Whether it is the old eight secret small burgers, or the classic lines of the black fly brother into internet hot words, or the disgusting people of each other, everyone seems to be very keen on the topic of.
Blah blah blah
Back to the point, throw away the bad taste, encourage everyone to eat dung, this thing is also in the minds of scientists for a long time (?) ）。
When advising others to be individuals, they often say that they should regard money as dung, but in the eyes of this group of scientists, dung is still a treasure. Basically all basic research on enterobacteria is indispensable to do fecal bacteria transplantation (FMT) for mice, that is, to feed mice to eat all kinds of rat feces or human feces (what a natural feces!). ）。 And these findings also show the value of feces, or more precisely, the value of enterobacteria.
Numerous studies have shown that enterobacteria are inseparable from obesity[1], cognitive behavior[2], aging[3], etc., and can even help immunotherapy [4]. By giving FMT to mice, it can effectively alleviate the adverse consequences of enterobacterial disorders.
So scientists wonder, can humans also come to an FMT, borrow intestinal bacteria for use, and give patients the fecal extract of healthy people and the fecal extract of fat people to eat lean people, so as to achieve miraculous curative effect? After all, if feces are used as a raw material for drugs, they are still in short supply.
Not long ago, the Journal of New England Medicine published data from a phase III clinical trial, ECOSPOR III, paving the way for the approval of the first human fecal extraction drug in human history.
The purpose of ECOSPOR III was to evaluate the clinical efficacy and safety of the stool extract oral pill SER-109 in the treatment of recurrent Clostridium difficile infection. The results showed that SER-109 treatment reduced the relative risk by 68% compared to placebo. Moreover, the flora carried in SER-109 drugs can also be effectively colonized in patients, and the safety is similar to that of the placebo group [5].
Screenshot of the first page of the paper
First of all, declare, do not ask if you can eat pure natural, even if you overcome multiple shocks such as smell, vision, taste, etc., the strange harmful bacteria on it are afraid that I and other mortal intestines will be difficult to withstand.
How to clean and hygienic feces, while also ensuring that the microbiota can thrive and thrive after changing the intestine, is also a long-term bottleneck and clinical limitation in the development of fecal extraction drugs [6-8].
A 2013 clinical study found that FMT was extremely effective in the treatment of recurrent Clostridium difficile infection. Since then, the clinical application of FMT has attracted widespread attention and discussion [6-8].
However, in 2019, there was an accident in a clinical trial, two immunocompromised participants developed a new infection after receiving FMT, and one of them died. This has forced a re-examination of the serious or life-threatening potential risk of infection in the clinical treatment of FMT, such as bloodstream infections and the spread of drug-resistant bacteria [6-8].
Coupled with the COVID-19 pandemic in recent years, the FDA issued a new warning in 2020 and updated the fecal donor screening requirements, and the clinical approval of fecal extraction drugs has been delayed [6-8].
However, this small matter did not fade the enthusiasm of scientists, especially the continuation of the clinical treatment of fecal extraction drugs in recurrent Clostridium difficile infection.
In our intestines, the colonization of toxic Clostridium difficile can lead to diarrhea, and patients are usually treated clinically with antibiotics vancomycin and fetamycin. However, vancomycin and feldamycin were unable to "kill the heart" and were unable to kill the spores of Clostridium difficile, resulting in a recurrence of Clostridium difficile infection [9].
So the researchers had a "two-pronged" countermeasure: kill these strains with antibiotics first, then airdrop rescue troops, take fecal extraction drugs to colonize the intestinal bacteria, repair intestinal homeostasis, inhibit the germination or replication of Clostridium difficile spores, and prevent recurrence.
This brings us to the SER-109. Let's see how SER-109 performs in this Phase III clinical trial.
ECOSPOR III included a total of 182 patients infected with Clostridium difficile, randomized in a 1:1 ratio into the SER-109 and placebo groups, who received SER-109 or placebo after receiving standard antibiotic (vancomycin or fendamycin) and followed up for up to 8 weeks after discontinuation.
Within 8 weeks of treatment, only 12% of people in the SER-109 group had relapse of Clostridium difficile infection, compared with 40% of people in the placebo group. SER-109 treatment reduced the relative risk of recurrence of Clostridium difficile infection by 68% (RR 0.32, 95% CI 0.18–0.58, P<0.001).
When analyzed further by age, the results showed that for patients younger than 65 years of age, SER-109 treatment reduced the relative risk of recurrence by 76% compared with placebo (RR 0.24, 95% CI 0.07 to 0.78). For patients aged 65 years and older, SER-109 treatment reduced the relative risk of recurrence by 64% (RR 0.36, 95% CI 0.18 to 0.72).
In addition, the researchers also considered whether the type of antibiotic used by patients in antibiotic therapy would have an impact on the efficacy of SER-109. The results of the analysis showed that SER-109 reduced the relative risk of recurrence by 59% or 91%, respectively, for patients treated with vancomycin or festamycin (RR 0.41, 95% CI 0.22-0.79 vs. RR 0.09, 95% CI 0.01-0.63).
A: risk of recurrence; B: ongoing clinical response; C: risk of recurrence under age stratification; D: risk of recurrence under different antibiotic therapy
In terms of safety, both groups of patients experienced a similar number of adverse events related to SER-109 or placebo (about 50%), and the most common were gastrointestinal disturbances, with mild or moderate, and no serious adverse events.
From the perspective of flora colonization and metabolite levels, the flora in SER-109 drugs grew well in the patient's intestine, and the abundance was still high at the 8th week after stopping the drug; in contrast, the flora that promoted intestinal inflammation decreased significantly. SER-109 treatment is able to more significantly increase bile acid levels compared to placebo therapy.
A: SER-109 drug ingredient colonization; B: bile acid level changes
Overall, the ECOSPOR III results demonstrated the clinical feasibility of the stool-derived oral drug SER-109 for the treatment of recurrent Clostridium difficile infection.
This phase III clinical trial not only brings new hope for the treatment of recurrent Clostridium difficile infection, but also an important step towards the official clinical application of fecal extraction drugs.
As mentioned at the beginning, the importance of enterobacteria has been deeply rooted in the hearts of the people in the past two years, especially the synergistic role of intestinal bacteria in cancer immunotherapy, and there have been more and more solid basic research results. Although fecal bacteria transplant therapy once became a new clinical artifact, in recent years it has fallen into the pending area due to problems such as donor screening. If fecal transplantation can be officially approved, it may also bring new solutions to cancer treatment.
Happily, Seres Therapeutics, the company that developed SER-109, said that it is expected to complete the application to the FDA for approval in the middle of this year, and I believe we will soon see the emergence of the "small manure bean" SER-109.
bibliography:
[1] Yoon H. S., Cho C. H., Yun M. S., et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice[J]. Nat Microbiol, 2021, 6(5): 563-573.
[2] Mossad, O., Nent, E., Woltemate, S. et al. Microbiota-dependent increase in δ-valerobetaine alters neuronal function and is responsible for age-related cognitive decline. Nat Aging 1, 1127–1136 (2021). https://doi.org/10.1038/s43587-021-00141-4
[3] Sato, Y., Atarashi, K., Plichta, D.R. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature (2021).
[4] L. F. Mager et al., Science 10.1126/science.abc3421 (2020).
[5]https://www.nejm.org/doi/10.1056/NEJMoa2106516
[6] Kate A. Markey, Marcel R.M. van den Brink, Jonathan U. Peled. Therapeutics Targeting the Gut Microbiome: Rigorous Pipelines for Drug Development. Cell Host & Microbe, 2020; 27 (2): 169 DOI: 10.1016/j.chom.2020.01.022
[7] Paul E. Carlson. Regulatory Considerations for Fecal Microbiota Transplantation Products. Cell Host & Microbe, 2020; 27 (2): 173 DOI: 10.1016/j.chom.2020.01.018
[8]https://www.science.org/content/article/pill-derived-human-feces-treats-recurrent-gut-infections
[9] Theriot CM, Young VB. Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol 2015;69:445-61.
This article is written by | Eddie Zhang