Tag Archives: Obesity

Microbiology

FLASH Capsules: First-Ever Ingestible Electroceutical to Control Appetite by Hormone Modulation

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Inspired by the water-wicking skin of the Australian thorny devil lizard, FLASH capsules can connect directly to stomach tissue to modulate hunger-triggering hormones.

A team of researchers at NYU Abu Dhabi (NYUAD), led by Professor Khalil Ramadi, Director of the Laboratory for Advanced Neuroengineering and Translational Medicine, have developed a first-of-its-kind ingestible electroceutical device for the neuromodulation of the gut-brain axis, the signaling pathway between the gastrointestinal tract and central nervous system. The ingestible capsule is a non-invasive and precise method that could be used to modulate hunger levels and treat metabolic and neurologic diseases. This was developed in collaboration with Professor Giovanni Traverso of MIT, who is a joint senior author of the study and James McRae, a graduate student at MIT, who is first co-author of the paper published in the journal Science Robotics.

The FLASH system utilizes electrodes on its surface to deliver electrical stimulation to stomach mucosal tissue. The gut-brain axis regulates several physiological functions, including feeding and emotional behavior. The existing pharmaceutical and surgical methods to modulate the axis, including implanting electrodes through surgery, are imprecise, invasive, and have been associated with significant recovery periods and associated risks. Inspired by the water-wicking skin of Moloch horridus, the Australian thorny devil lizard, FLASH features a fluid-wicking capsule coating with grooved patterns and a hydrophilic (water-compatible) surface, enabling them to bypass the gastric fluid in the stomach and achieve direct electrode-tissue contact.

Gastric electrical stimulation (GES) directly induces the release of the hormone ghrelin, which stimulates hunger, from the gastric mucosa through endoscopic stimulation. Oral ingestion of the FLASH capsule was shown to modulate levels of the ghrelin hormone significantly and repeatedly. In the paper titled Bioinspired, fluid-wicking, ingestible electroceutical capsules for hunger-regulating hormone modulation published on April 26, the researchers report the process of developing the FLASH capsules, which are swallowed, deliver stimulation to the stomach, and then excreted safely. The capsules are powered by ingestible batteries, which were shown to deliver stimulation for 20 minutes, and then be excreted within two weeks of ingestion in large animals.

Here the authors describe the development and application of a new ingestible electroceutical capable of supporting the stimulation of ghrelin release. Credit: Giancarlo Traverso (GT Reel Productions)

Current hormone medications have poor bioavailability when taken orally. This is why medications such as insulin need to be injected. FLASH can be taken orally to specifically target gastric neurohormonal circuits and modulate hormone levels in the blood. It is anticipated that this device could be used for a range of applications to treat metabolic, feeding, gastrointestinal, and neuropsychiatric disorders non-invasively, and with minimal off-target effects.

For more on this breakthrough device:

Reference: “Bioinspired, fluid-wicking, ingestible electroceutical capsules for hunger-regulating hormone modulation” by Khalil B. Ramadi, James C. McRae, George Selsing, Arnold Su, Rafael Fernandes, Maela Hickling, Brandon Rios, Sahab Babaee, Seokkee Min, Declan Gwynne, Neil Zixun Jia, Aleyah Aragon, Keiko Ishida, Johannes Kuosmanen, Josh Jenkins, Alison Hayward, Ken Kamrin and Giovanni Traverso, 26 April 2023, Science Robotics.
DOI: 10.1126/scirobotics.ade9676

NYU Abu Dhabi

Microbiology

Shrinking Immunity: Obesity’s Role in Rapid COVID-19 Vaccine Protection Decline

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The protection offered by COVID-19 vaccination declines more rapidly in people with severe obesity than in those with normal weight, scientists have found. The study suggests that people with obesity are likely to need more frequent booster doses to maintain their immunity.

Researchers at the Universities of Cambridge and Edinburgh have found that COVID-19 vaccine protection declines more rapidly in people with severe obesity compared to those with normal weight. The study, published in Nature Medicine, indicates that obese individuals may require more frequent booster doses to maintain immunity. While previous studies have suggested that antibody levels are lower in vaccinated people with obesity, this study is the first to show that the ability of antibodies to neutralize the virus declines faster in this group. The findings have significant implications for vaccine prioritization policies worldwide.

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalization, and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear.

Today’s study, published in the journal Nature Medicine, shows that the ability of antibodies to neutralize the virus declines faster in vaccinated people who have obesity. The findings have important implications for vaccine prioritization policies around the world.

During the pandemic, people with obesity were more likely to be hospitalized, require ventilators, and to die from COVID-19. In this study, the researchers set out to investigate how far two of the most extensively used vaccines protect people with obesity compared to those with a normal weight, over time.

A team from the University of Edinburgh, led by Prof Sir Aziz Sheikh, looked at real-time data tracking the health of 3.5 million people in the Scottish population as part of the EAVE II study. They looked at hospitalization and mortality from COVID-19 in adults who received two doses of COVID-19 vaccine (either Pfizer-BioNTech BNT162b2 mRNA or AstraZeneca ChAdOx1).

They found that people with severe obesity (a BMI greater than 40 kg/m2) had a 76% higher risk of severe COVID-19 outcomes, compared to those with a normal BMI. A modest increase in risk was also seen in people with obesity (30-39.9kg/m2), which affects a quarter of the UK population, and those who were underweight. ‘Break-through infections’ after the second vaccine dose also led to hospitalization and death sooner (from 10 weeks) among people with severe obesity, and among people with obesity (after 15 weeks), than among individuals with normal weight (after 20 weeks).

Prof Sir Aziz Sheikh said: “Our findings demonstrate that protection gained through COVID-19 vaccination drops off faster for people with severe obesity than those with a normal body mass index. Using large-scale data assets such as the EAVE II Platform in Scotland have enabled us to generate important and timely insights that enable improvements to the delivery of COVID-19 vaccine schedules in a post-pandemic UK.”

The University of Cambridge team – jointly led by Dr. James Thaventhiran, from the MRC Toxicology Unit and Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science – studied people with severe obesity attending Addenbrooke’s Hospital in Cambridge, and compared the number and function of immune cells in their blood to those of people of normal weight.

They studied people six months after their second vaccine dose and then looked at the response to a third “booster” vaccine dose over time. The Cambridge researchers found that six months after a second vaccine dose, people with severe obesity had similar levels of antibodies to the COVID-19 virus as those with a normal weight.

But the ability of those antibodies to work efficiently to fight against the virus (known as ‘neutralization capacity’) was reduced in people with obesity. 55% of individuals with severe obesity were found to have unquantifiable or undetectable ‘neutralizing capacity’ compared to 12% of people with normal BMI.

“This study further emphasizes that obesity alters the vaccine response and also impacts on the risk of infection,” said Dr. Agatha van der Klaauw from the Wellcome-MRC Institute of Metabolic Science and first author of the paper. “We urgently need to understand how to restore immune function and minimize these health risks.”

The researchers found that antibodies produced by people with severe obesity were less effective at neutralizing the SARS-CoV-2 virus, potentially because the antibodies were not able to bind to the virus with the same strength.

When given a third (booster) dose of a COVID-19 vaccine, the ability of the antibodies to neutralize the virus was restored in both the normal weight and severely obese groups. But the researchers found that immunity again declined more rapidly in people with severe obesity, putting them at greater risk of infection with time.

Dr. James Thaventhiran, a Group Leader from the MRC Toxicology Unit in Cambridge and co-lead author of the SCORPIO study said: “It is promising to see that booster vaccines restore the effectiveness of antibodies for people with severe obesity, but it is concerning that their levels decrease more quickly, after just 15 weeks. This shows that the vaccines work as well in people with obesity, but the protection doesn’t last as long.”

Prof Sadaf Farooqi from the Wellcome-MRC Institute of Metabolic Science and co-lead author of the SCORPIO study said: “More frequent booster doses are likely to be needed to maintain protection against COVID-19 in people with obesity. Because of the high prevalence of obesity across the globe, this poses a major challenge for health services.”

Reference: “Accelerated waning of the humoral response to COVID-19 vaccines in obesity” by A.A. van der Klaauw et al., 11 May 2023, Nature Medicine.
DOI: 10.1038/s41591-023-02343-2

University of Cambridge

Microbiology

Diet has a much stronger impact on intestinal microbiota than defensins

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Reviewed by Emily Henderson, B.Sc.May 3 2023

Researchers at Umeå University, Sweden, have found that among the many factors that shape the intestinal microbiota composition, diet has a much stronger impact than defensins, which are intestinal defence molecules produced by the body. Instead, they identified a possible role for these molecules in preventing increased blood glucose levels after consumption of high-caloric “Western-style diet”.

While the effect of defensins in shaping the adult microbiota composition is rather minor when compared to diet, defensins still have a very important role in protecting us against microbial infections; and our research highlights their protective role against the metabolic complications that can arise after the intake of a high-fat and high-sugar Western-style diet.”

Fabiola Puértolas Balint, PhD Student at the Department of Molecular Biology at Umeå University

She is working in Björn Schröder’s research group, which is also affiliated to Umeå Centre of Microbial Research, UCMR, and The Laboratory for Molecular Infection Medicine Sweden, MIMS, at Umeå University.

The gut microbiota refers to the community of trillions of microorganisms that live inside everyone’s gut. Over the past decades, the abundance of specific bacteria in this community has been extensively studied due to its connection to many diseases, including inflammatory bowel diseases, obesity and diabetes, and even psychological disorders. The microbial community is seeded during birth, after which several internal and external factors help shaping the community to its final composition. These factors include, among others, diet (especially fibre), genetics, medication, exercise, and defence molecules, the so-called antimicrobial peptides.

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Antimicrobial peptides can be regarded as the body´s own naturally produced antibiotic molecules. In particular, the largest group of antimicrobial peptides – the defensins – is produced by all body surfaces, including the skin, the lungs and the gastrointestinal tract. Defensins are considered the immune system´s first line of defence against infections but at the same time they have also been thought to be essential in shaping the microbiota composition in the small intestine. However, it was so far unclear how big their effect was as compared to diet, which is known to have a major impact.

To investigate this, the researchers from Björn Schröder lab used normal healthy mice and compared their microbiota composition in the small intestine to mice that could not produce functional defensins in the gut, and then both mouse groups were fed either a healthy diet or a low-fibre Western-style diet.
“When we analysed the microbiota composition inside the gut and at the gut wall of two different regions in the small intestine, we were surprised – and slightly disappointed – that defensins had only a very minor effect on shaping the overall microbiota composition,” says Björn Schröder.
However, the intestinal defensins still had some effect directly at the gut wall, where the defensins are produced and secreted. Here, a few distinct bacteria seemed to be affected by the presence of defensins, among them Dubosiella and Bifidobacteria, likely due to selective antimicrobial activity of the defensins.

“To our surprise, we also found that the combination of eating a Western-style diet and lacking functional defensins led to increased fasting blood glucose values, which indicated that defensins may help to protect against metabolic disorders when eating an unhealthy diet,” says Björn Schröder.
The results suggest that strategies that aim to positively modulate the microbiota composition should rather focus on diet, as modulation of the composition via increased production of own host defense molecules, such as defensins, may have only a small impact on the overall composition. However, it is possible that especially early in life, when the microbiota community is not fully matured yet, defensins may have a stronger effect on the microbial composition. Still, increasing the production of defensins may be a valuable option to prevent the development of metabolic disorders.

The results have been published in the scientific journal Microbiology Spectrum.

Source:

Umeå University

Journal reference:

Puértolas-Balint, F., & Schroeder, B. O. (2023). Intestinal α-Defensins Play a Minor Role in Modulating the Small Intestinal Microbiota Composition as Compared to Diet. Microbiology Spectrum. doi.org/10.1128/spectrum.00567-23.

Microbiology

MIT’s Ingestible “Electroceutical” Capsule Controls Appetite by Hormone Modulation

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The device, which uses electricity to boost hormone production in the stomach, could help to ease nausea and counteract appetite loss.

Hormones released by the stomach, such as ghrelin, play a key role in stimulating appetite. These hormones are produced by endocrine cells that are part of the enteric nervous system, which controls hunger, nausea, and feelings of fullness.

MIT engineers have now shown that they can stimulate these endocrine cells to produce ghrelin, using an ingestible capsule that delivers an electrical current to the cells. This approach could prove useful for treating diseases that involve nausea or loss of appetite, such as cachexia (loss of body mass that can occur in patients with cancer or other chronic diseases).

In tests in animals, the researchers showed that this “electroceutical” capsule could significantly boost ghrelin production in the stomach. They believe this approach could also be adapted to deliver electrical stimulation to other parts of the GI tract.

“This study helps establish electrical stimulation by ingestible electroceuticals as a mode of triggering hormone release via the GI tract,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study. “We show one example of how we’re able to engage with the stomach mucosa and release hormones, and we anticipate that this could be used in other sites in the GI tract that we haven’t explored here.”

Khalil Ramadi SM ’16, PhD ’19, a graduate of the Department of Mechanical Engineering and the Harvard-MIT Program in Health Sciences and Technology who is now an assistant professor of bioengineering at the New York University (NYU) Tandon School of Engineering and the director of the Laboratory for Advanced Neuroengineering and Translational Medicine at NYU Abu Dhabi, and James McRae, an MIT graduate student, are the lead authors of the paper, which was published on April 26 in the journal Science Robotics.

The enteric nervous system controls all aspects of digestion, including the movement of food through the GI tract. Some patients with gastroparesis, a disorder of the stomach nerves that leads to very slow movement of food, have shown symptomatic improvement after electrical stimulation generated by a pacemaker-like device that can be surgically implanted in the stomach.

Doctors had theorized that the electrical stimulation would provoke the stomach into contracting, which would help push food along. However, it was later found that while the treatment does help patients feel better, it affected motility to a lesser degree. The MIT team hypothesized that the electrical stimulation of the stomach might be leading to the release of ghrelin, which is known to promote hunger and reduce feelings of nausea.

To test that hypothesis, the researchers used an electrical probe to deliver electrical stimulation in the stomachs of animals. They found that after 20 minutes of stimulation, ghrelin levels in the bloodstream were considerably elevated. They also found that electrical stimulation did not lead to any significant inflammation or other adverse effects.

Once they established that electrical stimulation was provoking ghrelin release, the researchers set out to see if they could achieve the same thing using a device that could be swallowed and temporarily reside in the stomach. One of the main challenges in designing such a device is ensuring that the electrodes on the capsule can contact the stomach tissue, which are coated with fluid.

To create a drier surface that electrodes can interact with, the researchers gave their capsule a grooved surface that wicks fluid away from the electrodes. The surface they designed is inspired by the skin of the Australian thorny devil lizard, which uses ridged scales to collect water. When the lizard touches water with any part of its skin, water is transported by capillary action along the channels to the lizard’s mouth.

“We were inspired by that to incorporate surface textures and patterns onto the outside of this capsule,” McRae says. “That surface can manage the fluid that could potentially prevent the electrodes from touching the tissue in the stomach, so it can reliably deliver electrical stimulation.”

The capsule surface consists of grooves with a hydrophilic coating. These grooves function as channels that draw fluid away from the stomach tissue. Inside the device are battery-powered electronics that produce an electric current that flows across electrodes on the surface of the capsule. In the prototype used in this study, the current runs constantly, but future versions could be designed so that the current can be wirelessly turned on and off, according to the researchers.

The researchers tested their capsule by administering it into the stomachs of large animals, and they found that the capsule produced a substantial spike in ghrelin levels in the bloodstream.

“As far as we know, this is the first example of using electrical stimuli through an ingestible device to increase endogenous levels of hormones in the body, like ghrelin. And so, it has this effect of utilizing the body’s own systems rather than introducing external agents,” Ramadi says.

The researchers found that in order for this stimulation to work, the vagus nerve, which controls digestion, must be intact. They theorize that the electrical pulses transmit to the brain via the vagus nerve, which then stimulates endocrine cells in the stomach to produce ghrelin.

Traverso’s lab now plans to explore using this approach in other parts of the GI tract, and the researchers hope to test the device in human patients within the next three years. If developed for use in human patients, this type of treatment could potentially replace or complement some of the existing drugs used to prevent nausea and stimulate appetite in people with cachexia or anorexia, the researchers say.

“It’s a relatively simple device, so we believe it’s something that we can get into humans on a relatively quick time scale,” Traverso says.

For more on this breakthrough device, see Ingestible Electroceutical Tames Hunger Hormones.

Reference: “Bioinspired, fluid-wicking, ingestible electroceutical capsules for hunger-regulating hormone modulation” by Khalil B. Ramadi, James C. McRae, George Selsing, Arnold Su, Rafael Fernandes, Maela Hickling, Brandon Rios, Sahab Babaee, Seokkee Min, Declan Gwynne, Neil Zixun Jia, Aleyah Aragon, Keiko Ishida, Johannes Kuosmanen, Josh Jenkins, Alison Hayward, Ken Kamrin and Giovanni Traverso, 26 April 2023, Science Robotics.
DOI: 10.1126/scirobotics.ade9676

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institute for Diabetes and Digestive and Kidney Diseases, the Division of Engineering at New York University Abu Dhabi, a National Science Foundation graduate research fellowship, Novo Nordisk, and the Department of Mechanical Engineering at MIT.

Anne Trafton, Massachusetts Institute of Technology

Microbiology

Study offers novel insights into reducing adverse effects of antibiotics on the gut microbiome

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Reviewed by Emily Henderson, B.Sc.Apr 17 2023

Antibiotics help to fight bacterial infections, but they can also harm the helpful microbes living in the gut, which can have long-lasting health consequences.

Now new research being presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark (15-18 April) has identified several protective drugs that may lessen the collateral damage caused by antibiotics without compromising their effectiveness against harmful bacteria.

The unique study by Dr Lisa Maier and Dr Camille V. Goemans from the European Molecular Biology Laboratory, Heidelberg, Germany and colleagues, which analyzed the effects of 144 different antibiotics on the abundance of the most common gut bacteria, offers novel insights into reducing the adverse effects of antibiotic treatment on the gut microbiome.

The trillions of microorganisms in the human gut profoundly impact health by aiding digestion, providing nutrients and metabolites, and working with the immune system to fend off harmful bacteria and viruses.

Antibiotics can damage these microbial communities, resulting in an imbalance that can lead to recurrent gastrointestinal problems caused by Clostridioides difficile infections as well as long-term health problems such as obesity, allergies, asthma and other immunological or inflammatory diseases.

Despite this well-known collateral damage, which antibiotics affect which types of bacterial species, and whether these negative side effects be mitigated has not been studied systematically because of technical challenges.

To find out more, researchers systematically analyzed the growth and survival of 27 different bacterial species commonly found in the gut following treatment with 144 different antibiotics. They also assessed the minimal inhibitory concentration (MIC) – the minimal concentration of an antibiotic required to stop bacteria from growing – for over 800 of these antibiotic-bacteria combinations.

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The results revealed that the majority of gut bacteria had slightly higher MICs than disease-causing bacteria, suggesting that at commonly used antibiotic concentrations, most of the tested gut bacteria would not be affected.

However, two widely used antibiotic classes – tetracyclines and macrolides – not only stopped healthy bacteria growing at much lower concentrations than those required to stop the growth of disease-causing bacteria, but they also killed more than half of the gut bacterial species they tested, potentially altering the gut microbiome composition for a long time.

As drugs interact differently across different bacterial species, the researchers investigated whether a second drug could be used to protect the gut microbes. They combined the antibiotics erythromycin (a macrolide) and doxycycline (a tetracycline) with a set of 1,197 pharmaceuticals to identify suitable drugs that would protect two abundant gut bacterial species (Bacteriodes vulgatus and Bacteriodes uniformis) from the antibiotics.

The researchers identified several promising drugs including the anticoagulant dicumarol, the gout medication benzbromarone, and two anti-inflammatory drugs, tolfenamic acid and diflunisal.

Importantly, these drugs did not compromise the effectiveness of the antibiotics against disease-causing bacteria.

Further experiments showed that these antidote drugs also protected natural bacterial communities derived from human stool samples and in living mice.

“This Herculean undertaking by an international team of scientists has identified a novel approach that combines antibiotics with a protective antidote to help keep the gut microbiome healthy and reduce the harmful side effects of antibiotics without compromising their efficiency,” says Dr Ulrike Löber, of the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany who is presenting the research at ECCMID. “Despite our promising findings, further research is needed to identify optimum and personalized combinations of antidote drugs and to exclude any potential long-term effects on the gut microbiome.“

Source:

European Congress of Clinical Microbiology & Infectious Diseases

Microbiology

Long COVID linked to increased sick leave rate

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Tarun Sai LomteBy Tarun Sai LomteApr 5 2023Reviewed by Lily Ramsey, LLM

In a recent study posted to the medRxiv* preprint server, researchers in Denmark examined associations between coronavirus disease 2019 (COVID-19) and sick leave post-acute infection.

Study: Covid-19 and post-acute sick leave: a hybrid register and questionnaire study in the adult Danish population. Image Credit: OlivierLeMoal/Shutterstock.com

Study: Covid-19 and post-acute sick leave: a hybrid register and questionnaire study in the adult Danish population. Image Credit: OlivierLeMoal/Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Long COVID is defined as the persistence of post-acute symptoms in people previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20% of infected individuals are estimated to develop long COVID.

A prior study identified sick leave as a potential indicator of long COVID symptoms in Denmark. Still, the extent to which these symptoms translate to working ability is poorly defined.

About the study

In the present study, researchers evaluated the associations between COVID-19 and sick leave following acute infection in the adult Danish population.

Data were used from the nationwide EFTER-COVID (AFTER-COVID) survey, initiated in August 2021, to assess public health during the COVID-19 pandemic, focusing on long COVID.

Danish residents were invited to participate via a national digital mail system based on SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) test results in the Danish microbiology database.

Test-negative controls lacking a positive test result in the database at any time before the survey were randomly selected. This analysis included participants who took the survey nine months after their RT-PCR test. The survey data were integrated with register-based data on age, sex, vaccination, COVID-19 test results, reinfections, and comorbidities.

The questionnaire was designed for information on participants’ baseline characteristics and sick leaves(s) between test and survey dates. The team obtained data on inpatient and outpatient diagnoses from the Danish National Patient Register (DNPR).

All participants were asked if they took sick leave at the time of testing or after that. Those responding yes were asked to indicate the duration and whether the leave was part- or full-time.

The prevalence of substantial full- or part-time sick leave, viz., full- or part-time sick leave for more than four weeks after infection, was compared between test-positive and -negative subjects using risk differences.

Findings

Overall, 106,917 out of 294,035 invitees completed the survey nine months after the COVID-19 test. After exclusions, the study population comprised 88,818 participants, including 37,482 individuals who were SARS-CoV-2-positive. They were, on average, aged 45; most participants (64.3%) were females.

Less than 1% received at least one vaccine dose for COVID-19. Around 16.6% of participants were obese. Depression, anxiety, and high blood pressure were the other frequent pre-existing conditions. The prevalence of substantial sick leave was higher among test-positive subjects at 4.5% compared to 1.4% among controls.

It was similar across age groups in controls but increased with age in infected participants. Of note, 21% of test-positive individuals who took a substantial sick leave were diagnosed with long COVID, compared to 1.6% of infected individuals who did not take the leave. Infected individuals had a higher risk of taking a substantial full-time sick leave than controls.

The risk difference was attenuated when substantial sick leave was increased and defined as at least six months. Risk differences were higher for females than males and individuals aged 50 or above than the general population. The highest risk differences were for individuals with fibromyalgia, common obstructive pulmonary disease (COPD) or other lung diseases, and diabetes.

Healthcare workers had a larger risk differently than the general population. Infected individuals were also more likely to take a substantial part-time sick leave than controls.

However, the risk of a substantial part-time sick leave was lower for people aged 50 or above than that for substantial full-time sick leave but was similar to the general population.

Conclusions

The team noted that SARS-CoV-2-infected individuals had an increased risk of taking a substantial sick leave. More than a fifth of infected individuals also had a long COVID diagnosis. The study’s major limitations include the self-reporting design and potential recall bias.

Moreover, the duration of sick leave was not solely attributable to long COVID, as the questionnaire captured sick leave status in general. Further, participation bias was also likely, given that individuals with poor health or symptoms expressed more interest in participating.

Taken together, the findings suggest that among SARS-CoV-2-infected subjects, an additional 33 persons per 1,000 took a substantial sick leave between one and nine months post-acute infection compared to controls. Females, older adults, and those with pre-existing conditions such as fibromyalgia, obesity, and COPD were affected the most.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Microbiology

Review on factors related to variations in human microbiota

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Pooja Toshniwal PahariaBy Pooja Toshniwal PahariaMar 8 2023Reviewed by Aimee Molineux

In a recent review published in Current Opinion in Microbiology, researchers reviewed existing data on variations in human microbiota, emphasizing on ageing- and ethnicity-associated changes in the microbiota.

Study: Human microbiome variance is underestimated. Image Credit: Troyan/Shutterstock
Study: Human microbiome variance is underestimated. Image Credit: Troyan/Shutterstock

Background

Human microbial heterogeneity lays the foundation for precision therapeutics, and thus, the potential of personalized microbiota-based diagnostic and therapeutic strategies can be tapped fully by understanding human microbial variations. However, the factors associated with alterations in the human microbiome have yet to be well-characterized.

Further, most of the human microbiota data has been obtained from residents of westernized and socioeconomically developed nations, with the probable skewing of microbiota variations and their associations with health. Moreover, the under-sampling of ethnic minorities in microbiota analyses must be addressed for assessing the history, context, and evolving dynamics of the human microbiota in the context of disease risks.

About the review

In the present review, researchers highlighted recent advances in characterizing human microbiota variations associated with ageing and various ethnicities globally.

Age-related changes in the microbiota of humans

Factors that shape the human microbiota include birth type, family sizes, cohabitation, housing, domestic animals, age, sex, physical fitness, diet, antibiotics, non-antibiotic drugs, and alcohol intake. At the societal level, complex associations of health inequalities, socioeconomic status, and social networks with the human microbiome balance have been reported.

Studies have demonstrated an inverse association between the microbiota and an individual’s age, and conversely, microbial compositional variations contribute to the process of ageing and age-associated diseases. All individuals do not age uniformly, and the differential ageing rates reflect in the human microbiota. Therefore, the human microbiota abundance is evolving as a biomarker to evaluate differences in the biological age and chronological age and between health and disease. Human microbiomes lacking Bacteroides species have been strongly associated with a healthy type of ageing.

Other factors related to variations in the human microbiota composition

Mediterranean diets, involving reduced intake of saturated-type fats, red meat, and milk products, with high consumption of fruits, vegetables, fish, legumes, nuts, and olive oil, have been reported to reverse age-associated microbiota alterations and delay cognitive decline. Studies have reported the co-evolution of human beings and intestinal microbes, with notable variations in Helicobacter pylori diversity associated with human migration.

Microbiome compositions vary among individuals residing in industrialized or non-industrialized regions. Non-industrialized region-associated microbiomes or ancestral microbes have adapted to metabolizing complex-type carbohydrates from diets with high fibre content. The microbial compositions vary by season, climatic fluctuations, and accessibility to unprocessed-type foods. The microbiome of individuals living in non-industrialized regions reportedly has lower Bacteroides/Prevotella spp. ratio, elevated counts of Treponema species, and varying abundance of parasites that affect the immunity of the host.

Naturally maintained palaeofaeces microbiome genomes resemble the genomes of non-industrialized human intestinal microbiota. Socioeconomic developments and industrialization have been associated with microbiome diversity losses, lowered parasitism, reduced counts of ancestral microbes like Helicobacter pylori species and elevated counts of microbes associated with non-communicable and chronic metabolic and inflammatory diseases.

Immigration has been related to an increased abundance of microbes associated with obesity. A study on Irish travellers reported three key factors influencing the human microbiota composition, i.e., living conditions, closeness to domestic pets during childhood and family sizes, with the average number of siblings among traveller families and other families being 10, and one, respectively).

Conclusions

Based on the review findings, the human microbiome is influenced by age, diet, ethnicity and immigration. Further research is required to improve understanding of age-related microbiome changes to identify targets and develop tailored microbiota-based therapeutic interventions. The increase or decrease in microbial abundance associated with changes in dietary patterns and modernization needs to be assessed further to develop highly specific precision medicine catered to the residential locations and food consumed.

The co-diversification of microbes with humans globally warrants in-depth analysis of microbial compositions by ethnicity, region, diet, and industrialization status to maximize the benefit of microbiota-based interventions to one and all. Microbial analyses were performed to evaluate the risk of disease in relation to microbiome dysbiosis and abrupt changes following immigration could inform policy-makers and decision-making and aid in developing personalized therapeutics to improve the standard of care for all individuals across the globe.

Journal reference:
Microbiology

Gut-on-a-chip devices can bridge lab models and human biology

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Reviewed by Emily Henderson, B.Sc.Feb 28 2023

The gut is one of the most complex organs in the body. Inside, it teems with a diverse microbial population that interacts and cooperates with intestinal cells to digest food and drugs. Disruptions in this microbiome have strong links to a wide spectrum of diseases, such as inflammatory bowel disease, obesity, asthma, and even psychological and behavioral disorders.

Valid models of the gut are therefore immensely useful for understanding its function and associated ailments. In APL Bioengineering, by AIP Publishing, researchers from the University of California, Berkeley and Lawrence Berkeley National Lab described how gut-on-a-chip devices can bridge lab models and human biology.

Organ-on-a-chip devices are miniaturized models of human organs. They contain tiny microchannels where cells and tissue cultures interact with precisely controlled nutrients. Regulating the cell’s environment in such a way is crucial for creating realistic models of tissue.

Using these models avoids the time-consuming and costly challenges of clinical trials and the ethical issues behind animal testing.

“Medical research is currently facing major hurdles, both in terms of understanding the basic science governing the function of human organs and the research and development of new drugs and therapeutics,” said author Amin Valiei. “Access to valid models of human organs that can be studied conveniently in the lab can significantly accelerate scientific discoveries and the development of new medications.”

Modeling the microbiome is particularly difficult because of its unique environmental conditions. Through creative design, gut-on-a-chip devices can simulate many of these properties, such as the gut’s anaerobic atmosphere, fluid flow, and pulses of contraction/relaxation. Growing intestinal cells in this environment means that they more closely resemble human biology compared to standard laboratory cell cultures.

“Recent gut-on-a-chip models have demonstrated success in maintaining a viable coculture of the human intestinal cells and the microbiome for a few days and even up to weeks,” said Valiei. “This opens new ways to analyze the microbiome under biologically relevant conditions.”

The authors highlight key gut-on-a-chip devices and their success in simulating microbial and human cellular biology. They also describe current disease models and drug studies using the technology.

“Its unique capabilities make the organ-on-a-chip apt for plenty of research investigations in the future,” said Valiei.

The team is currently investigating dysbiosis, an imbalance in the gut microbial community with major health consequences. They aim to find innovative ways to diagnose, mitigate, and treat this condition.

Source:

American Institute of Physics

Microbiology

Differences in gut microbiome diversity attributed to dietary patterns in children with obesity

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Dr. Chinta SidharthanBy Dr. Chinta SidharthanFeb 16 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in Microbiology Spectrum, researchers found that differences in the dietary patterns of children with normal weight and those who were overweight or obese contributed to variations in the gut microbiome diversity, virulence factors of gut bacteria, and metabolic function.

Study: Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Image Credit: Africa Studio / Shutterstock.com

Study: Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Image Credit: Africa Studio / Shutterstock.com

Background

A growing body of evidence indicates that gut microbiota has a significant role in various aspects of host metabolism, including digestion, harvesting of energy, and induction of low-grade inflammation. In addition, the genetic factors of the host, as well as other characteristics such as age, diet, immunity, and gender, influence the gut microbiome composition.

Research shows that bacterial diversity in the gut and the individual’s functional capacity vary between those with normal weight and obese individuals. Gut microbiome profile variations have also been linked to metabolic disorders, lipid accumulation, and inflammation.

Lipogenesis in the liver and the regulation of appetite through hormones are also associated with gut microbiome genes.

Aside from its role in adipogenesis, superoxide reduction, and the metabolism of vitamins, gut microbiota also regulates innate immunity and the systemic, low-grade inflammatory state that can contribute to fat deposition and obesity. Therefore, Dysbiosis, which is the imbalance of gut microbiota, combined with diet, likely has a significant role in the development of obesity.

About the study

In the present study, researchers conducted a cross-sectional analysis of data from 45 children between the ages of six and 12 to determine the association between gut microbiota and obesity.

Questionnaires were used to obtain information on dietary frequencies, gender, age, and body mass index (BMI). Based on the World Health Organization (WHO) z-scores, in which BMI is adjusted for gender and age, the children were classified into two categories of overweight and obese (OWOB) and normal weight (NW).

Data from food frequency questionnaires were used to classify the dietary habits of children into two nutritional patterns. To this end, Pattern 1 was characterized by complex carbohydrates and proteins, whereas Pattern 2 comprised simple carbohydrates and saturated fats.

Shotgun metagenomics was used to assess the taxonomic diversity of the gut microbiota and metabolic capacity from genomic deoxyribonucleic acid (DNA) extracted from fecal samples. Clade-specific markers were used for the taxonomic and functional assessment of the gut bacteria. Additionally, reverse Simpson and Shannon diversity indices were calculated.

The virulence factor database was used to screen for virulence factor genes, whereas multivariate linear modeling was used to determine the association between the taxa, virulence factors, and function of gut microbes and covariates of diet, serology, and anthropometric measurements.

Study findings

Significant differences between the alpha and beta diversity of the gut microbiota were observed between the children in the NW and OWOB groups, thus suggesting that specific phyla of bacteria contribute to higher levels of energy harvest.

Furthermore, species such as Ruminococcus species, Victivallis vadensis, Mitsuokella multacida, Alistipes species, Clostridium species, and Acinetobacter johnsonii were linked to healthier metabolic parameters.

In contrast, an increase in the abundance of bacteria such as Veillonellaceae, Lactococcus, Fusicatenibacter saccharivorans, Fusicatenibacter prausnitzii, Eubacterium, Roseburia, Dialister, Coprococcus catus, Bifidobacterium, and Bilophila was identified in children with pro-inflammatory conditions and obesity.

Bacteria such as Citrobacter europaeus, Citrobacter youngae, Klebsiella variicola, Enterococcus mundtii, Gemella morbillorum, and Citrobacter portucalensis were associated with higher lipid and sugar intake, as well as higher blood biochemistry values and anthropometric measurements.

Diets high in fats and simple carbohydrates have been associated with the abundance of Citrobacter and Klebsiella species in the gut. Moreover, previous studies have indicated that these bacterial species are potential markers of inflammation, obesity, and an increase in fasting glucose.

The metabolism of menaquinones and gamma-glutamyl was negatively associated with BMI. Furthermore, the microbiomes of children in the NW group preserved a more consistent alpha diversity of virulence factors, while OWOB microbiomes exhibited a dominance of virulence factors.

Differences in the metabolic capacities pertaining to biosynthesis pathways of vitamins, carriers, amino acids, nucleotides, nucleosides, amines, and polyamines, as well as the degradation of nucleotides, nucleosides, and carbohydrate-sugars, were also found between the NW and OWOB groups.

Conclusions

Dietary profiles and the diversity of gut microbiota were found to be interconnected and associated with changes in metabolic parameters, the dominance of virulence factors, and obesity. Changes in gut microbiome diversity and relative abundance have been linked to obesity, inflammatory responses, and metabolic disorders.

Taken together, the study findings suggested that the prevalence of virulence factors, as well as the metabolic and genetic roles of gut microbiota in increasing inflammation, can help identify individuals at an increased risk of childhood obesity.

Journal reference:
  • Murga-Garrido, S. M., Ulloa-Pérez, E. J., Díaz-Benítez, C. E., et al. (2023). Virulence factors of the gut microbiome are associated with BMI and metabolic blood parameters in children with obesity. Microbiology Spectrum. doi:10.1128/spectrum.03382-22
Microbiology

Experiments Show Infection of Visceral Fat Cells May Contribute to Severe COVID-19

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Two types of adipocytes (fat cells) were infected in the laboratory: one obtained from human stem cells isolated from subcutaneous tissue and the other differentiated from stem cells taken from visceral fatty tissue.

Experiments show that visceral fat – fat around the liver, intestines, and other organs, considered a risk factor for cardiovascular disease, diabetes, and high blood pressure – contributes more to severe COVID-19 than subcutaneous fat (under the skin, as in “love handles”). The experiments were conducted in Brazil by researchers at the State University of Campinas (UNICAMP) and the University of São Paulo (USP).

In order to arrive at this conclusion, Marcelo Mori, a professor at the Institute of Biology at UNICAMP and one of the study’s leaders, infected in the lab two different types of fat cells: one obtained from human stem cells isolated from subcutaneous tissue and the other differentiated from stem cells taken from visceral fatty tissue.

“It was possible to observe that visceral adipocytes are more susceptible to infection by SARS-CoV-2. Viral load increased far more in this fat cell type than in subcutaneous adipocytes. We believe this was due mainly to higher levels of the protein ACE-2 [to which the virus binds to invade cells] on the cell surface,” Mori told Agência FAPESP.

Additionally, the researchers discovered that when visceral adipocytes were infected, they produced a larger amount of pro-inflammatory cytokines, which alert the immune system to the existence of a threat to be combated.

An article on the study was published recently in the scientific journal Nature Communications. Several research groups at UNICAMP collaborated with the group at USP, alongside colleagues at the Brazilian Bioscience National Laboratory (LNBio-CNPEM), National Cancer Institute (INCA) and D’Or Research and Education Institute (IDOR). The principal investigators were Luiz O. Leiria (USP), Mariana Osako (USP) and Daniel Martins-de-Souza (UNICAMP). The study was funded by FAPESP via 20 projects (17/08264-8, 20/05040-4, 20/04746-0, 19/00098-7, 19/05155-9, 20/04583-4, 20/15959-5, 19/26119-0, 16/00194-8, 20/04558-0, 20/04579-7, 21/10373-5, 20/08716-9, 13/07607-8, 20/04919-2, 17/01184-9, 17/23920-9, 16/24163-4, 19/04726-2 and 18/21635-8).

Mori’s team at UNICAMP was the first in the world to show – in July 2020 – that SARS-CoV-2 can infect human fat cells and to suggest that adipose tissue serves as a reservoir for the virus.

“After that, other studies confirmed that adipocytes can indeed be infected, and when we analyzed samples from patients who died of COVID-19, we found the presence of the virus in adipose tissue to be relatively frequent, corresponding to about 50% of cases,” Mori said.

The group then decided to investigate whether there were differences between the way visceral and subcutaneous adipose cells responded to infection. As far as metabolic diseases are concerned, the evidence in the scientific literature shows visceral fat to be the main villain, while subcutaneous fat tends to be neutral or even beneficial.

“We wanted to see if there was a similar association in the context of COVID-19,” Mori said. “And in fact, our model suggests that the more visceral adipose tissue there is in obese individuals, the more the virus can replicate, and this amplifies the inflammatory process.”

In subcutaneous adipocytes, on the other hand, the group observed a decrease in lipolysis, the breakdown of fats and other lipids by hydrolysis to release fatty acids, which can be used as a source of energy during physical activity or fasting periods.

“Our hypothesis is that this represents an antiviral cellular response,” Mori said. “There are studies showing that inhibition of lipolysis lowers the replicative capacity of SARS-CoV-2, which can be explained by the fact that the virus needs lipids to produce its envelope, as well as energy from cells to make copies of its genetic material.” Reduced lipolysis in subcutaneous adipose tissue, therefore, could be positive for the patient and bad news for the virus.

Visceral adipocytes were exposed to different strains of SARS-CoV-2: the ancestral lineage originally from Wuhan, China, and isolated from one of the first Brazilians diagnosed with COVID-19; and the gamma variant (P.1.), which emerged in late 2020 in Manaus, the capital of Amazonas state in Brazil. The difference in susceptibility compared to subcutaneous adipocytes was observed only in response to the ancestral virus.

“We concluded that the Manaus variant is less effective at infecting visceral fat cells than the ancestral strain,” Mori said. “A proteomic analysis [of all the proteins produced by the cells] showed that the Wuhan strain led to a reduction in several proteins associated with the cellular response to interferon [ an immune system mechanism to combat viruses], whereas the gamma variant led to an increase. In other words, the Manaus strain made adipocytes produce more proteins that promote an antiviral response.”

Recent research points to a downtrend in the number of severe cases of COVID-19 due to novel variants among people with obesity. “But this could be influenced by other factors, such as vaccination or prior infection. Or these individuals may have been taking extra care because they knew they belonged to a high-risk group,” Mori explained.

To try to deepen their understanding of all these processes, the group plans further experiments involving adipocytes cultured with the delta and omicron variants.

Another plan for future research is to investigate possible medium- to long-term metabolic impacts of infection by SARS-CoV-2. “We want to find out whether infection changes the risk of developing diabetes or cardiovascular disease, for example,” Mori said. “One way of doing so could be to analyze samples from patients who had COVID-19 and were later submitted to bariatric surgery, in order to see if morphological and functional alterations occurred in visceral adipose tissue as a result of the infection.”

Reference: “SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner” by Tatiana Dandolini Saccon, Felippe Mousovich-Neto, Raissa Guimarães Ludwig, Victor Corasolla Carregari, Ana Beatriz dos Anjos Souza, Amanda Stephane Cruz dos Passos, Matheus Cavalheiro Martini, Priscilla Paschoal Barbosa, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Julia Forato, Mariene Ribeiro Amorim, Rafael Elias Marques, Flavio Protasio Veras, Ester Barreto, Tiago Tomazini Gonçalves, Isadora Marques Paiva, Narayana P. B. Fazolini, Carolina Mie Kawagosi Onodera, Ronaldo Bragança Martins Junior, Paulo Henrique Cavalcanti de Araújo, Sabrina Setembre Batah, Rosa Maria Mendes Viana, Danilo Machado de Melo, Alexandre Todorovic Fabro, Eurico Arruda, Fernando Queiroz Cunha, Thiago Mattar Cunha, Marco Antônio M. Pretti, Bradley Joseph Smith, Henrique Marques-Souza, Thiago L. Knittel, Gabriel Palermo Ruiz, Gerson S. Profeta, Tereza Cristina Minto Fontes-Cal, Mariana Boroni, Marco Aurélio Ramirez Vinolo, Alessandro S. Farias, Pedro Manoel M. Moraes-Vieira, Joyce Maria Annichino Bizzacchi, Tambet Teesalu, Felipe David Mendonça Chaim, Everton Cazzo, Elinton Adami Chaim, José Luiz Proença-Módena, Daniel Martins-de-Souza, Mariana Kiomy Osako, Luiz Osório Leiria and Marcelo A. Mori, 29 September 2022, Nature Communications.
DOI: 10.1038/s41467-022-33218-8

São Paulo Research Foundation (FAPESP)