The probiotic bacteria engineered to treat diabetes

**Nick Petrachow** (0:24)
Welcome back to The Nature Podcast.

**Benjamin Thompson** (0:26)
This week, a probiotic to treat diabetes, and what scientists are hoping to learn from today's eclipse. I'm Benjamin Thompson.

**Nick Petrachow** (0:35)
And I'm Nick Petrachow. Researchers have developed a probiotic that can actively respond to high blood sugar levels, which they hope could one day be a new treatment for diabetes.

**Ninjie Guan** (0:56)
So we thought there was an opportunity to develop a treatment that behaves more like the body itself, that can respond to changes in glucose, rather than simply delivering a fixed amount of medicine.

**Nick Petrachow** (1:13)
This is Ninzi Guan, one of the team behind the new probiotic.
Now diabetes is a pretty common condition. The WHO estimates that around one in nine people live with the disease, the vast majority with type 2 diabetes, which is typically acquired late in life. In type 2 diabetes, the hormone insulin is either ineffective or produced at too low levels to control blood sugar. Over time, if blood sugar levels are left unchecked, this can lead to all sorts of complications, like kidney problems, blindness, and even amputation of limbs. So management is really important.
There are drugs that can manage type 2 diabetes. You've probably heard of GLP-1 agonists, for example, also known by their brand names like Azempig or Wigavy. These medications can ultimately help stimulate insulin production and keep blood sugar levels in check. But there can be an issue with this.

**Ninjie Guan** (2:14)
My major challenge is that blood glucose goes up and down throughout the day depending on meals, physical activity and many other factors. But most medicines are given at fixed dose and on a fixed schedule.
So there can be a mismatch between a treatment that is relatively fixed and a biological system that is highly dynamic.

**Nick Petrachow** (2:45)
Diabetes medications such as GLP-1 agonists can have side effects too, which can be exacerbated if they are given more than they are needed. So Ninzi and the team wanted to see if they could make something that just gave people medication when they needed it.
They decided to make a living drug. And I mean that in every sense of the word. Rather than giving a fixed medication, they wanted something that could respond to blood sugar levels. So they turned to probiotics, swallowable microorganisms.
The team genetically engineered a strain of the bacterium E coli that's commonly used in probiotic research, allowing it to sense glucose levels. When levels are high, the E coli produces and releases GLP-1 molecules.

**Ninjie Guan** (3:37)
A simple way to think about it is that the system has a molecular break. When glucose is low, that break keeps GLP-1 production switched off. When glucose rises, the bacterium generates a small signal. The signal releases the break, so the bacterium starts producing GLP-1.
As glucose comes back down, the signal decreases, and the break is applied again, reducing or switching off GLP-1 production.

**Nick Petrachow** (4:16)
The team nicknamed their glucose-responsive bacterium GIFT and tried it out in some animal models of diabetes. In this case, mice and macaques.
After giving the drug orally, they monitored the animal's responses.

**Ninjie Guan** (4:30)
The animal results were very encouraging. One of the first things we wanted to know was whether the bacteria could really tell the difference between a high glucose-diabetic state and a normal state.
In mice, we found that the glucose-responsive circuit was strongly activated under diabetic conditions.

**Nick Petrachow** (4:55)
And this response led to GLP-1 production.

**Ninjie Guan** (4:58)
The engineered GIFT cells significantly improved blood glucose control and glucose tolerance in diabetic mice. And when we then tested the treatment in monkeys, which is physiologically closer to humans, we were very pleased to see improved glucose control in these animals.

**Nick Petrachow** (5:22)
These results also showed that the orally taken probiotic was able to make its way through the stomach to the gut and still function.
Ninzi and the team also showed that GIFT seemed to help protect the animals against some of the complications associated with diabetes. The animals had less fat accumulation in the liver and lower levels of damage to the kidneys and colon, compared to the diabetic model animals that hadn't received GIFT. And that wasn't all.

**Ninjie Guan** (5:52)
In the diabetic mice, treatment with GIFT led to a reduction in both body weight and body fat. So although the main purpose is to improve glucose control, the results suggest that it may also provide an additional benefit in reducing excess weight and fat accumulation.

**Nick Petrachow** (6:14)
Such results may not be terribly surprising, given that GLP-1 agonists are often used for weight loss. But NINJI thinks that this could be helpful to people with diabetes, who often have excess weight, which can exacerbate their condition. And while these results may sound positive, NINJI cautions that GIFT is a long way away from human trials. She and the team want to understand more about how the bacteria behave, how long they remain active, for example, and therefore how often you need to take the probiotic. The team also need to ensure that the probiotic is perfectly safe, especially in the long term.