Bacterial warfare in the gut can have collateral beneficial effects

Nearly ten years ago, a graduate student at UO Jennifer Hampton Hill stumbled upon something fortunate: a peptide produced by gut bacteria that prompted the division of cells that make insulin. The protein was a crucial indicator of the biochemical underpinnings of Type 1 diabetes, an autoimmune condition where the pancreas is unable to produce insulin.

As a postdoctoral researcher at the University of Utah, Hill has continued to study this protein, known as BefA. Additionally, Karen Guillemin’s lab at UO has continued to research BefA. Together with other colleagues, they have now gained a new understanding of BefA’s functions and the causes of its production.

According to Guillemin, the findings have “important, profound implications. If we understand how BefA works, it could give us a way to stimulate beta cell production therapeutically.”

Treatment for Type 1 diabetes, which affects millions of people globally, may one day result from this discovery.

The study’s findings were published in Cell Metabolism on October 13th, 2022.

The body requires insulin to regulate blood sugar levels, but insulin is only produced by a group of pancreatic cells known as beta cells. And beta cells reproduce and enlarge their population over a small window of time throughout early childhood development. The immune system targets beta cells and depletes their population in persons with Type 1 diabetes, decreasing insulin production.

Immune development microbiome stimulation aids in the appropriate education of the immune system and the prevention of autoimmunity. Guillemin’s team’s findings point to a new role for the microbiome: It promotes beta cell proliferation early in development, protecting against autoimmune depletion later on.

Hill says that beta cell population growth “is happening at the same time that microbial communities are diversifying in the gut. A hallmark of diabetes is kids who develop it tend to have a less diverse gut microbiome. It’s possible they're missing some of the bacteria that make BefA.

Hill, Guillemin, and their colleagues researched deeper into BefA in their most recent study. They took precise images of BefA’s structure to pinpoint the parts that engage with cell membranes. The scientists subsequently sketched a picture of BefA’s function using zebrafish, mice, and cultured cells in a series of experiments.

Researchers demonstrated that BefA can damage the membranes of many different types of cells, both bacterial and animal. Gut bacteria attacking competing bacteria makes sense. However, scientists discovered that BefA’s attacks on the membranes of insulin-producing cells caused those cells to multiply.

The discovery shows that the body may benefit indirectly from bacterial warfare in the gut by having more cells that can produce insulin throughout life.

The group also examined a mutant form of BefA that had been altered to prohibit it from interfering with cell membranes. The fact that the protein’s production was unaffected by that variation further supports the notion that BefA’s actions are the result of membrane damage.

There are other examples in developmental biology where poking holes in membranes is critical in stimulating development.”

Jennifer Hampton Hill, University of Oregon

However, the precise mechanism by which the damage is inducing cell replication in this instance is still unknown.

Researchers do not really understand why BefA, which may modify the membranes of many different types of cells, particularly targets beta cells.

We think that there's something special about beta cells that they may be highly sensitized to respond to cues that cause membrane permeabilization. They're the only cell type in the whole body that can secrete insulin—they're highly important.”

Jennifer Hampton Hill, University of Oregon

This year, Hill received the NOSTER & Science Microbiome Prize for her work on BefA. The annual award is granted to an early career scientist who has made significant contributions to microbiome research that may have an impact on human health.

The microbiome plays a role in educating the immune system. If you don't have that education, the immune system can be hyper-reactive. We think there's also this other layer here—if you don't develop a pool of beta cells against future disruption, you're more at risk for Type 1 diabetes.”

Karen Guillemin, University of Oregon

And a healthy, diverse microbiome plays a significant role in building that cell population.

Guillemin’s group envisions potential therapeutic applications for the discovery. For instance, proactively supplementing high-risk infants’ microbiomes with BefA-producing bacteria could protect them from acquiring type 1 diabetes later in life.

Source:
Journal reference:

Hill, J. H., et al. (2022) BefA, a microbiota-secreted membrane disrupter, disseminates to the pancreas and increases β cell mass. Cell Metabolism. doi.org/10.1016/j.cmet.2022.09.001.

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