Release date: 2017-08-10
In the “Top Ten Medical Technology Innovations 2017†announced by the Cleveland Clinic, “using microbial groups to prevent, diagnose and treat diseases†ranked first [1]. This seems to be no accident. Whether it is a professional or a melon, in recent years, the "strength" of microbes has been seen in various studies.
The microbes are currently the most concerned, and the most "hot" is the gut microbe. If you want to treat the disease through it, you will definitely think of a very high-profile "fertilization transplant" in order to make it possible. The patient gained a better therapeutic experience, and the energetic industry rookie, Bres Therapeutics, also developed the SER-109, a fecal capsule for the treatment of C. difficile infection (CDI).
After experiencing a phase I clinical cure rate of 97% (29 patients cured in 29 patients), and the FDA's "breakthrough treatment" title and so on, this industry has high hopes for the drug in the phase II clinical in 2016 In the "folding", its therapeutic effect was not significantly different from placebo. As soon as the results were announced, Seres fell nearly 70% of the stock jump overnight, and the market value of $1.5 billion evaporated by 2/3.
The singularity cake is also thinking, why does Seres fail? Is there a problem with the ingredients of the drug? At the heart of SER-109 is intestinal bacteria, and researchers use bacterial spores in the feces of 50 healthy people who may benefit the "weak immune system" of CDI patients. Note that it is “may be beneficialâ€, which means that the role of R&D personnel in these bacteria can't be “in mind,†does this mean that if microbes that can regulate the immune system are found, Can you largely avoid this "ambiguity" and carry out "precise intestinal microbial transplantation"?
Professor Marco Colonna
On Friday, Professor Marco Colonna of the University of Washington School of Medicine led his team to publish an article in the journal Science. They really found the intestinal microbe that regulates specific immune cells, Lactobacillus reuteri. ! Not only that, but they also found that the beneficial bacteria that exist in the intestines of healthy people want to work, and the help of tryptophan is needed [2]. Professor Colonna said that this will be very helpful for many intestinal inflammatory diseases such as inflammatory bowel disease (IBD).
IBD has always been considered a “western disease†and is less common in economically underdeveloped areas. However, in the past 20 years, the incidence rate in Asia, especially in China, has risen rapidly. In the past 20 years, the total number of IBD cases has increased by more than 24 times in the past 10 years compared with the previous 10 years. According to a review published in the 2015 Nature Review: Gastroenterology and Hepatology magazine, in the next 10 years (2015-2025), the prevalence rate in China may reach 0.1%, and the number of patients in 2025 It will exceed 1.5 million and almost equalize the Western countries [3].
As a chronic disease, IBD can be described as "all-round and multi-angle". Repeated abdominal pain, diarrhea, and blood in the stool not only affect normal working life, but also affect mood. Therefore, IBD patients are often accompanied by different degrees of depression.
Past studies by T-cells have found that intestinal inflammation in patients with IBD is caused by hyperactivity of the immune system [4], and there is a special type of immune cell in our gut "double-positive intraepithelial T cells (double-positive intraepithelial) T lymphocytes (DPIELs), which are differentiated from CD4+ T cells, are responsible for regulating immune homeostasis, increasing tolerance of the immune system, and "settling" an overactive immune response that can reduce inflammation in patients.
For sterile mice, DPIELs are absent, so this suggests that gut microbes are essential for its production. But who is this mysterious microbe? What is the metabolite associated with it? These are not known. This time, the researchers have a definitive answer.
The findings of this research can also be attributed to an "accident", the researchers found that one of the two groups of mice in their lab carried a large number of DPIELs, while the other group was pitiful. To explore the reason, they transplanted the flora carrying DPIELs mice to another group of mice, and as a result these mice also had a significant number of DPIELs! The mice were treated with four antibiotics and the DPIELs no longer existed.
Lactobacillus reuteri
In order to identify the exact species, the researchers used four antibiotics separately and found that the true Gram-positive bacteria that are resistant to neomycin are related to the presence or absence of DPIELs. After narrowing the range, screening again, and finally delineating Six bacteria, one is Lactobacillus reuteri, and the other five are Bacteroides bacteria. After transplanting one by one, the researchers found that only Lactobacillus reuteri determines whether CD4+ T cells can differentiate into DPIELs, while other bacteria have only enhanced effects.
How does Lactobacillus reuteri differentiate T cells into DPIELs? Bacteria can direct T cell differentiation through their structural components (such as polysaccharides) or metabolites (such as short-chain fatty acids). After analyzing several metabolites of L. reuteri, the researchers found that å²å“š-3-lactic acid can cause a decrease in the transcription factor Thpok expression by activating a receptor in CD4+ T cells, CD4+ T cells. It can be divided into DPIELs. This is consistent with the differentiation mechanism guided by the down-regulation of Thpok found in the past [5].
So where does å²å“š-3-lactic acid come from? It comes from tryptophan, one of the eight essential amino acids in our body. The essential amino acids are amino acids that we can't self-synthesize or can't meet the demand and must be taken from food. In the daily diet, protein-rich foods. For example, meat, beans and dairy products are rich in tryptophan.
Proportion of DPIELs after 4 weeks of low-level (circular), standard (square) and high-level (triangle) tryptophan diets
So will supplementing tryptophan have a miraculous effect? The researchers conducted a mouse experiment. They divided the mice into three groups and fed a high-level tryptophan (0.48%), standard level tryptophan (0.24%) and low-level tryptophan (0.11%) for 4 weeks, respectively. For sterile mice with Lactobacillus reuteri strains, high levels of tryptophan supplementation also did not increase levels of DPIELs in mice. For normal mice with normal L. reuteri levels, standard tryptophan levels fed twice the low level of DPIELs and three times higher levels.
It is worth noting that DPIELs are shared between humans and mice. Moreover, studies have found that patients with IBD often have genetic defects associated with tryptophan metabolism, which adds credibility and practicality to the study.
Through this research, the singularity cake imagines that if these conclusions can be verified in the clinic, then for the IBD patients, can the doctor treat them with the method of “explanting bacteria and endogenous tryptophan�
In fact, for the development of intestinal microbial drugs, the leader of the intestinal microbiology in China, Professor Zhao Liping of Shanghai Jiaotong University once said that the biggest bottleneck at present is that the understanding of intestinal microbes is still not enough, we are different microorganisms. Function, which microbes increase or decrease can cause disease and cure the disease. It is necessary to identify the beneficial bacteria and harmful bacteria one by one in order to develop the drug in a targeted manner.
The singularity cake is also thinking, the emergence of this research, including the research on the role of a single bacterium against a certain disease in the past, is not to remind us that there is still much room for improvement in the treatment of "fertilization" ? In a sense, manure transplantation has always been in the state of “black boxâ€, and some researchers have suggested that it may be that such a comprehensive “micro-ecology†can really work. So, have these studies overturned such assumptions? Maybe we only need one or several microorganisms to achieve the same effect. Singularity cake thought, this problem probably needs researchers to slowly verify.
Reference materials:
[1] https://consultqd.clevelandclinic.org/2016/10/top-10-medical-innovations-2017-revealed/
[2] Cervantes-Barragan L, Chai J N, Tianero M D, et al. Lactobacillus reuteri induces gut intraepithelial CD4+ CD8αα+ T cells [J]. Science, 2017: eaah5825.
[3] Kaplan G G. The global burden of IBD: from 2015 to 2025 [J]. Nature reviews Gastroenterology & hepatology, 2015, 12(12): 720-727.
[4] Jostins L, Ripke S, Weersma R K, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease [J]. nature, 2012, 491(7422): 119.
[5] Reis B S, Rogoz A, Costa-Pinto F A, et al. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity [J]. Nature immunology, 2013, 14(3): 271-280
Source: Singularity Network
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