JAMA: what are the successful experiences and unknown challenges of the regulatory microbiome in the treatment of diseases?

In a healthy human body, the number of microbial cells is about 10 times that of human cells A large number of studies have explored the relationship between microorganisms and diseases It is one of the problems that the research expects to solve that microbiome is a treatment to improve human health What are the initial successes and existing challenges in this regard? Three experts from the National Institutes of Health (NIH) recently reviewed their opinion papers published in the Journal of the American Medical Association (JAMA) Relevant research shows that normal human related microorganisms are expected to alleviate or even cure diseases In 2013, a single center trial was published in the New England Journal of medicine, in which 43 patients with recurrent infection of C difficile were randomly divided into groups After taking vancomycin orally, the donor feces were infused through duodenum, or only vancomycin was taken orally, or only vancomycin was enema Results: as the fecal microbiome transplantation was more effective, the cure rate was as high as 81%, and the trial was terminated in advance At that time, the remission rates of C difficile infection in the other two groups were only 31% and 23%, respectively Further studies have shown that fecal microbiome transplantation can be used to treat Clostridium difficile infection, but the mechanism behind the clinical effectiveness has not been fully explained For example, can donor strains be stably colonized in the gut? What are the requirements for the complex diversity of fecal microbial components? Considering the possibility of severe infection or the spread of multidrug-resistant bacteria related to fecal microbiome transplantation, more mechanism studies are needed to understand the response differences of different receptors and sufficient safe treatment measures Inflammatory bowel disease is also an area of disease that is being explored by fecal microbiome transplantation In a multicenter trial published in the Journal of the American Medical Association in 2019, 73 patients with mild to moderate ulcerative colitis were randomly assigned to the donor or autofaecal microbiome group This also suggests that we need to know more about the role of microbiome in the pathogenesis of inflammatory bowel disease, including stratified analysis of the disease according to the characteristics of microbiome It is pointed out that the number and percentage of different bacteria in the microbiome may be the key factor for the feasibility of the intervention measures For example, diseases with lower microbial complexity, whether inherent or antibiotic induced, may be more likely to recover For example, the vaginal microbiome is less complex than the gut One of the characteristics of bacterial vaginitis is that anaerobic bacteria are more than lactobacilli This imbalance is related to the recurrence of the disease and the failure of antibiotic treatment In a preliminary trial published in 2019, chronic bacterial vaginitis patients can get long-term remission through vaginal microbiome transplantation, of course, the mechanism of which needs to be further clarified The complexity of the neonatal gut microbiome is not as high In a randomized, double-blind, placebo-controlled trial covering more than 4500 newborns in rural India in 2017, microbial intervention of a single strain (Lactobacillus plantarum) effectively reduced the risk of neonatal sepsis and death by 40% A key success factor for this trial was the extensive prior study to select specific probiotic strains that could be colonized in the gut of infants in the same population Of course, this is also related to the local geographical location, nutrition, socio-economic conditions and general health problems, so the beneficial discovery of probiotics cannot be extended to all newborns In obesity, type 2 diabetes and other diseases, the role of diet and intestinal flora is also of interest to many researchers In 2015, cell published a study, which showed that the individual differences in postprandial blood glucose response were affected by many factors, including biochemical indicators, eating habits, physical activity and microbiome In a 2019 science study of nearly 350 children with severe acute malnutrition in Bangladesh, standard nutritional supplementation improved malnutrition but did not improve long-term developmental sequelae Further analysis showed that specific intestinal bacterial species were related to growth biomarkers, and then found a combination of proteomics in various dietary supplements, which was more similar to the characteristics of healthy children These studies support the potential of beneficial diet to regulate microbiome, and suggest that more studies are needed to elucidate the complexity of diet, microbiome and human interaction A new opinion paper published in science recently points out more evidence: many diseases that are usually "non infectious", such as obesity, diabetes, cardiovascular diseases, may also be spread among people through microorganisms In March 2019, MD Anderson Cancer Center, in collaboration with Parker cancer immunotherapy Institute, reported the first study on the relationship between diet, microbiome and immunotherapy effect They found that among melanoma patients, if they took probiotic supplements at the same time, they were 70% less likely to respond to immunotherapy This suggests that probiotics may interfere with immune response by affecting the balance of intestinal flora The treatment of Parkinson's disease is another typical example In Parkinson's disease, with the death of dopamine producing neurons, patients will suffer from limb shaking and other symptoms due to the lack of dopamine The levodopa taken by the patients is very easy to have a "decarboxylation" reaction in the intestinal tract in advance and become dopamine, so they can not penetrate the blood-brain barrier and make up for the lack of dopamine in the brain Therefore, for a long time, patients have to accept decarboxylase inhibitors at the same time of taking drugs to prevent levodopa from becoming dopamine in the gut But even so, the response of different patients to levodopa is still different A massive discovery published in Science in 2019 found the culprit: levodopa was digested by intestinal flora! There are a lot of tyrosine decarboxylases in Enterococcus and Lactobacillus Among them, the enzyme in E faecalis can effectively "eat up" levodopa Then the newly synthesized dopamine is another "delicacy" of intestinal flora In the study, they also screened a small molecule that they hoped would "plug" the mouth of intestinal flora Another study published in Science in 2017 revealed the potential impact of the vaginal microbiome on the effectiveness of tenofovir use in women to prevent HIV infection Compared with women with normal vaginal flora (mainly lactobacilli), the prophylactic effect of bacterial vaginitis is only 1 / 3 In vitro tests have shown that the bacteria causing the infection metabolize tenofovir in the vagina, thereby inactivating the drug These studies all exemplify the relationship between microbiome and drug efficacy A very complex symbiont has been formed between human beings and bacteria in vivo In clinical application and research, more investment is needed to understand the role of microbiome According to the JAMA article, several microbiome studies suggest some common clues for clinical application: 1 Composition complexity of microbiome The infection state dominated by a single pathogen, or the host site with relatively uncomplicated composition of microbiome 2 Analysis of bacterial strains In the treatment of microbial group transplantation, it is often necessary to repeat the transplantation from the donor, and the selection of strains may be the potential reason 3 Disease status is very important Before using microbiome interventions to treat diseases such as inflammation or chronic diseases, researchers need to better understand the role of microbiome in the occurrence, maintenance and progress of diseases Only by strengthening the basic mechanism research, can we carry out large-scale clinical trials of microbiome intervention, and ultimately achieve the goal of precision medicine.