Engineering the Microbiome to Cure Disease

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/

Junk food linked to gut inflammation

Eating a Western diet impairs the immune system in the gut in ways that could increase risk of infection and inflammatory bowel disease, according to a study from researchers at Washington University School of Medicine in St. Louis and Cleveland Clinic.

The study, in mice and people, showed that a diet high in sugar and fat causes damage to Paneth cells, immune cells in the gut that help keep inflammation in check. When Paneth cells aren’t functioning properly, the gut immune system is excessively prone to inflammation, putting people at risk of inflammatory bowel disease and undermining effective control of disease-causing microbes. The findings, published in Cell Host & Microbe, open up new approaches to regulating gut immunity by restoring normal Paneth cell function.

A tiny, 3D model of the intestines formed from anti-inflammatory cells known as Paneth cells (green and red) and other intestinal cells (blue) is seen in the image above. Researchers at Washington University School of Medicine in St. Louis and Cleveland Clinic used such models, called organoids, to understand why a Western-style diet rich in fat and sugar damages Paneth cells and disrupts the gut immune system

Inflammatory bowel disease has historically been a problem primarily in Western countries such as the U.S., but it’s becoming more common globally as more and more people adopt Western lifestyles,” said lead author Ta-Chiang Liu, MD, PhD, an associate professor of pathology & immunology at Washington University. “Our research showed that long-term consumption of a Western-style diet high in fat and sugar impairs the function of immune cells in the gut in ways that could promote inflammatory bowel disease or increase the risk of intestinal infections.”

Paneth cell impairment is a key feature of inflammatory bowel disease. For example, people with Crohn’s disease, a kind of inflammatory bowel disease characterized by abdominal pain, diarrhea, anemia and fatigue, often have Paneth cells that have stopped working.

Source: https://medicine.wustl.edu/