Inflammaging refers to the chronic, low-grade inflammation that occurs with aging. Current research on aging suggests that inflammaging is the underlying cause for age-associated diseases, disorders, and conditions throughout the body. Along with this constant inflammation, studies have also found that intestinal permeability, or the degree to which the intestinal barrier is compromised, is greater in age-related diseases. This increased intestinal permeability and chronic inflammation have been associated with microbiome disruption and mortality in humans and other species.

How intestinal permeability affects other conditions observed in aging is still unknown, but researchers from Durham University in the UK show some semblance of a connection. Using fruit flies as a model organism, the researchers found that consistent activation of immune cells in the intestines triggers a domino effect that leads to hallmarks of aging.

Immune cells trigger inflammation by releasing chemical signals called TNF and IFN. When these signals are released in the intestines, the lining of the gut is disturbed and weakened, disrupting nutrient absorption, physical barriers, and microbiome maintenance and promoting more inflammation. In some studies, weakening of the intestinal lining occurred before inflammation, as shown in a 2020 study of Crohn’s disease patients from the University of Toronto.

This led researchers to believe that permeability caused the inflammation instead. While the relationship between intestinal inflammation and permeability is still debated, it has been confirmed that aging increases permeability. And with increased permeability comes disturbed microbiomes.

The relationship between inflammation and permeability was complex already, but the inclusion of the microbiome further complicates things. In some studies, when disturbed microbiomes or permeability are addressed separately, the other is impacted, showing a clear association. In animal studies at McMaster University, mice and flies that were completely sterile with no microbiomes whatsoever developed inflammation due to age, but they did not develop issues with permeability. These studies showed the complexity within an aging gut by suggesting that it’s an aging microbiome that drives inflammation and permeability.

Meanwhile, studies from the University of Rochester Medical Center and Anhui Agricultural University in China used fruit flies to show that the gut immune system disrupts the microbiome and that suppressing the immune system can prevent age-related microbiome changes. This raises more questions about how inflammation, permeability, and the microbiome relationship within the gut work, and how their interactions contribute to overall health during aging. This is the question the researchers from Durham tried to answer.

In their study, they used fruit flies with and without a microbiome, with an overactive immune response in their guts. The flies had a gene that was artificially activated by a drug to induce an immune response when eaten, which focused the immune response in the intestines. This activated gene led to inflammation through a cellular pathway that is similar to TNF and IFN in humans, making the fruit flies comparable to human physiology.

When this inflammation was triggered in the gut, it also triggered immune responses throughout the rest of the body. This domino effect shows the impact of gut health on overall health, and when one is impacted, so is the other. Previous studies confirm this, as the University of Tokyo showed that when the gut was impacted, wound healing throughout the body was disrupted. With this disruption of the gut comes permeability of the intestinal lining and its effect on mortality.

The research team found that the activation of immune cells in the gut led to the weakening of the intestinal lining and increased permeability. When they looked into the molecular methods for how this was done, they discovered that it was through the same inflammatory signals that TNF and IFN trigger. Upon the activation of this pathway, intestinal stem cells are triggered to multiply rapidly.

However, when a stem cell accelerates its multiplication, it cannot convert into the correct cell needed to support a role. In other words, the inflammation triggered by TNF and IFN made stem cells convert into the incorrect cells, preventing sealing of the intestinal lining and increasing permeability. Lack of proper healing of the intestinal lining led to no physical barriers and protection offered by the lining, resulting in the death of the experimental fruit flies. Interestingly enough, this mortality was seen even in flies that did not have a microbiome, contradicting previous studies that claimed the microbiome increased permeability.

For the flies that had microbiomes, immune activation led to an increase in the amount of microbes in their gut. The intestinal lining forms a barrier that prevents excessive microbial populations. As active immune cells activated inflammation, the lining was partially removed, allowing microbes to multiply unchecked. This is known as microbiome dysbiosis, the imbalance of microbial populations within the microbiome. The research team didn’t determine which specific microbial species benefited from the relaxed lining, but they were able to associate a loss of the lining with dysbiosis.

From this effort, the Durham team was able to uncover some semblance of a relationship between intestinal inflammation, permeability, and the microbiome. While some researchers believe that there is a specific order of events that need to occur, the Durham team shows that as long as one event occurs, then others will follow. In their work with fruit flies, the team showed that age-related inflammation increases intestinal permeability. With this increased permeability, the microbiome becomes unchained and enters a state of dysbiosis. However, they also show that even without a microbiome, increased intestinal permeability raises risks of mortality.

As research on the topic continues and is applied in medical practice, if an elderly patient has symptoms of inflammation, intestinal permeability, and microbiome dysbiosis, a physician cannot treat any single symptom. Rather, all symptoms must be addressed simultaneously, as if they were separate conditions. Despite research showing that they are related.

References

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