Posted on Lupus

Disturbed gut virome with potent interferonogenic property in lupus

The taxonomic profile and the interferon-α-stimulatory capacity of gut virus-like particles in patients with systemic lupus erythematosus


The taxonomic profile and the interferon-α-stimulatory capacity of gut virus-like particles in patients with systemic lupus erythematosus CREDIT ©Science China Press

This study is led by Prof. Xuan Zhang (Beijing Hospital) and Prof. Jun Wang (Chinese Academy of Sciences).

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease that can affect multiple tissues and organs. Common manifestations of SLE include fever, fatigue, malar rash, oral ulcer, alopecia, arthritis, and nephritis. Women of childbearing age are most likely to suffer from SLE. Currently, there is no cure for SLE and lacks an effective and safe treatment regimen because its underlying etiopathogenesis remains elusive.

The gut microbiota refers to the microbial community that distributes along the mucosal surface of gastrointestinal tract. The gut microbes participate in the development and function of host immune system. Disturbed gut microbiota has been associated with the pathogenesis of autoimmune diseases like SLE. However, given the technical limitations, previous studies mostly focused on the abundant gut bacteria, while the gut virome of SLE patients remains under-explored.

In this study, Chen et al. recruited 76 SLE patients and 75 matched healthy participants and collected their feces. The SLE patients are mostly treatment-naive and had not taken any corticosteroids, immunosuppressants, or antimalarials for the last 3 months. Human cells and bacterial cells were removed from the feces and free virus-like particles (VLPs) were enriched by ultracentrifugation. Then, viral nucleic acids were extracted and profiled by shotgun sequencing.

The community richness, evenness, and distribution of gut VLPs were not significantly different between SLE patients and healthy participants. However, the proportion of bacteriophages, the virus that infects bacteria instead of human cells, was significantly higher in SLE patients compared to healthy participants. As regards the differentially abundant viral genera and species, the most discriminating ones in SLE patients were Drulisvirus, Thermoanaerobacterium phage THSA-485A, Caeruleovirus, and Bacillus virus JBP901, whereas the predominant ones for HCs were crAss-like viruses and one of their species Cellulophaga phage phi14:2. Interestingly, the gut abundance of SLE-enriched Staphylococcus phage phiRS7 was positively associated with SLE disease activity index as well as the levels of inflammatory indicators, including C-reactive protein and erythrocyte sedimentation rate.

The intercorrelations between gut virome and bacteriome were also analyzed. Using the Procrustes analysis, a significant transkingdom association between the viral and bacterial community in the gut microbiota was found. In addition, some of the bacteriophages covary with bacterial genera that were not their hosts, suggesting a complicated interplay between the gut virome and bacteriome. Diagnostic models based on differentially abundant viruses and bacteria using a random forest algorithm were constructed. The combination of gut viral and bacterial markers displayed better performance (area under the curve = 0.948) than using data from one kingdom alone in distinguishing SLE patients from healthy participants.

Finally, VLPs were isolated from feces and added to the culture of human cells. VLPs from non-treated SLE patients promoted the transcription and production of interferon-α, a pivotal pathogenic factor in SLE, in both Caco cells (an epithelial cell line) and immune cells separated from human blood compared to VLPs from healthy people. Intriguingly, the interferon-stimulatory capacity diminished in VLPs from post-treated SLE patients.

In summary, this is the first VLPs profiling of the gut virome in SLE patients that revealed the viral signatures in the gut microbiota of SLE patients. They also shed novel insights into SLE pathogenesis by connecting the SLE-related gut virome with the promoted production of interferon-α.

Posted on Diet, Weight Loss

A ‘Keto-like’ diet may be linked to a higher risk of heart disease and cardiac events.

Popular weight-loss diet also associated with higher levels of LDL cholesterol
Popular weight-loss diet also associated with higher levels of LDL cholesterol


The ketogenic or “keto” diet, which involves consuming very low amounts of carbohydrates and high amounts of fats, has been gaining popularity. However, a new study presented at the American College of Cardiology’s Annual Scientific Session Together With the World Congress of Cardiology suggests that a “keto-like” diet may be associated with higher blood levels of “bad” cholesterol and a twofold heightened risk of cardiovascular events such as chest pain (angina), blocked arteries requiring stenting, heart attacks and strokes.

“Our study found that regular consumption of a self-reported diet low in carbohydrates and high in fat was associated with increased levels of LDL cholesterol— or “bad” cholesterol—and a higher risk of heart disease,” said Iulia Iatan, MD, PhD, attending physician-scientist at the Healthy Heart Program Prevention Clinic, St. Paul’s Hospital and University of British Columbia’s Centre for Heart Lung Innovation in Vancouver, Canada, and lead author of the study. “To our knowledge, our study is one of the first to examine the association between this type of dietary pattern and cardiovascular outcomes.”

Carbohydrates are the body’s first “go-to” source for fuel to provide energy for daily life. Low-carbohydrate, high-fat (LCHF) diets, like a keto diet, restrict consumption of carbohydrates (e.g., bread, pasta, rice and other grains, baked goods, potato products such as fries and chips, and high-carbohydrate fruits and vegetables). By depriving the body of carbohydrates, it is forced to start breaking down fat for energy instead. The breakdown of fat in the liver produces ketones, chemicals that the body uses as energy in the absence of carbohydrates—hence the name ketogenic, or “ketone producing.” Proponents of a ketogenic diet generally suggest limiting carbohydrates to 10% of total daily calories, protein to 20% to 30% and obtaining 60% to 80% of daily calories from fat.

Some previous studies have shown that an LCHF diet can lead to elevated levels of LDL cholesterol in some people. While elevated LDL cholesterol is a known risk factor for heart disease (caused by atherosclerosis, a buildup of cholesterol in the coronary arteries), the effects of an LCHF diet on risk for heart disease and stroke have not been well studied, Iatan said.  

For this study, Iatan and her colleagues defined an LCHF diet as consisting of no more than 25% of total daily energy or calories from carbohydrates and more than 45% of total daily calories from fat. They dubbed this an LCHF diet and “keto-like” because it is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet. They defined a “standard diet” as individuals not meeting these criteria and having more balanced eating habits.

The research team analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years. Upon enrollment in the biobank, 70,684 participants completed a one-time self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that their diet during the 24-hour reporting period met the study’s definition of an LCHF. These participants were matched by age and sex with 1,220 individuals who reported eating a standard diet. This resulted in 73% of the participants in each group being women and the group’s average age was 54 years. Those on an LCHF diet had an average body mass index (BMI) of 27.7; those on a standard diet, 26.7. A BMI of 25 to 30 falls within the overweight range.

Compared with participants on a standard diet, those on an LCHF diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (apoB), the protein component that sits on LDL and other atherogenic lipoprotein particles. Previous studies have shown that elevated apoB may be a better predictor than elevated LDL cholesterol for risk of cardiovascular disease, Iatan said. After an average of 11.8 years of follow-up—and after adjustment for other risk factors for heart disease, such as diabetes, high blood pressure, obesity and smoking—people on an LCHF diet had more than two-times higher risk of having several major cardiovascular events, such as blockages in the arteries that needed to be opened with stenting procedures, heart attack, stroke and peripheral arterial disease. In all, 9.8% of participants on an LCHF diet experienced a new cardiac event, compared with 4.3% of those on a standard diet, a doubling of risk for those on an LCHF diet.

“Among the participants on an LCHF diet, we found that those with the highest levels of LDL cholesterol were at the highest risk for a cardiovascular event,” Iatan said. “Our findings suggest that people who are considering going on an LCHF diet should be aware that doing so could lead to an increase in their levels of LDL cholesterol. Before starting this dietary pattern, they should consult a health care provider. While on the diet, it is recommended they have their cholesterol levels monitored and should try to address other risk factors for heart disease or stroke, such as diabetes, high blood pressure, physical inactivity and smoking.”

The study’s findings also suggest that not everyone responds to an LCHF diet in the same way.

“On average, cholesterol levels tend to rise on this diet, but some people’s cholesterol concentrations can stay the same or go down, depending on several underlying factors,” Iatan said. “There are inter-individual differences in how people respond to this dietary pattern that we don’t fully understand yet. One of our next steps will be to try to identify specific characteristics or genetic markers that can predict how someone will respond to this type of diet.”   

A limitation of the study is that participants provided dietary information at only one point in time, which should be considered when interpreting the study findings, Iatan said. Moreover, self-reports of food consumption can be inaccurate, though Iatan said this questionnaire has been extensively validated.    

Because the study was observational, it can only show an association between the diet and an increased risk for major cardiac events, not a causal relationship. However, Iatan said the findings merit further research in prospectively designed studies, especially when approximately 1 in 5 Americans report being on a low-carb, keto-like or full keto diet.

Posted on Pain Management, Rheumatoid arthritis

NB Folks with RA – Taking care of your teeth could help prevent chronic joint pain

research illustration


Proposed model for the role of periodontal inflammation in rheumatoid arthritis (RA). Periodontal inflammation is associated with a chemical change in supragingival bacteria caused by an enzyme released as part of an immune response mechanism known as NETosis. This chemical change ‘decorates’ bacterial antigens with a molecular tag. Periodontitis and inflammation can cause breaches of the mucous membrane lining inside the mouth, releasing the tagged bacterial antigens into the blood. As a result, antibodies that target these molecular tags are activated, and they bind or trap the tagged antigens, forming molecules known as immune complexes. Immune complexes and plasmablasts deposit in joint tissue, also known as synovium, and contribute to its inflammation. Repeated episodes of oral bacteremia cause a heightened autoimmune response, affecting join tissue. CREDIT Image courtesy of Dana Orange and Bill Robinson

 Regular visits to the dentist might help keep joint pain at bay, too.

When Rice University computational biologist Vicky Yao found traces of bacteria associated with periodontal disease in samples collected from rheumatoid arthritis patients, she was not sure what to make of it.

Her finding helped spark a series of experiments that confirmed a connection between arthritis flare-ups and periodontitis. The study is published in Science Translational Medicine.

Tracing this connection between the two conditions could help develop therapies for rheumatoid arthritis, an autoimmune inflammatory disease that attacks the lining of the joints and can cause heart-, lung- and eye-problems. The approach that led to the study could prove fruitful in other disease contexts, such as cancer.

“Data gathered in experiments from living organisms or cells or tissue grown in petri dishes is really important to confirm hypotheses, but, at the same time, this data perhaps holds more information than we are immediately able to derive from it,” Yao said.

Yao’s hunch was confirmed when she took a deeper look into data collected from rheumatoid arthritis patients by Dana Orange, an associate professor of clinical investigation and a rheumatologist, and Bob Darnell, a professor and attending physician at Rockefeller University and the Howard Hughes Medical Institute.

Yao was collaborating with Orange and others on a different project that tracked changes in gene expression during rheumatoid arthritis flare-ups.

“Orange, working with Darnell, collected data from arthritis patients at regular intervals while, at the same time, monitoring when the flares happened,” Yao said. “The idea was that perhaps looking at this data retroactively, some pattern would become visible giving clues as to what might cause the arthritis to flare up.

“While I was working on that project, I went to this talk that I thought was really cool because it pointed out that in the data that gets ignored or thrown out, you can actually find traces of microbes. You’re looking at a human sample but you get a snapshot of the microbes floating around. I was intrigued by this.”

When she looked into it, Yao found that the germs in the samples that changed consistently across patients prior to flares were largely ones associated with gum disease.

“I was curious about this tool that allowed you to detect microbes in human samples. It was sort of like, for free, you’re getting an extra perspective on the data,” Yao said. “At the time, I hadn’t worked much on microbial data at all. Since then, Dana leveraged all this expertise and got together with people studying these bacteria.

“One of the things that came up when we were discussing this was, how cool would it be if you could prescribe some kind of mouthwash to help prevent rheumatoid arthritis flares.”

Yao’s focus since joining Rice in 2019 has shifted to cancer research. The discovery of meaningful information in data that would usually be ignored or discarded inspired Yao to take a similar approach in looking at data from cancer patients.

“I got really interested in what else we can find mining for microbial signatures in human samples,” Yao said. “Now, we’re doing something similar in looking at cancer.

“The hope here is that if we find some interesting microbial or viral signatures that are associated with cancer, we can then identify productive experimental directions to pursue. For instance, if having a tumor creates this hotbed of specific microbes that we recognize, then we can maybe use that knowledge as a means to diagnose the cancer sooner or in a less invasive or costly way. Or, if you have microbes that have a very strong association with survival rates, that can help with prognosis. And if experiments confirm a causal link between a specific virus or bacteria and a type of cancer, then, of course, that could be useful for therapeutics.”

One of the better known examples of a pathogen associated with cancer is the human papillomavirus (HPV). Yao used this well-documented connection to verify her approach.

“When we did the same exercise looking at cervical cancer tumor samples, we consistently detected the virus,” she said. “It’s a nice proof-of-principle finding that shows that the presence of specific pathogens can be meaningful for certain types of cancer.

“I’m really interested in using computational approaches to bridge the gap between available experimental data and ways to interpret it. Computational analysis is a way to help interpret data and prioritize hypotheses for clinicians or experimental scientists to test.”

Posted on Diabetes

Incidence rates of diabetes continue to increase in children and young adults.

Lynne E. Wagenknecht, Dr.P.H.


Lynne E. Wagenknecht, Dr.P.H., professor and director of public health sciences at Wake Forest University School of Medicine CREDIT Wake Forest University School of Medicine

Study also shows that Asian or Pacific Islander, non-Hispanic Black and Hispanic children have higher incidence rates of both type 1 and type 2 diabetes.

New findings from researchers at Wake Forest University School of Medicine confirm that the rates of Type 1 and Type 2 diabetes continue to increase in children and young adults. Non-Hispanic Black and Hispanic children and young adults also had higher incidence rates of diabetes.

The study appears online in the current issue of The Lancet Diabetes & Endocrinology.

“Our research suggests a growing population of young adults with diabetes who are at risk of developing complications from the disease,” said Lynne E. Wagenknecht, Dr.P.H., professor and director of public health sciences at Wake Forest University School of Medicine and principal investigator. “It’s a troubling trend in young people whose health care needs will exceed those of their peers.”

The findings are from the final report from the SEARCH for Diabetes in Youth study, the largest surveillance effort of diabetes among youth under the age of 20 conducted in the U.S. to date. Wake Forest University School of Medicine served as the coordinating center of the multi-site study, which was launched in 2000 and supported by the Centers for Disease Control and Prevention and the National Institutes of Health.

The research team identified more than 18,000 children and young people from infants to 19 years of age with a physician diagnosis of Type 1 diabetes and more than 5,200 young people between the ages of 10 and 19 with Type 2 diabetes at five centers in the U.S. between 2002 and 2018. The annual incidence of Type 1 diabetes was 22.2 per 100,000 in 2017–18 and 17.9 per 100,000 for Type 2 diabetes.

“In our 17-year analysis, we found that the incidence of Type 1 diabetes increased by 2% per year, and the incidence of Type 2 diabetes increased by 5.3% per year,” Wagenknecht said.

The rates of increase were also higher among racial and ethnic groups than among non-Hispanic white children. Specifically, annual percentage increases for Type 1 diabetes and Type 2 diabetes were highest for Asian or Pacific Islander, Hispanic and non-Hispanic Black children and young people.

The peak age at diagnosis was 10 years for Type 1 diabetes and 16 years for Type 2 diabetes. Researchers also noted that the onset of Type 1 diabetes typically occurs in winter with a peak in January. Possible explanations for this seasonality include the fluctuation in daylight hours, lower levels of vitamin D and an increase in viral infections.

For Type 2 diabetes, the peak onset was August. Researchers attribute this to the increase in sports physicals and routine health screenings that occur more frequently at the beginning of the academic school year.

“These findings will help guide focused prevention efforts,” Wagenknecht said. “Now that we have a better understanding of risk factors, our next phase of research will be studying the underlying pathophysiology of youth-onset diabetes.”

Posted on autoimmune conditions, Multiple Sclerosis, Rheumatoid arthritis

Potential treatment of autoimmune diseases revealed in the new study like multiple sclerosis and rheumatoid arthritis.

Diagram showing the results of mice that were treated with PEP


Mice that have neuroinflammation caused by autoimmunity were treated with PEP. The results found that PEP-treated mice showed improved signs of recovery compared to mice not treated with PEP. CREDI Tsung-Yen Huang (OIST)

Scientists in Japan have revealed a chemical compound that could be used for the treatment of various autoimmune diseases like multiple sclerosis and rheumatoid arthritis. These diseases occur when the body’s immune response goes wiry. The immune system, which normally attacks pathogens and infections, instead attacks healthy cells and tissues. For the millions of people who suffer from autoimmune diseases worldwide, the result can be debilitating—rheumatoid arthritis causes excessive joint pain, while multiple sclerosis can disable one’s brain and spinal cord function.

“The key to the development of autoimmune diseases, and thus the way to inhibit this development, lies in our cells, but the underlying mechanism has always been unclear,” stated Prof. Hiroki Ishikawa, who leads the Immune Signal Unit at the Okinawa Institute of Science and Technology (OIST). “Now, our recent research has shed light on a compound that could suppress the development of these diseases.”

Prof. Ishikawa went on to explain that this research, published in Cell Reports, could lead to the development of treatments for autoimmune diseases.

The research focused on T helper 17 cells, or Th17 cells. Th17 cells are a type of T cell—a group of cells, which form major parts of the immune system. These cells, which exist in high numbers in our guts, evolved to help us fight invasive pathogens but, sometimes, they’re overactivated and mistake normal, healthy tissue as pathogens, resulting in autoimmunity. The generation of Th17 cells requires glycolysis, a metabolic process in which glucose is broken down and converted to energy to support the metabolic needs of cells. Glycolysis is essential for the growth of not only Th17 cells but also a variety of cells in our body.

“What’s interesting in that excessive glycolysis seems to suppress Th17 cell activity,” stated first author, Mr. Tsung-Yen Huang, a PhD candidate in the Immune Signal Unit. “So, we hypothesized that molecules produced during glycolysis may inhibit the cells.”

Enter phosphoenolpyruvate, or PEP for short. This chemical compound is a metabolite produced when glucose is converted to energy. Since it is part of such an important process, PEP is generated every day in our bodies. The researchers found that treatment with PEP can inhibit the maturation of TH17 cells, leading to resolution of inflammatory response.

Mr. Huang explained how this was, at first, a confusing result, as it went against all other research on the topic, but he decided to persevere and take a closer look at what could be occurring.

The research led them to a protein called JunB, which is essential for the maturation of Th17 cells. JunB promotes Th17 maturation by binding to a set of specific genes. The researchers found that PEP treatment inhibits the generation of Th17 cells by blocking JunB activity.

Armed with this knowledge, the researchers went on to treat mice that had neuroinflammation caused by autoimmunity with PEP. This disease is very similar to multiple sclerosis and these mice showed positive signs of recovery. The scientists have now filed a patent to continue with this research.

“Our results show the clinical potential of PEP,” explained Mr. Huang. “But first we need to increase its efficiency.”

In the past, researchers who were interested in developing a treatment for autoimmune diseases, often looked at inhibiting glycolysis and thus Th17 cells. But glycolysis is essential to various types of cells in the body and inhibiting it could have significant side-effects. PEP has the potential to be used as a treatment without resulting in such side-effects.