It is well known that the intestinal microbiome (i.e. intestinal flora ) is the largest bacterial "reservoir" in the human body. It is closely related to human health and has been considered to cause obesity and metabolic syndrome. It is the "initiator" of , inflammatory diseases , autoimmune diseases , and depression and other mental diseases.
Previously, extensive research has confirmed that the composition of intestinal flora varies from person to person, and healthy people are very similar; unhealthy people show great differences in the composition of bacteria, and therefore drive disease develop. A popular explanation for this unhealthy consequence is the "leaky gut" hypothesis, which is that potentially damaging bacteria escape from the intestines and trigger chronic inflammatory responses in other organs, laying the foundation for a variety of diseases. The "seed" was planted. However, what drives this process remains a mystery.
Beijing time on July 14th, in a latest study published in "Nature" , a research team from Yale University provided new insights into this puzzle. They found that gut bacteria continue to adapt and evolve throughout the life of the host to acquire the ability to cross the gut barrier and persist in organs outside the gut, leading to chronic inflammation and associated pathology, ultimately becoming more Pathogenicity.
A large number of previous studies have confirmed that intestinal pathogenic bacteria with pathogenic potential play a causal role in a variety of inflammation-related diseases. However, these pathogenic bacteria thought to drive the disease are also detected in healthy people, and they colonize years, even decades, before overt disease develops. Genetics, gut microbiota composition, and environmental factors are known to influence host susceptibility to disease. What are the full range of factors that contribute to stochasticity in pathogen-driven inflammatory diseases?
In the new study, the researchers focused on Enterococcus gallinarum (E. gallinarum). E. gallinarum is present in more than 6% of the human intestinal flora. Previous studies have found that it migrates (translocates) through leaky gut to accelerate the development of lupus, autoimmune hepatitis , and primary sclerosing cholangitis mouse models, and has been reported in patients with autoimmune diseases were detected in liver biopsies.
In the experiment, the researchers first isolated E. gallinarum from the liver and feces of automutated disease-like mice and introduced it into germ-free mice lacking intestinal flora.
They found that over time, these bacteria diverged into two lineages that occupied different host-associated niches and showed differences in translocation : one behaved similarly to the ancestral strain; the other acquired genetic mutations in , allowing them to colonize the intestinal mucosal lining and persist in lymph nodes and liver after escaping the intestine.
The researchers also found that unlike traditional pathogenic bacteria that promote rapid immune clearance, these translocated bacteria remain semi-hidden in the organs, that is, they can avoid detection by the immune system for a short period of time; but over time , the presence of these bacteria ultimately triggers inflammatory pathologies such as autoimmune diseases . This phenomenon may at least partially explain why some people with potentially disease-causing germs never get sick, but why the risk of illness increases with age.
Researchers say the ability of gut bacteria to become more pathogenic is driven by a phenomenon known as " intrahost evolution," which means that every bacterium living in our gut Bacteria adapt and evolve throughout our lives.
These findings suggest that environmental factors that influence the rate or trajectory of evolution within the host will also have important consequences for the development of bacterially driven diseases . For example, people who eat healthy diets tend to develop diverse flora in their guts, resulting in many different strains of bacteria that must compete for space and resources to survive. This limits the size of a single bacterial strain, thereby reducing the chance of potentially unhealthy mutant strains emerging and escaping the gut.However, in a less diverse gut microbiota, more niches and may form within the gut, increasing the likelihood of the emergence of damaging mutant strains.
It is worth noting that a similar within-host evolution situation may also occur in humans. For example, Clostridium innocuum ( Clostridium innocuum) strains isolated from the intestinal mucosa and mesenteric adipose tissue of patients with Crohn's disease are genetically distinct. Enterococcus faecalis (Enterococcus faecalis) blood-borne isolates acquire resistance to immune clearance through mutations in the transcriptional regulator gntR; furthermore, infection with Staphylococcus aureus (Staphylococcus aureus) is more effective than intranasal colonization of strains The mutant strains accumulated adaptive mutations in the rsp or agr genes that regulate bacterial quorum sensing and toxin production. "These bacteria are essentially pre-adapted to live in organs other than the gut," said Noah Palm, corresponding author of the study and assistant professor in the Department of Immunobiology at Yale School of Medicine. "We think that because non-pathogenic strains are more likely to survive in an individual The evolutionary process starts anew in each new host," he added. Understanding the role of intra-host evolution in shaping gut bacterial behavior will help scientists develop new treatments. Interventions to limit or redirect this process, thereby preventing the development of various diseases associated with "leaky gut".
paper link:
https://dx.doi.org/10.1038/s41586-022-04949-x
