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Koch's law is the golden rule for the identification of infectious disease pathogens.
The key step is to separate the pathogen into the culture medium and use it to multiply on healthy animals to induce disease.
At present, microbiologists also need to cultivate potential pathogenic bacteria in the gut microbiota and reproduce the disease in an appropriate model to determine their pathogenic effects.
Three studies published last year identified the role of certain key bacteria in aggravating/alleviating cancer and metabolic diseases through in vitro culture of intestinal microbes.
1.
Using organoid models to study pathogenic bacteria that produce gene toxins.
A key issue in using potential pathogenic bacteria cultured in vitro to reproduce the disease is how to establish a reliable host model to detect the pathogenic effects of microorganisms.
Pleguezuelos-Manzano et al.
found that an E.
coli strain isolated from colorectal cancer (CRC) tissue can produce a gene toxin that induces human intestinal organoids to develop mutations similar to those of CRC patients.
The bacterial gene toxin colibactin exists on a 50kb genome island and is encoded by a hybrid polyketide non-ribosomal peptide synthase (pks) operon.
An early study showed that the Escherichia coli that produces colibactin is enriched in colon biopsy samples of CRC patients.
The genotoxic pks+ E.
coli strain isolated and cultured from CRC tumor samples was inoculated into 5-6 weeks old C57BL/6J-ApcMin/+ mice (CRC model mice).
Compared with the uninfected control group, the experimental group Colon polyps and high-grade cancer are more likely to occur, but the specific mechanism is unknown. In this in vitro study in 2020, researchers exposed human intestinal organoids to pks+E.
coli (using an allelic knockout strain that cannot produce colibactin as a negative control) and found that the organoids are unique under the action of colibactin.
Mutation characteristics.
A metagenomic study of 3668 solid cancer metastases and 496 CRC metastases from the Netherlands found that these pks features were enriched in metastases caused by CRC.
At the same time, these pks-specific mutations are more likely to occur in oncogenes such as APC.
Using the in vitro research system of human organoids, it is possible to directly observe the influence of gene toxin-producing bacteria on susceptible gene mutations in human cells.
This study provides key molecular mechanism evidence for the causal relationship between pks+ E.
coli strains and cancer.
This also opens up new ways to identify more new intestinal bacteria and the potential pathogenic effects of their genetic toxins in human colorectal cancer.
2.
The role of intestinal flora in preventing and alleviating diseases.
Some intestinal bacteria may play an important role in preventing or alleviating chronic diseases.
Research by Zagato et al.
showed that two isolated and cultured strains showed anti-tumor effects in ApcMin/+ mice.
The changes in the gut microbiome of ApcMin/+ mice at 12 weeks were monitored by 16SrRNA gene sequencing, and it was found that Faecalibaculum spp.
, one of the ten most abundant taxa, decreased significantly from the 8th week, which was consistent with the onset of tumor development.
Then they isolated the strain Faecalibaculum rodentium PB1 from the intestines of wild-type mice.
In the restricted ApcMin/+ mice treated with antibiotics, F.
PB1 significantly reduced the tumor size.
At the same time, the medium in which F.
PB1 has been cultured also has a tumor suppressive effect on ApcMin/+ mice, and after removing the volatile components in the medium, the tumor suppressive ability on mice disappears.
This discovery prompted the authors to focus on short-chain fatty acids as a potential factor that mediates and inhibits tumorigenesis.
F.
PB1 can produce butyrate (histone deacetylase inhibitor), which can inhibit tumor formation by inhibiting calcineurin-mediated activation of the NFATc3 transcription factor.
This study shows that Koch's Law can be used to identify and isolate specific intestinal probiotics and prove its important role in disease prevention.
In the study of obesity-related diseases, gene regulation between the host and bacteria can provide stronger evidence of intervention for causality.
Studies have confirmed that Enterobactercloacae B29 is a strain that can cause obesity.
It accumulates in the intestines of morbidly obese people and disappears before and after the patient successfully loses weight.
E.
B29 can cause obesity, insulin resistance and fatty liver in high-fat diet (HFD) sterile mice, but has no effect on normal diet mice.
HFD administered to sterile mice alone did not cause obesity-related phenotypes.
Knock out the waaG gene in the lipopolysaccharide synthesis pathway of E.
B29, and the ability of E.
B29 to cause obesity disappears.
No obesity-related phenotypes were observed after the introduction of wild-type E.
B29 into Toll-like receptor 4 (TLR4)-deficient germ-free mice, indicating that TLR4 may be an upstream molecule that induces the progression of obesity-related phenotypes.
Restricted mice colonized with E.
B29 can build a new drug screening platform to identify chemicals that compete with endotoxins and prevent them from binding to TLR4 to inhibit obesity.
This study not only confirmed the pathogenic role of intestinal bacteria in obesity-related diseases, but also provided a new solution for obesity control.
These latest studies mark the transition from correlation to causality in the study of intestinal flora.
So far, many studies of the microbiome have been suspended due to difficulties in identifying, isolating and cultivating gut bacteria.
Because bacteria in the same genus or species all have the genetic ability to produce the same biologically active substances, it is difficult for microbiologists to identify and isolate candidate bacteria based on characteristics at the genus, family, or phylum level.
Before we can systematically use methods based on in vitro isolation and culture to prove the causal relationship between microorganisms and diseases, we still need new methods to conduct correlation studies of the whole microbiome, so as to better generate biomarkers and guide us to find the right ones.
Pathogenic bacteria or probiotics.
This annual review article published in NatureReviews GastroEntErology & HEpatology focuses on the use of pure bacterial cultures published last year to explain the pathogenic/protective effects of specific intestinal bacteria on the host and its biological mechanisms.
Koch's law is the gold standard for proving that pathogens cause diseases.
The key is to isolate and cultivate pathogens in in vitro culture medium and use them to infect healthy individuals to observe whether they can cause the same diseases.
The current research on the intestinal flora is gradually moving from correlation to causal research.
It also requires the idea of Koch's rule.
Through genetic manipulation of key genes in the host and bacteria to clarify the bacteria-host interaction mechanism, and finally confirm the specific intestinal tract The causal relationship between bacteria and health or disease phenotypes.
References: [1] Zhao L, Zhao N.
Demonstration of causality: back to cultures.
Nat RevGastroenterol Hepatol 2020.
END Call for Papers "Medical Fang" is now officially open to fans! The content must be originally published and related to scientific research.
Once adopted, a generous reward (300-2000 yuan) will be given.
Please stamp for details.
"Medical side" has always been committed to serving "medical people", pushing the most cutting-edge and most valuable original clinical and scientific research articles to clinicians and scientific researchers.
The medical department has launched "Laboratory Basics", "SCI Writing Skills", "Intensive Reading and Analysis of Literature", "Easy Learning of Medical English", "National Natural Science Foundation of China", "Clinical Data Mining", "Gene Data Mining", "R Language Tutorial", "Medical Statistics", "Minimally Invasive Animal Experiment Training" and many other special courses, if you need to know the detailed tweets of the courses, you can follow the "Medical Party" public account, click "Exquisite Topics" to enter the Tencent classroom: https://medfun .
ke.
qq.
com NetEase Cloud Classroom: http://study.
163.
com/u/ykt1467466791112 Customer Service Tel: 15821255568 Customer Service WeChat: yixuefang1234
Koch's law is the golden rule for the identification of infectious disease pathogens.
The key step is to separate the pathogen into the culture medium and use it to multiply on healthy animals to induce disease.
At present, microbiologists also need to cultivate potential pathogenic bacteria in the gut microbiota and reproduce the disease in an appropriate model to determine their pathogenic effects.
Three studies published last year identified the role of certain key bacteria in aggravating/alleviating cancer and metabolic diseases through in vitro culture of intestinal microbes.
1.
Using organoid models to study pathogenic bacteria that produce gene toxins.
A key issue in using potential pathogenic bacteria cultured in vitro to reproduce the disease is how to establish a reliable host model to detect the pathogenic effects of microorganisms.
Pleguezuelos-Manzano et al.
found that an E.
coli strain isolated from colorectal cancer (CRC) tissue can produce a gene toxin that induces human intestinal organoids to develop mutations similar to those of CRC patients.
The bacterial gene toxin colibactin exists on a 50kb genome island and is encoded by a hybrid polyketide non-ribosomal peptide synthase (pks) operon.
An early study showed that the Escherichia coli that produces colibactin is enriched in colon biopsy samples of CRC patients.
The genotoxic pks+ E.
coli strain isolated and cultured from CRC tumor samples was inoculated into 5-6 weeks old C57BL/6J-ApcMin/+ mice (CRC model mice).
Compared with the uninfected control group, the experimental group Colon polyps and high-grade cancer are more likely to occur, but the specific mechanism is unknown. In this in vitro study in 2020, researchers exposed human intestinal organoids to pks+E.
coli (using an allelic knockout strain that cannot produce colibactin as a negative control) and found that the organoids are unique under the action of colibactin.
Mutation characteristics.
A metagenomic study of 3668 solid cancer metastases and 496 CRC metastases from the Netherlands found that these pks features were enriched in metastases caused by CRC.
At the same time, these pks-specific mutations are more likely to occur in oncogenes such as APC.
Using the in vitro research system of human organoids, it is possible to directly observe the influence of gene toxin-producing bacteria on susceptible gene mutations in human cells.
This study provides key molecular mechanism evidence for the causal relationship between pks+ E.
coli strains and cancer.
This also opens up new ways to identify more new intestinal bacteria and the potential pathogenic effects of their genetic toxins in human colorectal cancer.
2.
The role of intestinal flora in preventing and alleviating diseases.
Some intestinal bacteria may play an important role in preventing or alleviating chronic diseases.
Research by Zagato et al.
showed that two isolated and cultured strains showed anti-tumor effects in ApcMin/+ mice.
The changes in the gut microbiome of ApcMin/+ mice at 12 weeks were monitored by 16SrRNA gene sequencing, and it was found that Faecalibaculum spp.
, one of the ten most abundant taxa, decreased significantly from the 8th week, which was consistent with the onset of tumor development.
Then they isolated the strain Faecalibaculum rodentium PB1 from the intestines of wild-type mice.
In the restricted ApcMin/+ mice treated with antibiotics, F.
PB1 significantly reduced the tumor size.
At the same time, the medium in which F.
PB1 has been cultured also has a tumor suppressive effect on ApcMin/+ mice, and after removing the volatile components in the medium, the tumor suppressive ability on mice disappears.
This discovery prompted the authors to focus on short-chain fatty acids as a potential factor that mediates and inhibits tumorigenesis.
F.
PB1 can produce butyrate (histone deacetylase inhibitor), which can inhibit tumor formation by inhibiting calcineurin-mediated activation of the NFATc3 transcription factor.
This study shows that Koch's Law can be used to identify and isolate specific intestinal probiotics and prove its important role in disease prevention.
In the study of obesity-related diseases, gene regulation between the host and bacteria can provide stronger evidence of intervention for causality.
Studies have confirmed that Enterobactercloacae B29 is a strain that can cause obesity.
It accumulates in the intestines of morbidly obese people and disappears before and after the patient successfully loses weight.
E.
B29 can cause obesity, insulin resistance and fatty liver in high-fat diet (HFD) sterile mice, but has no effect on normal diet mice.
HFD administered to sterile mice alone did not cause obesity-related phenotypes.
Knock out the waaG gene in the lipopolysaccharide synthesis pathway of E.
B29, and the ability of E.
B29 to cause obesity disappears.
No obesity-related phenotypes were observed after the introduction of wild-type E.
B29 into Toll-like receptor 4 (TLR4)-deficient germ-free mice, indicating that TLR4 may be an upstream molecule that induces the progression of obesity-related phenotypes.
Restricted mice colonized with E.
B29 can build a new drug screening platform to identify chemicals that compete with endotoxins and prevent them from binding to TLR4 to inhibit obesity.
This study not only confirmed the pathogenic role of intestinal bacteria in obesity-related diseases, but also provided a new solution for obesity control.
These latest studies mark the transition from correlation to causality in the study of intestinal flora.
So far, many studies of the microbiome have been suspended due to difficulties in identifying, isolating and cultivating gut bacteria.
Because bacteria in the same genus or species all have the genetic ability to produce the same biologically active substances, it is difficult for microbiologists to identify and isolate candidate bacteria based on characteristics at the genus, family, or phylum level.
Before we can systematically use methods based on in vitro isolation and culture to prove the causal relationship between microorganisms and diseases, we still need new methods to conduct correlation studies of the whole microbiome, so as to better generate biomarkers and guide us to find the right ones.
Pathogenic bacteria or probiotics.
This annual review article published in NatureReviews GastroEntErology & HEpatology focuses on the use of pure bacterial cultures published last year to explain the pathogenic/protective effects of specific intestinal bacteria on the host and its biological mechanisms.
Koch's law is the gold standard for proving that pathogens cause diseases.
The key is to isolate and cultivate pathogens in in vitro culture medium and use them to infect healthy individuals to observe whether they can cause the same diseases.
The current research on the intestinal flora is gradually moving from correlation to causal research.
It also requires the idea of Koch's rule.
Through genetic manipulation of key genes in the host and bacteria to clarify the bacteria-host interaction mechanism, and finally confirm the specific intestinal tract The causal relationship between bacteria and health or disease phenotypes.
References: [1] Zhao L, Zhao N.
Demonstration of causality: back to cultures.
Nat RevGastroenterol Hepatol 2020.
END Call for Papers "Medical Fang" is now officially open to fans! The content must be originally published and related to scientific research.
Once adopted, a generous reward (300-2000 yuan) will be given.
Please stamp for details.
"Medical side" has always been committed to serving "medical people", pushing the most cutting-edge and most valuable original clinical and scientific research articles to clinicians and scientific researchers.
The medical department has launched "Laboratory Basics", "SCI Writing Skills", "Intensive Reading and Analysis of Literature", "Easy Learning of Medical English", "National Natural Science Foundation of China", "Clinical Data Mining", "Gene Data Mining", "R Language Tutorial", "Medical Statistics", "Minimally Invasive Animal Experiment Training" and many other special courses, if you need to know the detailed tweets of the courses, you can follow the "Medical Party" public account, click "Exquisite Topics" to enter the Tencent classroom: https://medfun .
ke.
qq.
com NetEase Cloud Classroom: http://study.
163.
com/u/ykt1467466791112 Customer Service Tel: 15821255568 Customer Service WeChat: yixuefang1234
