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The Young Mouse Microbiome Protects the Gut Barrier

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A new study has shown how the microbiome, the complex ecosystem of microbes that inhabit our digestive system, protects the health of the gut from the very moment we are born.

What is the microbiome?

The gut microbiome is a complex and ever-changing ecosystem populated by a myriad of archaea, eukarya, viruses, and bacteria. Four microbial phyla, Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria, make up 98% of the total population of the intestinal microbiome.

The microbiome is a complex ecosystem that regulates various aspects of gut function along with the immune system, the nutrient supply, and metabolism. It also helps to control the growth of pathogenic bacteria, protects from invasive microorganisms, and maintains the intestinal barrier.

The microbes within the microbiome play a key role in helping the gut barrier maintain its integrity and preventing microbial products from leaking through it to penetrate deeper into the body. The leakage of microbial products into the bloodstream due to a compromised gut barrier has been implicated in a number of health conditions, including ulcerative colitis.



However, this protective effect appears to decline with age as the composition of the microbiome changes. It is well known that these microbiome changes occur not only in mice but also in humans, and they may be an origin of inflammaging, the chronic low-grade inflammation typically present in older people.

In order to maintain the gut barrier in pristine condition, the body must constantly replenish the cells forming this barrier. Old cells are removed via a process known as cell shedding, which is normally a tightly regulated process; however, under certain conditions, it can become dysregulated, resulting in uncontrolled cell shedding and the onset of conditions like ulcerative colitis.

The microbiome appears to protect us from an early age

A team of researchers at the Quadram Institute and the University of East Anglia discovered that in young mice, the microbiome protects the cells lining the gut from inflammatory damage, which is apparently achieved through the microbes’ metabolites [1].

In a new study published in the FASEB Journal, and researchers attempted to induce harmful cell shedding in mice. They found that while this was possible to do in adult mice, they could not achieve it in newborn mice in the same way. These very young mice seemed to resist induced cell shedding, which kept their gut barrier protected and healthy.



The research team examined the young mice, and their analysis showed that the cellular signals that trigger cell shedding were present in these mice just as they were in the adult mice. However, in the young mice, there were also elevated levels of the cellular signals associated with activation of the immune system, which suggested that it was suppressing inflammation and other processes linked to cell shedding. Some of these cell signals which regulate the immune system are also known to be produced by certain bacteria in the microbiome.

The researchers found that the microbiome and the species of bacteria within it changed as the mice grew older. Along with the changes in bacteria came dramatic changes of the metabolites they produce. These changes coincided with changes in the diet as the mice moved from weaning to adult food.

To confirm that the microbiome was responsible for mediating the immune system to inhibit cell shedding and inflammation, they disrupted the microbiomes of the very young mice. They used antibiotics, which are known to harm the microbiome, and gave the young mice fecal transplants from adult mice. With their microbiomes replaced by the bacteria from adult mice, the young mice experienced harmful cell shedding and lost the protection given by their young microbiomes.

The researchers’ next step will be to identify the microbes and metabolites responsible for the protective effect and see how these findings might be translated to humans.

The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS‐induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect. Our findings further support the importance of the early life window for microbiota‐epithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation.

Conclusion



This study once again highlights the complex interaction between the microbiome, the cells of the gut membrane, the immune system, and the impact of diet on them. A deeper understanding of the microbiome could allow therapies to be developed that help us to optimize health, maintain gut membrane integrity, and prevent the diseases associated with its loss.

Literature

[1] Hughes, K. R., Schofield, Z., Dalby, M. J., Caim, S., Chalklen, L., Bernuzzi, F., … & Hall, L. J. (2019). The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding. bioRxiv, 789362.



About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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