cancers. > [5 ] .

Colorectal cancer has always been one of the high-profile cancers worldwide. Gut microbes have long been thought to be involved in the development of colorectal cancer. Although there have been previous reports that 60% of colorectal cancer patients have a genotoxic E. coli (E. Coli) , can produce a substance that causes DNA mutation——colibactin (synthesized from a group of genes called pks islands in the E. coli genome) . Colibactin is able to alkylate adenine in double-stranded DNA in both in vitro cultured cells and mouse colorectal cancer models, causing double-strand breaks to cause DNA damage and cause canceration. [6, 7 ] . But the relationship between pks + E. coli and mutation sites in human colorectal cells is unclear.

In this latest study, scientists use organoid models that mimic the human intestine to study this issue. Organoids are mini versions of 3D organs cultivated in petri dishes. The researchers placed the stem cells taken from the intestine in a suitable growth environment. After rapid reproduction and development, they grew into a mini version of the intestine, which can reproduce the characteristics of the intestine from the tissue structure. The researchers then injected pks + E. coli into the cultured intestinal organoid cavity, and used E.coli as a negative control, which could not produce genotoxic substances.

Using immunostaining tests, the researchers found that pks + E. coli can also cause double-stranded cross-linking and DNA double-strand damage in human intestinal organoids. After culturing this intestinal organoid for up to 5 months and continuously injecting pks + E. coli, the researchers performed a whole genome sequencing analysis and found that the injection of pks + The proportion of single base substitutions in the experimental group of E. coli has increased significantly, and there is a clear phenomenon of T base substitutions. > (Figure 3) . And the three bases upstream of the mutant thymine position tend to be three adenines. These genetic mutations are also present in tumor samples from real patients.

Figure 3: pks + Mutated thymine upstream in organoids injected with E. coli tends to be triad adenine p>

Researchers compared and analyzed the entire genome of more than 5,500 tumor samples from the United Kingdom and the Netherlands. The results showed that some of the mutational features found in organoid experiments were concentrated in samples derived from colorectal cancer. The most common mutations in rectal cancer are consistent with mutations, deletions, and insertions that occur after organoid treatment. This result suggests that exposure to pk s + coli, which can produce colibacin, is likely to directly cause mutations in colorectal cancer. This study provides an important reference for further investigation of the pathogenesis of colorectal cancer and its clinical diagnosis and prevention.

There are many different E. coli strains in the human intestine. Maybe more than one strain can secrete substances that cause gene mutations in human cells. In the future, it may be necessary to re-evaluate the functions of secretions of other strains and re-evaluate the corresponding E. coli Probiotics. But undoubtedly, the study foreshadows that detecting and removing pks islands of E. coli in the gut may help reduce the risk of colorectal cancer in a large number of people.

The above two studies show that Microbes can affect the expression of human genes and may also cause gene mutations. This shows that our genotype and phenotype are not completely determined by our own genes, but may be jointly determined by the genes of other organisms. Although we still don’t know how many microorganisms can regulate human genes, and what kind of consequences these regulations can have on downstream genes, or how we should intervene to improve human health, this is still a future treatment of human diseases. Provides new directions.

With more and more evidence showing the importance of intestinal microbiota to health, various studies on intestinal microbes have shown a blowout trend in recent years. These studies link the microbiome to various human chronic diseases, and researchers often use experimental animal models to provide evidence for the role of the microbiome in chronic diseases. However, many causal inferences are difficult to verify in a population.

In the January 23rd issue of Cell, Professor Jens Walter of the University of Alberta in Canada published an article and reflected on the study of intestinal flora. He believes that many researchers are trying to use the (Human-microbiota-associated, HMA) Data from rodents to explain the relationship between host pathology and changes in microbial populations, but this cross-species inference is unconvincing, and Exaggerated the role of the gut microbiome in human disease References

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[2] Heintz-Buschart A, Wilmes P. Human Gut Microbiome: Function Matters. Trends Microbiol. 2018; 26 (7): 563–574.

[3] Quinn RA, Melnik AV, Vrbanac A, et al. Global chemical effects of the microbiome include new bile-acid conjugations [published online ahead of print, 2020 Feb 26 ] .Nature. 2020; 10.1038 / s41586-020-2047-9. Doi: 10.1038 / s41586-020-2047-9

[4] Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014; 30 (3): 332–338.

[5] Pleguezuelos-Manzano C, Puschhof J, Huber AR, et al. Mutational signature in colorectal cancer caused by genotoxic pks + E. coli [published online ahead of print, 2020 Feb 27]. Nature. 2020; 10.1038 / s41586-020-2080-8. doi: 10.1038 / s41586-020-2080-8

[6] Nougayrede, JP et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313, 848-851, doi: 10.1126 / science.1127059 (2006 ).

[7] Arthur, JC et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120-123, doi: 10.1126 / science.1224820 (2012).

[8] Walter J, Armet AM, Finlay BB, Shanahan F. Establishing or Exaggerating Causality for the Gut Microbiome: Lessons from Human Microbiota-Associated Rodents. Cell. 2020; 180 (2): 221–232. Doi: 10.1016 / j.cell.2019.12.025

Article is from WeChat public account: Back to Park (ID: fanpu2019) , author: Gushu Chen (Institute of life Science, Zhejiang University young Investigator)