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Gut Bacteria Trigger Immune Defense Mechanism to Protect against Viral Infections


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Ground breaking stuff for anyone that follows gut biome research  

 

Harvard Medical School researchers have, for the first time, described in mice how bacteria residing in the gut can protect from viral infections. Their work pinpointed a group of gut microbes—and a particular species—that trigger immune cells to release virus-repelling type 1 interferons. The studies further identified the molecule—an outer membrane (OM) polysaccharide A (PSA)—that unlocks the immune-protective cascade.

The researchers say the molecule could become the basis for drugs that boost antiviral immunity in humans. “Given the critical role that interferons play in disease and health, our identification of a bacterial molecule that can induce interferon protective signaling points to a promising new approach to develop a therapeutic compound that could boost antiviral immunity to reduce the risk for viral infections,” said study senior author Dennis Kasper, PhD, professor of immunology in the Blavatnik Institute at Harvard Medical School.

Kasper and colleagues report on their studies in Cell, in a paper titled, “Commensal Microbiota Modulation of Natural Resistance to Virus Infection.”

The human body, like that of other mammals, is colonized by trillions of microbes, including bacteria, viruses, and fungi, which are collectively referred to as the commensal microbiota, the authors wrote. “Current estimates suggest that there are roughly as many bacterial cells as human cells in the body, the vast majority of which reside in the lower gastrointestinal (GI) tract, which is colonized by an estimated 1014 bacteria.” And although scientists know relatively little about the molecular mechanisms by which commensal microbes interact with the mammalian host, research does suggest that they play an important role in modulating key physiological systems in the body.

One mechanism by which microbes can modulate the host immune system is through regulating cytokine signaling, the team continued. Type 1 interferons (IFN-Is) are a family of structurally similar cytokines, which are involved in the body’s response to viral infections. “Indeed, IFN-Is play a critical role in the response to the majority of virus infections through induction of a restrictive anti-viral state in cells, induction of apoptosis in infected cells, and regulation of immune cell subsets crucial to the antiviral response,” the team noted.

Low-level interferon signaling that offers antiviral protection in the absence of active infection is present in all humans shortly after birth, but where and how this signaling occurs has remained unclear. The newly reported work offers up an explanation for this phenomenon, with the finding that this protective response arises from immune cells that reside in the walls of the colon. These dendritic cells, the work shows, release protective interferons when stimulated by the PSA molecule residing on the outer surface membrane of the Bacteroides fragilis gut bacterium.

In a series of experiments conducted in cells and in virus-infected mice, the researchers found that Bacteroides fragilis, which is present in the majority of human GI tracts, effectively initiates a signaling cascade that induces the immune cells in the colon to release interferon-ß (IFN-ß), an important immune chemical that confers antiviral protection both by inducing virus-infected cells to self-destruct, and by stimulating other classes of immune cells to attack the virus.

The studies indicated that the bacterial molecule stimulates the immune-signaling pathway initiated by one of the nine toll-like receptors (TLR) that are part of the innate immune system. Specifically, the experiments by Kasper’s team showed that B. fragilis unlocks the signaling pathway when its surface molecule communicates with immune cells of the colon through their TLR-4 TRIF receptors, to secrete virus-repelling IFN-ß. The pathway is effectively activated when proteins on the surface of the immune cells recognize certain molecular patterns on the surface of various infectious organisms, and marshal immune defenses against these invaders through one of the nine toll-like receptor pathways.

Because the bacterial cell surface that triggers the immune cascade is not unique to B. fragilis and is also present on multiple other gut bacteria of the same family, the researchers tested whether similar immune signaling could be triggered by other bacterial species carrying that molecule. Through a subset of experiments in a group of mice the team showed that membranes containing this molecule, which were found in multiple other species of Bacteroides bacteria, could successfully initiate similar signalling, a finding that suggest a broader immune-protective signaling common to a wide range of gut bacteria. “Our findings suggest that induction of IFN-ß through TLR4 signaling is not limited to B. fragilis but is a shared function of an entire class of commensal microbial molecules,” they suggested.

To determine whether B. fragilis could protect animals from infection, the researchers tested two groups of mice. One group was treated with antibiotics to deplete their gut microbiota and the other retained an intact gut microbiota. Both groups of mice were exposed to vesicular stomatitis virus (VSV), an organism that infects nearly all mammals, but which leads to largely asymptomatic infections in humans. Compared with mice that did not receive antibiotics and had intact gut microbiota, antibiotic-treated animals with depleted gut microbiota were more likely to develop active infections after exposure to VSV, and to have worse disease when they did get infected.

The results demonstrated the role of gut microbes in inducing protective IFN-ß signaling and in boosting natural resistance to viral infection. Interestingly, there were no differences among mice that lacked receptors for IFN-ß regardless of whether their gut microbiota was depleted. The observations confirmed that it was via IFN-ß signaling that the commensal microbiota exerted their protective effects.

Finally, to investigate whether the B. fragilissurface molecule that triggers interferon signaling in cells could also modulate how animals respond to viral infection, researchers gave animals with depleted microbiotas a purified form of the molecule in their drinking water. When the animals were a few days later exposed to VSV, those pretreated with the molecule had markedly milder infections and identical survival to mice with intact gut microbiota and intact immune defenses.

“We have described a novel mechanism of immunomodulation by the commensal microbiota through IFN-mediated regulation of the homeostatic IFN-I response,” the investigators wrote. “Furthermore, we identified the mechanism by which a specific species of commensal bacteria regulates this response, signaling of B. fragilis glycolipids through TLR4 to induce expression of IFN-ß by colon LP [lamina propria] DCs.”

The researchers say their findings demonstrated that supplementation with this commensal microbial molecule is sufficient to restore the protective effects of the whole microbiota in animals with depleted gut microbiota. Commenting on their results, the team noted, “These findings demonstrate that not only is commensal induction of IFN-ß necessary for protection against VSV, but treatment with a single IFN-ß-inducing commensal microbial molecule is sufficient to restore the protective effects of the whole microbiota in this model … Indeed, OM extracts from all of the Bacteroides sp. tested were able to induce IFN-ß. OMs comprise numerous bacterial molecules, all of which have the potential to interact with immune cells and influence their response,” They concluded, “Delivery of an IFN-ß-inducing microbial molecule thus represents a novel IFN-I-based therapeutic approach, which could enhance the IFN-I response while still being subjected to homeostatic regulatory mechanisms, reducing the potential for undesired side effects.”

 

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Always been a big believer in "gut health" and a strong immunity connection.  Remember our nutritionist at U of I talking about it back when I was playing in the early 90's.  

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1 minute ago, teamgreen02 said:

Has to be the natural stuff with the probiotics. The canned stuff is heated high enough to kill everything.

Ahhh...OK...thanks for the heads up!👍🏼

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15 minutes ago, Highmark said:

Always been a big believer in "gut health" and a strong immunity connection.  Remember our nutritionist at U of I talking about it back when I was playing in the early 90's.  

Indeed. Gut flora finally is getting its due. We have 200mg of bacteria in our gut. That equals out to more than a trillion organisms. Our current diets are literally killing off the bacteria. Artificial sweetners lead the pack. Along with antibiotics. 

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41 minutes ago, Jimmy Snacks said:

Best way to ensure proper gut health? Yogurt? Probiotic Supplements? 

Kimchi, kefir milk, quality yogurt, kraut, quality probiotics with no more than 4-5 strains. Lactobacillus acidophilus being probably the oldest known strain in humans. 

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10 minutes ago, spin_dry said:

Indeed. Gut flora finally is getting its due. We have 200mg of bacteria in our gut. That equals out to more than a trillion organisms. Our current diets are literally killing off the bacteria. Artificial sweetners lead the pack. Along with antibiotics. 

:thumbsup:   Couldn't agree more.   Want to feel good and stay healthy....limit or eliminate processed foods especially processed sugars. 

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