Are probiotics really useful when taken in the stomach? Colonization antagonism is a big problem

You Wenjuan, Editorial Director of World Science, Shanghai Institute of Science of Science

“When in doubt, look at quantum mechanics; when it’s hard to find the mechanism, look at intestinal flora.” What the ridicule of cutting-edge technologies such as quantum mechanics and intestinal flora reflects is that the scientific principles have not been fully understood yet, but the products have already become popular in the market.

You must be familiar with this example: Research has found that certain bacteria are effective in regulating the intestines, and even found that they can affect brain health. Soon after, corresponding nutritional products or supplements became popular on the market.

This product seems scientific, but can it really achieve the same results as in the experimental stage? Are there any side effects? At the same time, when faced with exciting new products, do you often wonder: Is this a "tax on IQ"?

What is certain is that there is a rationale behind these products. After all, authoritative scientific studies have confirmed that some common diseases in modern life interact with intestinal flora[i]. For example, substances secreted by intestinal flora are transmitted to the brain through the vagus nerve, thereby affecting Parkinson's patients[ii]; small molecule metabolites produced by intestinal bacteria can enter the brain of mice and change brain cell function, thereby causing the animals' anxiety behavior to increase[iii]. These studies have gradually deconstructed the pathways and certain signal molecules for intestinal flora to communicate with the brain, further clarifying the impact of intestinal flora on the brain.

Precisely because of the endorsement of authoritative research, people often think: Since healthy intestinal flora is so important to the human body, does it mean that if I have healthy intestinal flora, I can have a healthy body. Then, if I supplement more beneficial flora or take bacteria that fight against pathogens, I will have a greater probability of being healthy?

The fact is, there is a long way to go before a product can achieve the results observed in the experimental stage in the human body. In other words, "eating" does not mean "supplementing".

The “colonization antagonism” that cannot be avoided

What's the problem with wanting to supplement beneficial bacteria by taking nutritional supplements? The biggest obstacle to doing so actually comes from the intestinal flora that coexists with you. They will resist the ingested flora in various ways, which is professionally called "colonization antagonism."

Why does this happen? Just think about it, a group of happy native bacteria that originally lived in the intestines and lived a happy life suddenly had to face a group of foreign bacteria under the banner of "probiotics" or "anti-disease bacteria" - they wanted to occupy territory and grab food and drink, but the space in the intestines was fixed and the nutrition was limited, and the intestinal flora was unwilling to be replaced. At the same time, the intestinal flora in your body has long adapted to the surrounding environment, that is, it has already seized the ecological niche advantage. At this time, it is a bit difficult for the bacteria that come in to settle down, and they must have a strong competitive advantage. This competitive advantage does not lie in whether these flora are beneficial to the human body, but in whether they themselves have a "foothold" and whether they are firmly attached. At the same time, they have to bear the pressure of joint exclusion formed by the original intestinal flora. Because of this, the flora you want to supplement often "passes through the intestines."

However, the antagonistic effect of intestinal flora is essentially to promote the stability of the body and reduce the risk of conditional pathogens growing in the body. This effect can be achieved through competition for nutrients and through the production of bacteriocins and toxic metabolites. Exploring the relevant mechanisms may help people find ways to break through colonization antagonism. For example, Bacteroidetes exist in the human intestine. They have a symbiotic relationship with humans and are an important component of the intestinal flora. On December 11, 2023, Gao Xiang's team at Shandong University published the mechanism of Bacteroidetes antagonism in the journal Nature Microbiology: Bacteroidetes in the human intestine will evolve a variety of specific bactericidal proteins to fight other Bacteroidetes. This provides clues for the antagonism against Bacteroidetes in the human intestine [iv]. On December 15, 2023, the Oxford University research team published an article in the journal Science, revealing that the higher the metabolic overlap between the intestinal flora and the "invading" microorganisms, the more likely they are to become the core of colonization antagonism. In other words, when intestinal bacteria are transplanted, colonization may be achieved by avoiding key core bacterial species.

Although we have said so much, we still know very little about how the intestinal flora excludes foreign flora. There are still many unknown mechanisms about the phenomenon of "colonization antagonism" waiting for people to conduct more in-depth exploration. However, the good news is that scientists have made good progress in intestinal bacterial transplantation therapy.

Big data analysis may be a shortcut to achieve precise intestinal bacterial transplantation

In order to promote the successful colonization of transplanted intestinal bacteria, researchers are actively trying another approach, that is, when the scientific mechanism is not yet clear enough, to guide intestinal bacteria transplantation therapy by exploring the laws behind those cases that successfully break through colonization antagonism.

To achieve this method, we need to know at least the intestinal flora of healthy people and patients with different diseases, and the performance of different patients in the intestinal flora of healthy people, so that we can treat the symptoms. This requires large-scale research on enough samples to find the rules.

Professor Qin Huanlong of the Tenth People's Hospital Affiliated to Tongji University led a team to collect intestinal flora data from nearly 10,000 healthy people and people with various diseases, and sequenced the intestinal flora of thousands of patients before and after "intestinal flora transplantation" treatment, and built a special database. At present, a classification model of intestinal flora for 18 diseases has been successfully established to provide guidance for the precise matching of healthy and diseased people, and the matching success rate for some diseases can reach 90%. This research result won the first prize of Shanghai Science and Technology Progress in 2021 [v].

Some research teams have also made progress in improving the matching success rate of intestinal microbiota transplantation through data modeling. Zhao Fangqing's team from the Beijing Institute of Life Sciences of the Chinese Academy of Sciences and Zhang Faming's team from the Second Affiliated Hospital of Nanjing Medical University collaborated to use intelligent analysis methods to build an artificial intelligence model (EDS) for donor-recipient matching in fecal microbiota transplantation, which can increase the transplantation efficiency from 57.1% to 93.3%. At the same time, the joint team also found that the greater the genetic distance between the donor and the patient's microbiota, the more suitable it is for transplantation. This is consistent with the findings of Gao Xiang's team at Shandong University, and provides a more effective way to successfully achieve fecal microbiota transplantation. The research results were published in Gut Microbes on July 20, 2022 [vi].

Dai Lei's research group at the Center for Synthetic Microbiome Research at the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, and the Shenzhen Institute of Synthetic Biology used a data-driven research method to successfully infer key species that resist colonization. Therefore, fecal microbiota transplantation has a clearer range of bacteria for selecting bacteria with a genetically distant distance to achieve colonization. The research findings were published in the journal Nature Communications on March 16, 2024 [vii].

In addition to the continuous pursuit of precision, standardization of "intestinal bacteria transplantation" treatment is also a very important research direction, that is, how to transform the active bacteria in the feces of healthy people into clinically usable products through modern industrial processes, including decolorization and deodorization.

Returning to the original question, regarding the phenomenon of cutting-edge scientific discoveries skipping clinical research and going straight to market application, Emeran Mayer, a neuroscientist at the University of California, Los Angeles, warned: "A lot of people are actually making a lot of money by 'taking advantage' of selling supplements."[viii]

At this point, I think you have some idea of ​​whether those attractive products are just a waste of money.

[i] https://doi.org/10.1146/annurev-med-042320-014032

[ii] Vagotomy and Parkinson disease: A Swedish register-basedmatched-cohort study. https://pubmed.ncbi.nlm.nih.gov/28446653/

[iii] A gut-derived metabolite alters brain activity and anxietybehaviour in mice https://www.nature.com/articles/s41586-022-04396-8

[iv] https://www.nature.com/articles/s41564-023-01541-5

[v] The new magic of turning waste into treasure: turning “poop” into “cure for disease”. World Science, Issue 3, 2024.

[vi] Theinterplay of gut microbiota between donors and recipients determines the efficacy of fecal microbiota transplantation DOI:10.1080/19490976.2022.2100197

[vii] Data-driven prediction of colonization outcomes for complex microbial communities https://www.nature.com/articles/s41467-024-46766-y

[viii]https://knowablemagazine.org/content/article/health-disease/2024/gut-brain-axis-parkinsons-disease-microbiome

This article is a work supported by the Science Popularization China Creation Cultivation Program

Author: You Wenjuan

Review: Tao Ning

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.