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/

Eye-scanning App Screens People for Alzheimer’s, ADHD

Researchers at the University of California San Diego (UC San Diego) have developed a smartphone app that could allow people to screen for Alzheimer’s disease, ADHD (Attention Deficit Hyperactivity Disorder) and other neurological diseases and disorders—by recording closeups of their eye. The app uses a near-infrared camera, which is built into newer smartphones for facial recognition, along with a regular selfie camera to track how a person’s pupil changes in size. These pupil measurements could be used to assess a person’s cognitive condition. The technology is described in a paper that will be presented at the ACM Computer Human Interaction Conference on Human Factors in Computing Systems (CHI 2022), which will take place from April 30 to May 5 in New Orleans as a hybrid-onsite event.

A smartphone user can image the eye using the RGB selfie camera and the front-facing near-infrared camera included for facial recognition. Measurements from this imaging could be used to assess the user’s cognitive condition

While there is still a lot of work to be done, I am excited about the potential for using this technology to bring neurological screening out of clinical lab settings and into homes,” said Colin Barry, an electrical and computer engineering Ph.D. student at UC San Diego and the first author of the paper, which received an Honorable Mention for Best Paper award. “We hope that this opens the door to novel explorations of using smartphones to detect and monitor potential health problems earlier on.

Pupil size can provide information about a person’s neurological functions, recent research has shown. For example, pupil size increases when a person performs a difficult cognitive task or hears an unexpected soundMeasuring the changes in pupil diameter is done by performing what’s called a pupil response test. The test could offer a simple and easy way to diagnose and monitor various neurological diseases and disorders. However, it currently requires specialized and costly equipment, making it impractical to perform outside the lab or clinic.

Engineers in the Digital Health Lab, led by UC San Diego electrical and computer engineering professor Edward Wang, collaborated with researchers at the UC San Diego Center for Mental Health Technology (MHTech Center) to develop a more affordable and accessible solution.

A scalable smartphone assessment tool that can be used for large-scale community screenings could facilitate the development of pupil response tests as minimally-invasive and inexpensive tests to aid in the detection and understanding of diseases like Alzheimer’s disease.  This could have a huge public health impact,” said Eric Granholm, a psychiatry professor at UC San Diego School of Medicine and director of the MHTech Center.

Source: https://ucsdnews.ucsd.edu/

Eyes Provide Peek at Alzheimer’s Disease Risk

Protein deposits in retina and brain appear to parallel possible neurodegeneration, an insight that might lead to easier, quicker detection. Amyloid plaques are protein deposits that collect between brain cells, hindering function and eventually leading to neuronal death. They are considered a hallmark of Alzheimer’s disease (AD), and the focus of multiple investigations designed to reduce or prevent their formation, including the nationwide A4 study.

But amyloid deposits may also occur in the retina of the eye, often in patients clinically diagnosed with AD, suggesting similar pathologies in both organs. In a small, cross-sectional study, a team of researchers, led by scientists at University of California San Diego School of Medicine, compared tests of retinal and brain amyloids in patients from the A4 study and another study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) assessing neurodegeneration risk in persons with low levels of amyloid.

Like the proverbial “windows to the soul,” the researchers observed that the presence of retinal spots in the eyes correlated with brain scans showing higher levels of cerebral amyloid. The finding suggests that non-invasive retinal imaging may be useful as a biomarker for detecting early-stage AD risk.

Amyloid deposits tagged by curcumin fluoresce in a retinal scan.

This was a small initial dataset from the screening visit. It involved eight patients,” said senior author Robert Rissman, PhD, professor of neurosciences at UC San Diego School of Medicine. “But these findings are encouraging because they suggest it may be possible to determine the onset, spread and morphology of AD — a preclinical diagnosis — using retinal imaging, rather than more difficult and costly brain scans. We look forward to seeing the results of additional timepoint retinal scans and the impact of solanezumab (a monoclonal antibody) on retinal imaging. Unfortunately we will need to wait to see and analyze these data when the A4 trial is completed.”

The findings published in the journal Alzheimer’s & Dementia.

https://ucsdnews.ucsd.edu/