Engineering the Microbiome to Cure Disease

Calendar August 8, 2022 | Posted by admin

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease. Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don’t involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems.

Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment.

The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly.

“The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. “Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.”

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell , Zarrinpar and colleagues at University of California San Diego School of Medicine report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.

Source: https://health.ucsd.edu/

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How To Reverse Aging in the Brain

Calendar February 1, 2021 | Posted by admin

The aging global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of aging. The risk of death from the virus roughly doubles for every nine years of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?

It turns out that a major hallmark of the aging process in many mammals is inflammation. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of atherosclerosis (the buildup of fat in arteries), diabetes, high blood pressure , frailty, cancer and cognitive decline.

Now a new study published in Nature reveals that microglia — a type of white blood cells found in the brain — are extremely vulnerable to changes in the levels of a major inflammatory molecule called prostaglandin E2 (PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes.

Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it, they were able to normalize cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of aging of the brain. Levels of PGE2 increase as mammals age for a variety of reasons — one of which is probably the increasing number of cells in different tissues entering a state termed cellular senescence. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules.

But the researchers also found that macrophages — another type of white blood cells related to microglia — from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their mitochondria — the nearest thing a cell has to batteries — to function. This meant that the entire pattern of energy generation and cellular behavior was disrupted.

Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?

The researchers took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behavior in an “object location test.” This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed.

It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders.

Source: https://www.theconversation.com/

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Nanotherapy Reduces Plaque Buildup

Calendar January 28, 2020 | Posted by admin

A drug-coated nanoparticle reduces plaque buildup in mouse arteries without causing harmful side effects, researchers have found.

Atherosclerosis, the accumulation of plaque inside artery walls, can lead to heart attacks and strokes. It’s the world’s No. 1 killer. Available therapies treat risk factors such as high blood pressure and high cholesterol but fail to address the accumulation of diseased cells and inflammation within artery walls.

“This is precision medicine,” said Nicholas Leeper, MD, professor of vascular surgery and cardiovascular medicine. “We used the nanotubes to deliver a payload like a Trojan horse.”

Leeper, who sees patients at Stanford Health Care’s vascular and endovascular care clinic, is a senior author of a paper about the research that was published Jan. 27 in Nature Nanotechnology. The other senior author is Bryan Smith, PhD, a former visiting associate professor at the School of Medicine. He is now an associate professor of biomedical engineering at Michigan State University.

Source: http://med.stanford.edu/

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How To Detect Blocked Arteries Effectively

Calendar December 11, 2019 | Posted by admin

Heart disease and stroke are the world’s two most deadly diseases, causing over 15 million deaths in 2016 according to the World Health Organization. A key underlying factor in both of these global health crises is the common condition, atherosclerosis, or the build-up of fatty deposits, inflammation and plaque on the walls of blood vessels. By the age of 40, around half of us will have this condition, many without symptoms.

A new nanoparticle innovation from researchers in USC Viterbi’s Department of Biomedical Engineering may allow doctors to pinpoint when plaque becomes dangerous by detecting unstable calcifications that can trigger heart attacks and strokes. The research ­­— from Ph.D. student Deborah Chin under the supervision of Eun Ji Chung, the Dr. Karl Jacob Jr. and Karl Jacob III Early-Career Chair, in collaboration with Gregory Magee, assistant professor of clinical surgery from Keck School of Medicine of USC — was recently published in the Royal Society of Chemistry’s Journal of Materials Chemistry B on 25 September 2019.

When atherosclerosis occurs in coronary arteries, blockages due to plaque or calcification-induced ruptures can lead to a clot, cutting blood flow to the heart, which is the cause of most heart attacks. When the condition occurs in the vessels leading to the brain, it can cause a stroke.

A MICROSCOPIC VIEW OF ATHEROSCLEROSIS IN A PULMONARY ARTERY

“An artery doesn’t need to be 80 percent blocked to be dangerous. An artery with 45% blockage by plaques could be more rupture-prone,” Chung said. “Just because it’s a big plaque doesn’t necessarily mean it’s an unstable plaque.”

Chung said that when small calcium deposits, called microcalcifications, form within arterial plaques, the plaque can become rupture prone. However, identifying whether blood vessel calcification is unstable and likely to rupture is particularly difficult using traditional CT and MRI scanning methods, or angiography, which has other risks.

“Angiography requires the use of catheters that are invasive and have inherent risks of tissue damage,” said Chin, the lead author. “CT scans on the other hand, involve ionizing radiation which can cause other detrimental effects to tissue.”

Source: https://viterbischool.usc.edu/

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