Gastroduodenal disorder

Bioengineers developed a platform that enhances survival and function of probiotics engineered to diagnose inflammatory bowel disease in animals. The technology holds promise for minimally invasive disease monitoring and advanced smart therapeutics. Trust your gut? Your doctor likely will, too. Probiotics engineered to sense and report signs of bowel inflammation could deliver firsthand knowledge of your system's inner workings -- provided they are not killed or dispersed in the process. Working toward making this scenario a clinical reality, Rice University bioengineers developed a platform that allows engineered biosensor bacteria safe passage through the gastrointestinal (GI) tract in an animal model, according to a study published in Biomaterials. "Good" bacteria designed to produce a fluorescent protein in response to physiological signs of disease fared and performed well inside the rat gut, protected inside alginate particles. By combining synthetic biology with creative biomaterial design, the research groups of Rice faculty members Jeffrey Tabor and Omid Veiseh designed a platform that could eventually be deployed in a clinical setting not only to diagnose inflammatory bowel disease (IBD), but also to monitor disease progression, assess treatment response and help provide care tailored to individual patients' unique gut microbiome. "For our proof-of-concept study, we chose inflammatory bowel disease, an autoimmune disorder that causes painful and recurrent inflammation flares," said Elena Musteata, a graduate student in systems, synthetic and physical biology in the Tabor lab. "But gut health plays many important roles in the human body, affecting metabolism, immunity, brain function and other systems. As we discover more biomarkers for different diseases, we can use this platform to diagnose and monitor a lot of different health conditions." The platform could help replace what is often a prolonged and complex diagnostic process for IBD -- which involves invasive, time-consuming procedures like colonoscopies and biopsies and relies, in part, on subjective self-monitoring -- with a much simpler and faster procedure. "With our system, patients could theoretically receive a prescription for the capsules and simply drop off a stool sample after ingestion, eliminating the need for repeated colonoscopies or biopsies," said Samira Aghlara-Fotovat, a bioengineering graduate student in the Veiseh lab. "Monitoring disease progression over time or keeping track of how a patient is responding to a given therapy could be much more accessible using a platform like this." According to Musteata, a quicker diagnosis could lead to better patient outcomes: "Especially with IBD, it's very important to minimize the delay between symptom onset and treatment," she said. "Having a way to assess gut health within a short amount of time and then take action could really generate a significant advance in the clinical management of chronic inflammation and other gut-related disorders." Another reason the platform may lead to improved patient outcomes is the ability to tailor treatments to individual patients' physiology. "If, in the future, we encapsulate a diverse range of biosensor strains, we could get an idea about a specific person's inflammatory pro then use that information to develop a more personalized diagnosis and treatment," Aghlara-Fotovat said. While it's not new for bacteria to be genetically programmed to detect disease biomarkers in the GI tract, once inside the body, they face challenges surviving harsh conditions like low pH, destructive enzymes and bile salts. Moreover, free bacteria can disperse widely in the gut, making analysis more difficult and potentially less accurate. "Our study demonstrated that encapsulating biosensor bacteria in protective alginate particles enables their robust survival and diagnostic function in live animals," Musteata said. "We characterized the effect of encapsulation on the viability, population dynamics and performance of a thiosulfate-sensing bacterial strain previously developed in our lab." The engineered strain produces a fluorescent green protein in response to thiosulfate -- a compound associated with gut inflammation -- making it possible to assess colon inflammation by measuring bacterial fluorescence after passage through the animal GI tract. "We found that encapsulation offers several advantages for intestinal biosensing with engineered bacteria," Musteata said. "First, because capsules are macroscopic, they can be more easily identified and analyzed than free bacteria. Additionally, because bacteria are spatially concentrated within the capsules, their reporter gene expression is easier to visualize than in the same number of free bacteria. Finally, encapsulation can protect bacteria from environmental hazards. For example, we were able to improve the survival of probiotic E. coli under acidic conditions." While developing and optimizing the platform was a challenging process, the researchers stressed the necessity of ensuring its reproducibility as a prerequisite for eventual clinical use. "As we worked on developing our platform, we encapsulated bacteria countless times, optimizing each step of the process along the way. There were so many aspects that needed to be characterized well in order to make a clinically translatable product," Aghlara-Fotovat said. "It was really cool to see two exciting technologies come together and expand their existing capabilities," she added. Musteata said she values the experience of working "not only to design biosensor bacteria as potential diagnostics, but also to collaborate so closely on interdisciplinary projects that seek to translate these systems into medical applications." "Even 10 years ago, this idea of engineered probiotics acting as small diagnostic robots that could travel inside your body and detect your disease state was largely in the realm of science fiction. However, groups at Rice and numerous other institutions are now making real progress toward deploying this kind of technology," Musteata said. Tabor is a professor of bioengineering and biosciences. Veiseh is a Rice associate professor of bioengineering and Cancer Prevention and Research Institute of Texas scholar. The research was supported by the National Science Foundation (15533317, 1842494) and the National Institutes for Health (R01AI155586, 1RO1DK120459-01) and a Rice University seed grant.

A study of the genetic variation that makes mice more susceptible to bowel inflammation after a high-fat diet has identified candidate genes which may drive inflammatory bowel disease (IBD) in humans. A study of the genetic variation that makes mice more susceptible to bowel inflammation after a high-fat diet has identified candidate genes which may drive inflammatory bowel disease (IBD) in humans. The findings are published as a Reviewed Preprint in eLife. Described by the editors as a fundamental study, the work provides a framework for using systems genetics approaches to dissect the complex mechanisms of gut physiology. The authors show how it is possible to use genetically diverse but well-characterised mice to interrogate intestinal inflammation and pinpoint genes influenced by the environment - in this case, a high-fat diet - and identify potential treatment targets for IBD in mice and humans. The editors describe the strength of the analyses as compelling and add that, as a resource, it will be useful for linking genetic variations and diet to gut-related disorders. It is well established that a high-fat diet can increase the risk of IBD. However, the impact of diet varies between individual people, suggesting an interplay with genetic factors. More than 200 risk genes have been identified for IBD, but there is still no effective treatment, and it is therefore important to understand the gene-by-environment interactions underpinning the inflammation that eventually evolves into IBD. "Differences in the clinical presentation of IBD among patients, as well as diversity in diet and lifestyle, render human genetic studies challenging," explains lead author Xiaoxu Li, a Doctoral Research Assistant at the Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland. "Genetically diverse populations of mice allow us to mirror the differences in human populations, while controlling several environmental factors, such as temperature and diet, when exploring the genetic modulators of IBD in the laboratory." Li and colleagues used mouse genetic reference populations (GRPs) to map the genetic factors that are important in IBD induced by a high-fat diet. They measured the levels of gene expression in the colons of 52 mice fed with either a chow or a high-fat diet and identified a subset of mice that were more susceptible to high-fat-diet-induced intestinal inflammation. Moreover, they found that levels of a pro-inflammatory cytokine called interleukin-15 were increased in the mice more likely to develop IBD, while levels of the anti-inflammatory cytokine, Interleukin-10, were decreased. This indicates that changes in the levels of genes associated with IBD reflect the general inflammatory status of mice. After classifying different mouse strains based on their likelihood of developing IBD-like genetic signatures, the team explored this further using gene co-expression network analysis. This identified two distinct modules (clusters) of genes that are related to known genetic signatures of human IBD. Next, they looked at the function of these genes and how they are controlled. Both IBD-associated modules largely consisted of immune response-related genes, including those known to be involved in Crohn's disease, and the team identified the likely regulators of the expression of these genes. But the genetic drivers behind the different susceptibility in the mice were still elusive. To find the candidate genes that influence gut inflammation specifically following a high-fat diet, they performed QTL analysis to identify quantitative trait loci (QTL) - regions of genes that interact with the environment to impact the observable trait data. This revealed a QTL that is related to chronic intestinal inflammation in mice. To see whether genes under this QTL could play a role in human IBD, the team then cross-checked their findings with risk genes for IBD by conducting an analysis using genome-wide association study data from UK Biobank*. They identified two plausible gene candidates, called EPHA6 and MUC4. In addition, using publicly available genetic variation data for IBD, Crohn's disease and ulcerative colitis, they found evidence to suggest that increased expression of the MUC4 gene in part of the colon may increase the risk of IBD in humans. A limitation of this analysis is that there were no mechanistic investigations or studies that directly provide a causative link between the candidate genes and IBD. The results are primarily observational and correlative, but they provide a dataset that generates hypotheses that can be studied further. "Our results point to important potential roles of two gene candidates in gut chronic inflammation that may lead to inflammatory disorders," says senior author Johan Auwerx, a Professor at the Institute of Bioengineering, EPFL. "Our systems genetics approach using GRP mice where the genetic backgrounds are known and the environment can be controlled enables the prioritisation of candidate genes in a complex disease which, when combined with human genome-wide association studies from UK Biobank, are generalisable to human patients and may have clinical value."

Alzheimer’s disease (AD) is not totally understood. The abnormal accumulation of proteins in the brain, such as beta-amyloid and tau, is involved with the disease, as is neuroinflammation. But other factors are also associated with this disease, including gut disorders. For that and more research news, continue reading. A Link Between Gut Disorders and Alzheimer’s Disease People with certain disorders of the gut may be at greater risk of developing Alzheimer’s disease, and a study from Edith Cowan University confirmed the association. The latest research analyzed large genetic data sets from AD and several gut-disorder studies of approximately 400,000 people. Their analysis found that people with AD and gut disorders have genes in common. Although the study didn’t conclude that gut disorders cause AD or vice versa, they do support the concept of the so-called “gut-brain” axis, a two-way relationship between the brain’s cognitive and emotional centers and the functioning of the intestines. The research was published in the journal Communications Biology. In addition, they found that abnormal cholesterol levels were a risk for both AD and gut disorders. “Looking at the genetic and biological characteristics common to AD and these gut disorders suggests a strong role for lipids metabolism, the immune system, and cholesterol-lowering medications,” Emmanuel Adewuyi, Ph.D., research lead of the study, said. “Whilst further study is needed into the shared mechanisms between the conditions, there is evidence high cholesterol can transfer into the central nervous system, resulting in abnormal cholesterol metabolism in the brain. There is also evidence suggesting abnormal blood lipids may be caused or made worse by gut bacteria (H.pylori), all of which support the potential roles of abnormal lipids in AD and gut disorders. For example, elevated cholesterol in the brain has been linked to brain degeneration and subsequent cognitive impairment.” The research also supports the theory that some cholesterol-lowering drugs, such as statins might be beneficial in treating both AD and gut disorders. More research is needed. A New Approach to Treating Cystic Fibrosis Researchers at Cold Spring Harbor Laboratory discovered how antisense oligonucleotides (ASOs) could create a protein missing in cystic fibrosis (CF) patients. ASOs are molecules that can be leveraged to control cellular protein levels. CF is caused by any one of hundreds of mutations in the gene that encodes for a protein called CFTR. The research group found a new way to use ASOs to make more of a functional, although not perfect, version of CFTR. The imperfect CFTR protein is caused by a gene mutation, which results in cells receiving the wrong instructions for making the CFTR protein. The mistaken instructions are eliminated, and the protein isn’t made. But what the research did was trick the cells into using the imperfect instructions and making the slightly abnormal CFTR protein. In CF, they found that an imperfect CFTR protein is better than none. This approach improved lung cell function. A Better Understanding of How Melanoma Spreads in the Brain Investigators with Columbia University Irving Medical Center completed what is believed to be one of the most comprehensive studies of the cells inside melanoma brain metastases. It’s not well understood why melanoma, a kind of skin cancer, spreads to the brain and generally has lower response rates to many treatments. The researchers invented new techniques for analyzing single-cell genetics of frozen brain samples, which allowed them to analyze tissue from patients who had not been treated. They analyzed the genes expressed in more than 100,000 individual cells. They found that melanoma brain metastases are more chromosomally unstable than melanoma metastases in other body parts. This, in turn, triggers signaling pathways that increase the likelihood of metastases and the ability of the cancer cells to suppress the immune system. They believe these newfound pathways could be potential targets for new therapies. How Belly Fat Increases Risk of Metabolic Disease Researchers with King’s College London studied data from TwinsUK to learn more about how belly fat increases the risk of metabolic disease. They leveraged samples from 538 participants that combined genetic, gene function, diet, and health data. Their particular focus was epigenetic markers. These are like molecular switches that turn genes on or off based on different environmental factors. One was a gene where the identified epigenetic changes were known to be a potential mechanism where diet affects belly fat accumulation. Others were epigenetic markers that have effects on metabolic health. They were able to develop an epigenetic predictor of insulin resistance associated with their findings of elevated belly fat. After controlling for BMI, the SAT methylome showed a distinct epigenetic signature linked with visceral fat. Booster Shots Help Battle Omicron The Omicron subvariants of COVID-19 are particularly adept at evading immunity caused by previous infection and vaccines. However, a new study out of the University of Washington School of Medicine/UW Medicine evaluated a panel of vaccines available in the U.S. and globally and found that booster shots offset some of these variants’ immune evasion tactics. The research supported earlier evidence that a third vaccine dose expands existing memory B cells specific to the viral spike protein as well as stimulating new memory B cells. This causes the production of antibodies with enhanced potency against the Omicron subvariants. Their research also showed that the Omicron BA.5, which along with BA.4, is now the dominant strain globally, has an ability to bind with its host ACE2 receptor that is six times stronger than the ancestral SARS-CoV-2 (Wuhan) strain. However, they’re all slower at the next step, fusing with the membrane on the host cell. They evaluated vaccines produced by Moderna, Pfizer-BioNTech, Novavax, Janssen (J&J), AstraZeneca, Sinopharm and Sputnik V. The authors wrote, “The marked improvement in plasma neutralizing activity for subjects that received a booster dose over those that did not highlights the importance of vaccine boosters for eliciting potent neutralizing antibody responses against Omicron sublineages.”