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Different groups of people have different effects of the same medicine, and even side effects
.
In the past, it was believed that genetic differences in different populations were the source of such response differences.
However, it is estimated that genetic factors can only explain 20%-95% of response differences to individual drugs [1]
.
Therefore, other factors must be involved
.
In recent years, people have realized that the intestinal flora has become an "organ" that plays an important role in health and disease, and they constitute a complex ecosystem
.
Early research pointed out that drugs can change the intestinal microenvironment, thereby changing the composition and function of intestinal bacteria
.
On the contrary, intestinal bacteria can also directly participate in the chemical transformation of drugs or change the metabolism or immune system of the host to change the efficacy of drugs [2]
.
Recently, Peer Bork, Athanasios Typas and Kiran R.
Patil from the European Molecular Biology Laboratory (EMBL) and the Toxicology Research Group of the University of Cambridge Medical Research Council (MRC) published important research results in the journal Nature[3]
.
They found that common drugs accumulate in certain types of intestinal bacteria
.
At the same time, intestinal bacteria do not chemically modify them, and most of these drugs do not affect bacterial growth
.
This kind of bioaccumulation will not only reduce the efficacy of the medicine, but also change the composition and function of the intestinal flora
.
In order to deepen the understanding of drug-bacterial interactions, the researchers systematically studied 15 common human targeted drugs (including 12 oral small molecule drugs, covering anti-inflammatory drugs, antidepressants, and diabetes drugs) and 25 Interaction of representative strains of human gut bacteria
.
In the end, the researchers conducted a total of 375 bacterial-drug interaction tests and found 70 bacterial-drug interactions, 29 of which have never been reported before
.
Among the 29 newly discovered interactions, as many as 17 (14 bacteria and 4 drugs) are bacteria that “store” the drugs without changing the activity of the drugs (Figure 1)
.
For example, the antidepressant duloxetine and the antidiabetic drug rosiglitazone are examples of being "stored" by bacteria (Figure 1)
.
Figure 1 What is the molecular mechanism of intestinal bacteria "storing" drugs for drug accumulation without changing the activity of drugs? The researchers chose duloxetine and conducted an in-depth study on it
.
The researchers found that in the thermal proteomic analysis (TPP), E.
coli IAI1 (bioaccumulates in the gut microbial culture medium (GMM)) and E.
coli ED1a (no bioaccumulation in GMM) have a positive effect on duloxetine Different reactions affect metabolic pathways including amino acid metabolism, purine and pyrimidine biosynthesis, and the pentose phosphate pathway, which provides precursors for nucleotide biosynthesis
.
This result indicates that protein binding is a contributing factor to the bioaccumulation of duloxetine (Figure 2d)
.
Specifically, in the live bacterial TPP experiment, the drug response protein of the IAI1 strain was almost twice that of the ED1a strain (388 VS 222 proteins) (Figure 2e main image)
.
In contrast, in the TPP of bacterial lysate, the two strains showed very similar characteristics (397 vs.
412 proteins) (Figure 2e panel)
.
This indicates that the specific characteristics of drug accumulation of the two strains are likely to be caused by the differences in the drug uptake and efflux system of the strains
.
At the same time, the combination of duloxetine and metabolic enzymes also caused changes in bacterial metabolism
.
After duloxetine was added to GMM, the metabolites of three duloxetine accumulating bacteria-Clostridium saccharolyticum, Lactobacillus plantarum, Escherichia coli IAI1 and one non-accumulating bacteria-Lactococcus lactis had significant metabolites.
In addition, the metabolic response of bacteria to duloxetine is concentration-dependent (Figure 2g)
.
Therefore, data from the proteome and metabolome indicate that duloxetine can bind to the abundant metabolic enzymes of intestinal bacteria to promote its "storage" by bacteria (Figure 2)
.
Figure 2 Differential metabolic interaction of bacterial metabolic enzymes (d, e) and metabolism (f, g) that bind or react with duloxetine is the basis for shaping the structure of the intestinal flora, so the metabolic changes related to drug "storage" Will it also affect the structure of the intestinal flora? To this end, the researchers constructed an intestinal flora composed of 5 types of intestinal bacteria (Bacteroides multiforme, Eubacterium rectum, Lactobacillus gasseri, Gastrococcus rumen and Streptococcus salivarius).
Among them, Streptococcus salivarius ( S.
salivarius) can "store" duloxetine, while E.
rectal bacteria (E.
rectate) will be inhibited by duloxetine (Figure 3b)
.
After 48 hours of culturing the above-mentioned flora in the intestinal microbial medium, the researchers transferred it to a medium with or without duloxetine
.
16s rRNA sequencing results showed that the presence of duloxetine significantly changed the structure of the flora, and the abundance of Eubacterium rectum that should have been suppressed increased by more than 100 times (Figure 3a)
.
This is because, in the presence of duloxetine, the medium supernatant of Streptococcus salivarius promotes the growth of Eubacterium rectum (Figure 3c, d)
.
Therefore, the source of this change is the accumulation of Duloxetine by Streptococcus salivarius.
In this case, Streptococcus salivarius promotes the growth of Eubacterium rectum through "cross-feeding"
.
Figure 3 Duloxetine changes the structure of the flora and induces "cross-feeding".
In addition, the researchers used nematodes as a model to study the impact of the bioaccumulation of duloxetine on the host.
Duloxetine is a serotonin -Norepinephrine reuptake inhibitors that regulate the behavior (muscle movement) of Caenorhabditis elegans in a concentration-dependent manner
.
Compared with nematodes raised in bacteria (E.
coli ED1a) that cannot "store" duloxetine, nematodes raised in bacteria that can "store" duloxetine (E.
coli IAI1) have their locomotion behavior Significantly changed (Figure 4)
.
Figure 4 Duloxetine bioaccumulative bacteria can attenuate the effect of duloxetine on host behavior.
In general, this study reveals a new mechanism of flora-drug interaction and further expands the flora-drug interaction boundary! Unexpectedly, the intestinal flora "storage" drugs not only affect the efficacy, but also affect the structure of the flora and regulate the physiological state of the host through metabolic interactions! This research also opened a door for us
.
Looking forward to more in-depth and detailed research on the interaction of flora-drug-host in the human body in the future
.
For us, understanding the role of intestinal flora in drug response lays the foundation for the development of intestinal flora targeting methods that improve drug efficacy
.
At present, the intestinal flora is becoming an important target for the development of personalized medicines.
It is more and more promising to improve the efficacy, safety or reduce side effects by adjusting the intestinal flora! References [1] Kalow W, Tang BK, Endrenyi L.
Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research.
Pharmacogenetics.
1998;8(4):283-289.
doi:10.
1097 /00008571-199808000-00001[2] Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL.
Mapping human microbiome drug metabolism by gut bacteria and their genes.
Nature.
2019;570(7762):462-467.
doi: 10.
1038/s41586-019-1291-3[3] Klünemann M, Andrejev S, Blasche S, et al.
Bioaccumulation of therapeutic drugs by human gut bacteria [published online ahead of print, 2021 Sep 8].
Nature.
2021;10.
1038/ s41586-021-03891-8.
doi:10.
1038/s41586-021-03891-8 Responsible Editor | Dai Siyu
.
In the past, it was believed that genetic differences in different populations were the source of such response differences.
However, it is estimated that genetic factors can only explain 20%-95% of response differences to individual drugs [1]
.
Therefore, other factors must be involved
.
In recent years, people have realized that the intestinal flora has become an "organ" that plays an important role in health and disease, and they constitute a complex ecosystem
.
Early research pointed out that drugs can change the intestinal microenvironment, thereby changing the composition and function of intestinal bacteria
.
On the contrary, intestinal bacteria can also directly participate in the chemical transformation of drugs or change the metabolism or immune system of the host to change the efficacy of drugs [2]
.
Recently, Peer Bork, Athanasios Typas and Kiran R.
Patil from the European Molecular Biology Laboratory (EMBL) and the Toxicology Research Group of the University of Cambridge Medical Research Council (MRC) published important research results in the journal Nature[3]
.
They found that common drugs accumulate in certain types of intestinal bacteria
.
At the same time, intestinal bacteria do not chemically modify them, and most of these drugs do not affect bacterial growth
.
This kind of bioaccumulation will not only reduce the efficacy of the medicine, but also change the composition and function of the intestinal flora
.
In order to deepen the understanding of drug-bacterial interactions, the researchers systematically studied 15 common human targeted drugs (including 12 oral small molecule drugs, covering anti-inflammatory drugs, antidepressants, and diabetes drugs) and 25 Interaction of representative strains of human gut bacteria
.
In the end, the researchers conducted a total of 375 bacterial-drug interaction tests and found 70 bacterial-drug interactions, 29 of which have never been reported before
.
Among the 29 newly discovered interactions, as many as 17 (14 bacteria and 4 drugs) are bacteria that “store” the drugs without changing the activity of the drugs (Figure 1)
.
For example, the antidepressant duloxetine and the antidiabetic drug rosiglitazone are examples of being "stored" by bacteria (Figure 1)
.
Figure 1 What is the molecular mechanism of intestinal bacteria "storing" drugs for drug accumulation without changing the activity of drugs? The researchers chose duloxetine and conducted an in-depth study on it
.
The researchers found that in the thermal proteomic analysis (TPP), E.
coli IAI1 (bioaccumulates in the gut microbial culture medium (GMM)) and E.
coli ED1a (no bioaccumulation in GMM) have a positive effect on duloxetine Different reactions affect metabolic pathways including amino acid metabolism, purine and pyrimidine biosynthesis, and the pentose phosphate pathway, which provides precursors for nucleotide biosynthesis
.
This result indicates that protein binding is a contributing factor to the bioaccumulation of duloxetine (Figure 2d)
.
Specifically, in the live bacterial TPP experiment, the drug response protein of the IAI1 strain was almost twice that of the ED1a strain (388 VS 222 proteins) (Figure 2e main image)
.
In contrast, in the TPP of bacterial lysate, the two strains showed very similar characteristics (397 vs.
412 proteins) (Figure 2e panel)
.
This indicates that the specific characteristics of drug accumulation of the two strains are likely to be caused by the differences in the drug uptake and efflux system of the strains
.
At the same time, the combination of duloxetine and metabolic enzymes also caused changes in bacterial metabolism
.
After duloxetine was added to GMM, the metabolites of three duloxetine accumulating bacteria-Clostridium saccharolyticum, Lactobacillus plantarum, Escherichia coli IAI1 and one non-accumulating bacteria-Lactococcus lactis had significant metabolites.
In addition, the metabolic response of bacteria to duloxetine is concentration-dependent (Figure 2g)
.
Therefore, data from the proteome and metabolome indicate that duloxetine can bind to the abundant metabolic enzymes of intestinal bacteria to promote its "storage" by bacteria (Figure 2)
.
Figure 2 Differential metabolic interaction of bacterial metabolic enzymes (d, e) and metabolism (f, g) that bind or react with duloxetine is the basis for shaping the structure of the intestinal flora, so the metabolic changes related to drug "storage" Will it also affect the structure of the intestinal flora? To this end, the researchers constructed an intestinal flora composed of 5 types of intestinal bacteria (Bacteroides multiforme, Eubacterium rectum, Lactobacillus gasseri, Gastrococcus rumen and Streptococcus salivarius).
Among them, Streptococcus salivarius ( S.
salivarius) can "store" duloxetine, while E.
rectal bacteria (E.
rectate) will be inhibited by duloxetine (Figure 3b)
.
After 48 hours of culturing the above-mentioned flora in the intestinal microbial medium, the researchers transferred it to a medium with or without duloxetine
.
16s rRNA sequencing results showed that the presence of duloxetine significantly changed the structure of the flora, and the abundance of Eubacterium rectum that should have been suppressed increased by more than 100 times (Figure 3a)
.
This is because, in the presence of duloxetine, the medium supernatant of Streptococcus salivarius promotes the growth of Eubacterium rectum (Figure 3c, d)
.
Therefore, the source of this change is the accumulation of Duloxetine by Streptococcus salivarius.
In this case, Streptococcus salivarius promotes the growth of Eubacterium rectum through "cross-feeding"
.
Figure 3 Duloxetine changes the structure of the flora and induces "cross-feeding".
In addition, the researchers used nematodes as a model to study the impact of the bioaccumulation of duloxetine on the host.
Duloxetine is a serotonin -Norepinephrine reuptake inhibitors that regulate the behavior (muscle movement) of Caenorhabditis elegans in a concentration-dependent manner
.
Compared with nematodes raised in bacteria (E.
coli ED1a) that cannot "store" duloxetine, nematodes raised in bacteria that can "store" duloxetine (E.
coli IAI1) have their locomotion behavior Significantly changed (Figure 4)
.
Figure 4 Duloxetine bioaccumulative bacteria can attenuate the effect of duloxetine on host behavior.
In general, this study reveals a new mechanism of flora-drug interaction and further expands the flora-drug interaction boundary! Unexpectedly, the intestinal flora "storage" drugs not only affect the efficacy, but also affect the structure of the flora and regulate the physiological state of the host through metabolic interactions! This research also opened a door for us
.
Looking forward to more in-depth and detailed research on the interaction of flora-drug-host in the human body in the future
.
For us, understanding the role of intestinal flora in drug response lays the foundation for the development of intestinal flora targeting methods that improve drug efficacy
.
At present, the intestinal flora is becoming an important target for the development of personalized medicines.
It is more and more promising to improve the efficacy, safety or reduce side effects by adjusting the intestinal flora! References [1] Kalow W, Tang BK, Endrenyi L.
Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research.
Pharmacogenetics.
1998;8(4):283-289.
doi:10.
1097 /00008571-199808000-00001[2] Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL.
Mapping human microbiome drug metabolism by gut bacteria and their genes.
Nature.
2019;570(7762):462-467.
doi: 10.
1038/s41586-019-1291-3[3] Klünemann M, Andrejev S, Blasche S, et al.
Bioaccumulation of therapeutic drugs by human gut bacteria [published online ahead of print, 2021 Sep 8].
Nature.
2021;10.
1038/ s41586-021-03891-8.
doi:10.
1038/s41586-021-03891-8 Responsible Editor | Dai Siyu
