Researchers in the UAE have found that some bacteria in the gut may impact the severity of Covid-19 infections. Certain types of anti-inflammatory bacteria linked to fatty acids metabolism in the intestines strengthen the body’s immune response, indicating that the makeup of the gut microbiome may influence the severity of infection and susceptibility to the SARS-CoV-2 virus.��

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The human gut houses a complex community of microbes, a dynamic population of microorganisms that differs from one person to another and impacts the balance of the whole human body. Evidence suggests the human microbiome even modulates the systemic immune response: in some patients suffering from other respiratory illnesses, the gut microbiota affects the immunity and inflammation in the lungs. It’s possible that a similar link exists between Covid-19 and the body’s gut microbiome. A team of researchers explored the role of gut microbiome diversity and its potential as an intervention target in modifying Covid-19 outcomes.

Dr. Mohammad Al Bataineh, Assistant Professor of Molecular Biology and Genetics, Dr. Habiba Alsafar, Associate Professor of Molecular Biology and Genetics and Director of the Khalifa University Center for Biotechnology, and six other KU researchers collaborated with a team of researchers who make up the UAE Covid-19 Collaborative Partnership to investigate the microbiomes of patients presenting with Covid-19. Their results were published in

The gut microbiome exists in a symbiotic relationship with its host, facilitating digestion and aiding in the delivery of essential nutrients to the cells making up the gastrointestinal tract. It helps protect against pathogenic microbes and plays a role in preserving intestinal homeostasis by modulating local and systemic immune responses. It keeps the local immune system in a perpetual vigilant state and remains relatively stable throughout life.

Although most people with Covid-19 recover within weeks of infection, some experience symptoms long after testing negative. Studies show that up to 75 percent of patients hospitalized with Covid-19 described at least one symptom six months after discharge, including respiratory, gastrointestinal, and memory symptoms, as well as fatigue. Although the exact causes for this are unknown, there is increasing evidence that the gut is linked to the severity of infection and that changes to the microbiome persist after the disease passes.

“The role of the human gut microbiome in health and disease conditions is yet to be fully understood. The gastrointestinal symptoms have been linked to the dysbiosis of the intestinal microbiome, where the normal gut bacterial makeup is altered,” Dr. Al Bataineh said. “Invading viruses can alter our immune responses – responses that are usually regulated by the microbiota in the gut. The infections interrupt the normal programming, and create a microenvironment that helps allow these pathogens to proliferate. We think the Covid-19 virus works in this way, altering the regulatory functions of microorganisms in the GI tract. Patients with Covid-19 tend to have lower levels of the beneficial microbes. Whether this is an association or causation is yet to be established.”

“Alterations in the gut microbiome are quite common among people with infectious diseases,” Dr. Alsafar explained. “We weren’t surprised to see this association with Covid-19 too. A substantial portion of patients presented with gastrointestinal symptoms, and when we identified that Covid-19 patients shed viral RNA in their stool, this was another indication that the virus was getting into the gut.”

SARS-CoV-2, the virus causing Covid-19, enters the human body by binding to a protein called ACE2. ACE2 is present in all people, but the quantity of this protein can vary among individuals and in different tissues and cells throughout the body, including the lungs, small intestine and the nasal cavity.

“The most important connection between the gut microbiome and Covid-19 is the involvement of the ACE2 receptor,” Dr. Alsafar explained. “SARS-CoV-2 enters cells through ACE2 receptors, which regulate the gut microbiota, and when disturbed by infection, cause a dysregulation of the intestinal system.”

It is understandable, then, that higher ACE2 expression in the body is correlated with higher infectivity, suggesting that increased ACE2 levels may predispose individuals to Covid-19. In a healthy gut, bacteria called Bacteroidetes are known as ‘good’ bacteria and downregulate the expression of the ACE2 receptor; this has a protective role in Covid-19 infections as it minimizes the amount of ACE2 receptors on the cell surfaces, meaning there are fewer potential entry points for the SARS-CoV-2 virus.

Unfortunately, patients with Covid-19 are more likely to present with lower levels of these commensal bacteria and higher levels of what are known as ‘opportunistic pathogens’. Together, the imbalance results in the gastrointestinal symptoms prevalent in Covid-19 patients, and these perturbations persist even after patients recover.

The data indicates a direct correlation between the composition of the gut microbiome and Covid-19 infection severity. Meaning, the microbial ecosystem before and during infection can help predict severity and mediate the immune response. However, since the gut microbiota were only sampled after they were infected with the virus, the research team was unable to determine whether pre-existing gut dysbiosis contributed to the severe symptoms, or whether the Covid-19 infection itself was the cause of the gut dysbiosis.

“This is very similar to the chicken and the egg question: which came first?” Dr. Alsafar said.

In addition, we know that dietary changes happen when patients fall ill: when people feel tired, diets often shift towards higher energy food in the hope it will help tackle their symptoms. These dietary changes also come with a change in the direct components of the microbiome, so it’s also possible this contributes to the changes in the gut. However, the participants in this study shared similar lifestyle and dietary habits, including dietary fiber intake.

The research team found that various differences in the microbiome could explain susceptibility and infection severity. Gender has been found to significantly correlate with overall microbiome variation, which may partially explain why men are more likely to contract Covid-19. At the same time, gut microbiota changes with age, with the elderly more likely to have lower levels of protective ‘good’ bacteria. One of these bacteria is Lachnospiraceae, which plays an essential role in gut barrier function and immune tolerance, especially among local inflammation. This commensal bacteria may be protecting the younger population from infection.

Lachnospiraceae also produce butyrate, a fatty acid that can strengthen immune response.

“Fatty acids play various critical cellular functions and are implicated in several stages of viral replication,” Dr. Alsafar explained. “They are directly linked to coronavirus spread and multiplication, and we found lower levels of the good bacteria that produce them in patients with Covid-19.”

Further longitudinal studies would be beneficial to understanding the relationship between Covid-19 susceptibility and changes in the gut microbiome, but this study represents the first to investigate a Middle Eastern cohort. The results show a significant compositional and functional shift in the gut microbiota of Covid-19 patients, suggesting interventions that target the gut could be used to mediate Covid-19 infection.

Jade Sterling
Science Writer
22 February 2022

The post Can You Stomach It? The Link between Covid-19 and the Gut Microbiome appeared first on Khalifa University.

Khalifa University’s Dr. Peter Corridon has advanced tissue engineering with the development of bioengineered scaffolds made from ‘decellularized’ mouse, rat, pig, camel and sheep tissue segments, such as blood vessels, trachea, esophagi, and whole organs like the kidney and eye that may be used as replacement tissues and organs . His research is among the first to evaluate the integrity of bioartificial blood vessels and whole organs under human physiological conditions, examining how they function over time and how they can be extended to make any decellularized architecture less susceptible to degradation and more viable for long-term transplants.

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Taking organs from animals and stripping the cells from the blood vessels could be the new solution to treating medical problems, including retinopathy, amputations, and kidney failure.

After this cleaning process, all that remains is a web of collagen and protein called the extracellular matrix, which gives the blood vessel its structure. This is tissue engineering, and it forms the basis of research from Khalifa University focused on designing scaffolds for tissue and organ regrowth in patients with diseases that lead to organ failure.

Dr. Peter Corridon, Assistant Professor of Physiology and Immunology at Khalifa University, investigated the integrity of vascular networks in decellularized tissues to support the development of blood vessels for kidneys. The results of this study, published in Scientific Reports, wil aid in implementing lifesaving treatments for conditions including diabetes-induced kidney failure. Indeed, to receive a bioengineered blood vessel implant was a patient with late-stage kidney disease in 2013. Earlier this month, a US man became the first person in the world to get a heart transplant from a genetically-modified pig.

Diabetes is the leading cause of kidney disease, with about one-third of diabetic adults suffering. The kidneys function to filter wastes and water out of the blood, helping to control blood pressure and maintain a healthy balance of water, salts and minerals in the blood. Blood flows into the kidney through the renal artery, is filtered in the functional units of the kidney, called nephrons, by clusters of tiny blood vessels called glomeruli, and then flows out of the kidney through the renal vein. This occurs throughout the day, with kidneys filtering around 150 quarts of blood every day.

Over time, poorly controlled diabetes can cause damage to the blood vessels in the kidneys, eyes, legs, and feet leading to uncontrolled damage and high blood pressure. High blood pressure can cause further organ damage by increasing the pressure in the delicate capillary systems. Severe damage to these blood vessel clusters can lead to diabetic nephropathy, retinopathy and amputations.

“By the end of this year, it is expected that 30 percent of the adult population in the United Arab Emirates will be diabetic,” Dr. Corridon said. “Almost half of those with diabetes develop significant vascular complications, which can lead to chronic conditions and even end-stage organ failure. These are substantial public health problems, highlighting the need for safe, effective, and innovative ways to treat the underlying conditions of vascular dysfunction.”

For the kidney specifically, traditional methods of treating renal problems include dialysis and transplantation; while dialysis can replace lost filtration capacities, a kidney transplant is the only way to restore all kidney function. However, there is a severe global shortage of transplantable kidneys and other organs. This, coupled with the issue of organ rejection, accentuate the demand for alternative solutions.

“Recent findings suggest that one possible way of addressing this growing issue is to develop replacement blood vessels, which could be used to treat those needing surgical intervention within the UAE,” Dr. Corridon said.

Bioengineered scaffolds can be used to develop bioartificial blood vessels known as human acellular vessels. They are a scaffold for the body to incorporate and provide a platform for cell growth, tunable to each recipient. They also act immediately as blood vessels, allowing the flow of blood through the kidneys while the body’s own cells grow into the matrix.

However, there are circumstances that limit scaffold viability. Dr. Corridon investigated a simplified model to analyze conditions needed to prepare more durable scaffolds for long-term transplantation.

He is developing his scaffolds using decellularized large and small animals to achieve an accurate biomimetic vascular architecture and functionality.

Decellularization is the process of taking an existing natural organ, either from a human or a nonhuman animal donor, and sterilizing it to the extent that only the collage network base remains, forming a natural scaffold. The decellularized scaffold can then be repopulated with a patient’s own cells to produce a personalized tissue.

These porcine scaffolds were subjected to a continuous blood flow at normal human physiological rates through the arteries to examine any dynamic changes in flow through the vessels and to determine their structure.

“Few studies have evaluated the integrity and function of the decellularized vasculature in whole porcine kidneys under physiological conditions,” Dr. Corridon explained. “The majority of these studies have primarily focused on demonstrating the preservation of structure and patency after decellularization and implantation.”

Under normal conditions, the kidneys autoregulate blood flow to maintain blood pressure through the delicate smaller vessels in the glomeruli. Decellularized kidneys, and kidneys in vitro, however, are incapable of autoregulation – meaning, they would be damaged under higher flow rates.

In this study, rates of 500ml/minute and 650ml/minute were used to represent the amount of blood each kidney would receive during resting conditions. The decellularized kidneys suffered damage at these levels, presumably due to their inability to autoregulate, which suggests that the elastin and collagen fibers in the scaffold would be damaged. In comparison, native kidneys possessed ‘sufficient structural barriers’ that prevented comparable damage, even though they were affected by the continuous flow of unfiltered and unreplenished blood.

“What’s important is that the perfusion process, which is the process of bathing an organ or tissue with a fluid, damaged the internal structures of both native and decellularized organs,” Dr. Corridon said. “While a significant difference was observed between perfused and non-perfused native kidneys, no significant difference was detected between perfused native and decellularized organs when perfused at the same rate.”

These findings reveal that the decellularized organs Dr. Corridon developed behave similarly to the native organs in disease conditions.

Dr. Corridon’s study provides a means to investigate how these blood vessels function over time and can be extended to other platforms to identify ways to make any decellularized architecture less susceptible to degradation and more viable for long-term transplantation.

Decellularization technologies hold great promise for the bioartificial tissue and organ industry, and understanding the limitations of these scaffolds will provide insight into the biomechanical improvements needed to increase their quality and support their clinical utility.��

Jade Sterling
Science Writer
21 January 2022

The post Testing Bioartificial Organs for Diabetic Disease Treatments appeared first on Khalifa University.

Bioelectronics are anticipated to play a major role in the transition away from animal studies, offering a much needed technology to push forward the drug discovery paradigm.

An accidental discovery in 1928 marked a turning point in human history, when Dr. Alexander Fleming returned from a summer vacation to find his petri dishes of Staphylococcus aureus covered in mold.

Penicillin is famous as a serendipitous result, but for the first period of modern drug discovery, new drug discoveries primarily relied on luck and accidents. Nowadays, powerful techniques, including molecular modelling, automated high-throughput screening and recombinant DNA technology, allow us to develop potential drug candidates methodically and intentionally.

However, potential drug candidates must be tested under laboratory conditions “in vitro” before they can proceed to clinical trials in humans. In vitro is Latin for ‘within the glass’ and refers to work that is performed outside a living organism—such as in the petri dish on Fleming’s messy lab bench. In vitro methods are used to study bacterial, animal, or human cells in culture, providing a controlled environment for an experiment. The key challenge for cell-based in vitro models is to mimic, as accurately as possible, the state of the actual biological system being studied. Integrating electrical components offers an opportunity to noninvasively interface with these biological models for more accurate and quantifiable information.

Dr. Charalampos Pitsalidis, Assistant Professor of Physics at Khalifa University, reviews the advances in an emerging class of electronics made from organic electronic materials (conjugated polymers), for bridging the gap between the human body and the technology. The research team investigated the possibilities and challenges for conjugated polymers in clinical translation of in vitro systems involving biological models of varying complexity.

In this study, Dr. Pitsalidis and ��Dr. Anna-Maria Pappa, Assistant Professors of Physics and Biomedical Engineering at Khalifa University, respectively, collaborated with Prof. Owens’s team in Cambridge University and teams from University of Strathclyde and Universite de Lyon.

Their study was published in.

“In recent years, there has been a marked decline in the number of approved therapeutics, with attrition rates in drug discovery increasing at an alarming rate,” Dr. Pitsalidis said. “In addition, tighter safety regulations result in increasing development costs and decreasing profitability of new medicines, associated with the high costs of animal studies and their failure to predict adverse effects of promising drug candidates.”

Fortunately, there are two key areas that can be investigated to improve success rates: we can focus on discovering new biomarkers and more specific drug targets, or we can improve our modelling technologies that better portray biology within full organisms, or in vivo biology, and allow us to test thousands of potential drugs quickly and accurately. Dr. Pitsalidis research team focuses on the development of new technologies for mimicking and monitoring biological systems as accurately as possible using organic bioelectronics technologies as reviewed in this work.

“Cell-based in vitro models have been increasingly adopted for applications ranging from tissue engineering to drug discovery and toxicology,” Dr. Pitsalidis said. “Besides being ethically advantageous, they are faster and more cost-effective, and can be easily standardized and validated. Advances in 3D cell cultures and the advent of microfluidics have heralded a new era of in vitro models, but there are some issues with the authenticity and validity of these systems. Plus, we currently lack a standardized and adaptable technology for meaningfully converting biological signals to a readable output.” In this regard, incorporating biosensors for in situ sensing of metabolites or critical biomarkers in the biological systems, will result in more accurate and holistic in vitro systems, critical for clinical translation said Dr. Pappa.

Key to developing these new technologies is a fundamental understanding of the interface between electronic materials and biology. Organic electronics are devices containing carbon and are anticipated to play a key role for biointerfacing—bridging the gap between the biotic and the abiotic.

“The advent of microfluidics and the considerable advances in reliability and complexity of in vitro models promise to eventually significantly reduce or replace animal studies, currently the gold standard in drug discovery and toxicology testing,” Dr. Pitsalidis said. “Organic electronic materials, notably conjugated polymers, have demonstrated technological maturity in fields such as solar cells and light emitting diodes, and are the obvious route forward for bioelectronics due to their biomimetic nature.”

Recent endeavors have seen organic electronic materials used in biologically relevant ion sensing, ion pumps and transducers of neural activity. They more seamlessly integrate with complex biological systems and offer more effective signal transduction of biological events.

Conjugated polymers are mixed conductors. The electronics surrounding us in our daily lives use electrons as the dominant charge carrier; biological systems use ions. Conjugated polymers can use both, which makes them a logical choice for direct coupling with biological systems.

“Typically, interfacing has been thought of as two-sided: stimulation on one side and monitoring on the other,” Dr. Pitsalidis explained. “We introduced a third component, where the chemical or physical characteristics of the active layer of the device can alter the biological system being studied.”

Interfacing can be a powerful means of controlling biological systems when used carefully. However, direct contact with biological tissue poses specific complications, and the set of requirements that a conjugated polymer has to meet is demanding in order to noninvasively exchange electrochemical signals. The polymer and the tissue must not damage each other. Aside from their electronic properties allowing them to be used in bioelectronics, they must remain stable for many cycles of operation, be flexible enough for a wide range of applications, and avoid injurious effects to biological systems.

“Most conjugated polymers are inherently biocompatible because they are mainly made of chemical elements that match the organic composition of cells and tissue, such as carbon and hydrogen,” Dr. Pitsalidis said. “However, biocompatibility cannot be universally defined because they can elicit different biological responses depending on the type of cells and the local tissue environment. Additionally, they are often modified or mixed with additives, which could be harmful to the in vitro system.”

The research team believes three-dimensional conjugated polymer-based scaffolds have the potential to be integrated with microfluidics to meet all the requirements of in vitro drug discovery.

“Now is the time to push forward accurate and reliable in vitro models that truly represent the in vivo situation,” Dr. Pitsalidis concluded. “We expect that the next few years will see conjugated polymers meeting all the scalability, accuracy and reliability requirements to replace animal models in drug discovery and disease research.”

Jade Sterling
Science Writer
19 January 2022

The post Organic Bioelectronics for In Vitro Systems appeared first on Khalifa University.

Two patients with unique genetic mutations in a single gene sparked the investigation of 40 researchers into the effects of gene expression on diabetes��

The discovery and mapping of the complete human genome in 2003 introduced the possibility of individualized medicine to a person’s physical and genetic makeup. Increasing evidence is now demonstrating that a patient’s unique genetic profile can be used to detect a disease’s onset, prevent its progression, and optimize its treatment.

This has led to enhanced global efforts to implement precision (personalized) medicine and pharmacogenomics in clinical practice. One such area of clinical practice is the treatment of diabetes.

In contrast, the most common types of diabetes are caused by multiple genes or lifestyle factors. Most cases of monogenic diabetes are inherited.

Dr. Pierre Zalloua, Professor and Chair of the Department of Molecular Biology and Genetics, collaborated with researchers from France, Germany, Austria, the United States, and Singapore to determine the gene responsible for two cases of monogenic diabetes. Their results were published in.

“Diabetes affects over 350 million people worldwide, and the discovery and study of genes responsible provide important insights for understanding disease mechanisms,” Dr. Zalloua explained. “With better understanding, we can improve quality of life and develop cost-effective care for diabetes patients.”

Diabetes mellitus is a group of metabolic diseases, all of which are characterized by high blood glucose levels. If left untreated, diabetes can lead to severe complications including blindness, kidney and heart disease, stroke, loss of limbs, and reduced life expectancy. It is a major public health problem, affecting hundreds of millions of people worldwide and representing a substantial economic burden on society.��

There are two types of diabetes: Type 1 and Type 2 diabetes. Type 1 usually begins in childhood with individuals suffering from their body’s inability to produce enough insulin, while Type 2 is commonly associated with obesity and usually occurs during middle age. Both types tend to run in families and genetic factors contribute to the disease, with interactions between genetic and environmental factors being critical.��

Dr. Zalloua said. “Remarkably, many of these genes encode key proteins for pancreas development.”

To determine which genes play a part in the development of diabetes, the research team examined two different patients with diabetes: one, a young French boy with neonatal diabetes, and a second Turkish child with diabetes diagnosed at 14 months. They showed that the patients inherited mutated alleles of one particular gene, ONECUT1. Two mutated alleles led to a severe form of neonatal diabetes where the child developed a small pancreas and a missing gall bladder, while one mutated allele saw an increased risk of diabetes in the second patient. The researchers were able to determine that ONECUT1 and its expression is a major player in diabetes.

Dr. Zalloua was the person who originally identified additional cases from the region linked to this gene, including a case from a patient in Lebanon. Analysis of these patients revealed various different ONECUT1 mutations, all linked to a risk of diabetes.

ONECUT1 affects a variety of processes including glucose metabolism, an important factor in the disease mechanism of diabetes. Its expression also influences the development of the pancreas and the gallbladder. Previous studies of ONECUT1 have focused on the gene’s role in retinal development, but it is now clear that ONECUT1 acts to determine what type of cell a stem cell becomes. Some human stem cells are pluripotent, meaning they can become any kind of cell in the body, and genes including ONECUT1 are the deciders. Mutations in this gene can therefore disrupt a very complex process at various stages.

The pancreas plays an essential role in converting food to fuel in the body: it helps in digestion and in regulating blood sugar. Two of the main pancreatic hormones are insulin, which acts to lower blood sugar, and glucagon, which acts to raise blood sugar. A functioning healthy pancreas automatically produces the right amount of insulin; in people with diabetes, the pancreas either produces little or no insulin, or the cells do not respond to the insulin that is produced.

To further validate their findings, the researchers examined a cohort of over 2000 German people with presumed type 2 diabetes, and identified 13 incidences of ONECUT1 mutations. In another, larger and multi-ethnic, cohort of almost 20,000 people with type 2 diabetes, the researchers also found that people with variants of the ONECUT1 gene were more likely to develop type 2 diabetes. However, they noted that the risk varied with the specific variant.

Identifying the cause means we can pinpoint the best treatment, offering an opportunity to shift focus from broad population-based standards of care to tailored treatments targeted to an individual molecular profile.

“We found that ONECUT1 controls mechanisms regulating endocrine development, which is involved in a wide spectrum of diabetes types,” Dr. Zalloua said. “We highlighted the broad contribution of ONECUT1 to diabetes pathogenesis, marking an important step towards precision medicine for diabetes.”

Jade Sterling
Science Writer
18 January 2022

The post Khalifa University Researcher Contributes to the Finding of a Novel Gene Involved in Human Diabetes appeared first on Khalifa University.