New research in Cell details the microbial origins of type 1 diabetes

About a decade ago, UO graduate student Jennifer Hampton Hill made a serendipitous discovery: a protein produced by gut bacteria that triggers insulin-producing cells to replicate
.
This protein is an important clue to
the biological basis of type 1 diabetes.
Type 1 diabetes is an autoimmune disease in which a patient's pancreas is unable to produce insulin
.

As a postdoc at the University of Utah, Hill has continued to study the protein
, known as BefA.
Karen Guillemin's lab at UO has also been working on BefA
.
Together with other colleagues, they uncovered new insights
into what BefA does and why bacteria produce it.

Guillemin said the findings have "important and far-reaching implications.
"
"If we understand how BefA works, it may give us a treatment
that stimulates β cell production.
" This could one day lead to the treatment of type 1 diabetes, which affects millions of people
worldwide.

The researchers published their findings
in the Oct.
13 issue of the journal Cell Metabolism.

The body needs insulin to regulate blood sugar, but insulin is produced
only by a specific type of cell in the pancreas called β cells.
During early childhood development, β cells have a short window of time during which the cells replicate and expand in number
.
In people with type 1 diabetes, the immune system attacks β cells, depleting their number and limiting insulin production
.

The stimulation of immune development by the microbiome helps to properly educate the immune system and prevent autoimmunity
.
Guillemin's team shows that the microbiome has an additional role: it stimulates the growth of β cell numbers early in development, buffering the depletion
of autoimmune attacks later in the development period.

Hill said the growth in β cell number "happens at the same time as the gut microbiome is
diversifying.
" "A characteristic of diabetes is that children with diabetes tend to have a lower
diversity of gut microbiota.
It's possible that they missed some of the bacteria
that make BefA.
”

In their recent paper, the researchers took a deeper look at
BefA.
They captured detailed images of the BefA structure to determine the part of
it that interacts with the cell membrane.
Then, through a series of experiments on zebrafish, mice, and cultured cells, the researchers outlined the function of
BefA.

They found that BefA can damage the membranes of a variety of cells, including bacterial and animal cells
.
It makes sense that
gut bacteria attack competing bacteria.
But unexpectedly, they also found that BefA's attack on the cell membranes of insulin-producing cells triggered the reproduction
of these cells.

This finding suggests that bacterial warfare in the gut can have collateral beneficial effects on the body, increasing the number
of cells that can make insulin throughout the lifespan.

The team also tested a modified mutant version of BefA so that it doesn't disturb cell membranes
.
This protein did not affect the production of β cells, further suggesting that membrane damage caused the role
of BefA.

"There are other examples in developmental biology where poking holes in cell membranes is critical
to stimulating development.
" But researchers don't yet know how this damage triggers cell
replication here.

They also don't know why BefA, which can alter the membranes of many types of cells, targets beta cells
so specifically.

"We think there is something special about β cells, they may be highly sensitive to
clues that cause membrane permeability.
" "They're the only cell type in the whole body that can secrete insulin — they're very important
.
"

Hill received the NOSTER & Science Microbiome Award
this year for his work on BefA.
This annual award is given to early-career scientists
who develop a new understanding of microbiome research that may affect human health.

"The microbiome plays an important role
in cultivating the immune system.
If you don't have this education, the immune system overreacts," Guillemin said
.
"We think there's another layer here — if you don't grow a pool of β cells to withstand future damage, you're at greater
risk of developing type 1 diabetes.
" A healthy, diverse microbiome plays a key role
in building a cell population.

In the future, Guillemin's team envisions possible therapeutic applications for
this discovery.
For example, actively strengthening the microbiome of high-risk infants so that they produce BEFA bacteria can prevent them from developing type 1 diabetes
later in life.