The gut-muscle axis, or the relationship between gut microbiota and muscle mass and physical function, has gained momentum as a research topic in the last few years as studies have established that gut microbiota influences many aspects of health. While researchers have begun exploring the connection between the gut microbiome, muscle, and physical function in mice and younger adults, few studies have been conducted with older adults.

To gain insight into this population, the researchers compared bacteria from the gut microbiomes of 18 older adults with high-physical function and a favorable body composition (higher percentage of lean mass, lower percentage of fat mass) with 11 older adults with low-physical function and a less favorable body composition. The small study identified differences in the bacterial profiles between the two groups.

Similar bacterial differences were present when mice were colonized with fecal samples from the two human groups, and grip strength was increased in mice colonized with samples from the high-functioning older adults, suggesting a role for the gut microbiome in mechanisms related to muscle strength in older adults.

Specifically, when compared to the low-functioning older adult group, the researchers found higher levels of Prevotellaceae, Prevotella, Barnesiella, and Barnesiella intestinihominis — all potentially good bacteria — in the high-functioning older adults and in the mice that were colonized with fecal samples from the high-functioning older adults.

No significant differences in body composition or endurance capacity were observed in the colonized mice; however, the researchers note that the length of the intervention period was short and these data may warrant further study.

“While we were surprised that we didn’t identify a role for the gut microbiome on the maintenance of body composition, with these results we now start to understand the role of gut bacteria in the maintenance of muscle strength in older adults,” said Michael Lustgarten, last and corresponding author on the study and a researcher in the Nutrition, Exercise Physiology & Sarcopenia (NEPS) Laboratory at the HNRCA. “For example, if we were to conduct an intervention to increase Prevotella levels in the gut microbiome, we would expect to see an increase in muscle strength if these bacteria are involved. Prevotella’s role in the maintenance of muscle strength in older adults is one area we expect to continue to explore.”

“As we age, body composition, muscle strength, and lean mass all decrease,” said first author Roger Fielding, director of the NEPS Laboratory at the HNRCA. “Identifying differences in bacteria present in the high-functioning and low-functioning groups in this study moves us toward a fuller understanding of both the gut microbiome and healthy aging.”

For the study, the researchers measured lower extremity function, mobility, and strength in the sedentary older adult group (ages 70-85) at the first and one-month study visits. In the mice, they measured body composition with quantitative magnetic resonance imaging, and grip strength and treadmill endurance capacity to test physical function. Fecal samples from the older adults were transplanted into young, gender-matched germ-free mice. Four weeks after fecal transfer, the researchers measured body composition, physical function, and gut microbiome in the 18 mice colonized with fecal samples from the high-functioning human group and the 18 mice colonized with fecal samples from the low-functioning human group.

The authors note the small sample size and brief time period as potential study limitations.

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“Our work is very suggestive that microbial community composition drives, at least in part, how the organisms in which they live are evolving,” says Paul Schmidt, a biologist at Penn and senior author on the work, which appears in the journal PNAS. “The fact that we can see this effect in experiments done over such a short time scale suggests that the magnitude of the fitness effects the microbes have is incredible.”

Unlike a laboratory experiment, where every possible aspect of the environment is controlled, from the genetics of the flies themselves to the temperature and diet, in order to magnify differences between treatments this set of experiments took place outdoors, at Pennovation Works on Penn’s campus. The setting more closely mirrors nature, subject to weather, seasonal changes, even the odd spider or fleck of dirt intruding in the enclosures.

The fact that, despite the potential influences of these outside factors, the researchers still found the microbiome shifts to have a significant effect on the genomes of fly populations, makes the finding even more compelling, Schmidt says.

“I think it’s fair to say we preserved as much ecological realism as we could at the expense of detecting large effects,” he says. “We just shifted the relative abundance of these microbes in the flies’ diet, and that was enough to see an effect.”

Schmidt and postdoctoral fellow Seth Rudman, the lead author on the paper, took advantage of the fact that flies have relatively simple microbiome communities compared to other organisms, such as humans.

“If you do a survey of a mammalian microbiome, many of the bacteria you find in the gut are unknown,” says Rudman. “But that’s not the case with flies. It just happens that Drosophila have only about 100 species in their microbiome community.”

Other benefits of fruit flies for this type of study include their short generation time — one can study several generations in a matter of months — and the fact that they can be reared to extremely high population sizes. In this case, that meant hundreds of thousands of flies in each experiment.

From earlier work, scientists had an inkling that the microbiome was linked to changes in the fitness of the fly. Flies from more northern latitudes tend to have more Lactobacillus bacteria as part of their microbiome, and also live longer, have fewer eggs and are more tolerant to stress. More southerly populations, on the other hand, which tend to have more of the bacteria Acetobacter, had shorter lifespans, more eggs, and were less stress-tolerant. Work in the lab showed that exposing flies to these two types of bacteria elicited these same traits.

But could the microbes drive the evolution of whole populations of flies? To test that, Schmidt, Rudman, and colleagues designed an experimental setup to manipulate the flies’ microbiomes. They introduced a thousand flies into each of several outdoor mesh enclosures, 2 cubic meters in size and adorned with groundcover and a peach tree. They varied the food in some of the enclosures, supplementing it with either Acetobacter or Lactobacillus.

The researchers confirmed that the feeding altered the microbiomes of the flies, though just slightly. That was enough, however, to affect their genes. Comparing the genomes of the flies at the start of the study to the conclusion, after five generations, the team could pick out distinct changes in the frequency of certain alleles — one variant of a gene — that were consistent with what has been seen in natural populations of flies.

“We found that the allele that was more common in the Lactobacillus solution cages was also the allele that’s more common in the north, where Lactobacillus itself is more common,” says Rudman. “And the allele that was more common in the Acetobacter cages was also the allele that is more common in the south, where Acetobacter is more common.”

To the researchers, that finding hammered home the significance of the microbes’ influence.

“The bottom line is, microbes drive rapid adaptation,” Schmidt says.

Whether that effect translates to humans and other animals is a matter for further study, the authors say, but numerous studies have underscored the potent effect of the microbiome.

In future work, the researchers will be flipping the script, testing to see whether changes in the flies’ genetic profiles influence which microbes can gain a foothold in their microbiomes. And they’ll also probe more deeply into determining precisely how the changing microbiome affects its host.

The results of the first study to investigate this show that the eNose is more accurate than the current gold standard of immunohistochemistry (IHC) for selecting patients who will respond to anti-PD-1 immunotherapies such as nivolumab or pembrolizumab. IHC involves testing tissue samples for the presence of the protein called programmed death ligand 1 (PD-L1), which is the target for anti-PD 1 therapies, but it is invasive and takes time to obtain results.

Professor Michel van den Heuvel, professor of thoracic oncology at the Radboud University Medical Centre (Nijmegen,The Netherlands), who led the research, said: “The introduction of immunotherapy has dramatically improved the treatment of advanced stage non-small cell lung cancer but unfortunately it is only effective in a subset of patients, which was about 20% when we started the study. Currently, there is no test available that can accurately predict who will benefit from this treatment, apart from PD-L1 testing by immunohistochemistry. This is today’s biomarker of choice, despite its analytic and predictive limitations, when making clinical decisions about whether or not to treat a patient with immunotherapy.”

Ms Rianne de Vries, a PhD student in the department of respiratory medicine at Amsterdam University Medical Centres (The Netherlands), who is joint first author of the study, said: “We hypothesised that exhaled breath analysis using eNose technology might be a non-invasive and rapid alternative to the current standard and would enable doctors to avoid treating patients with an immunotherapy to which they would not respond.”

The eNose is a small device [2] that contains sensors to detect chemicals called volatile organic compounds (VOCs), which are present in about one per cent of our exhaled breath. The rest of our breath mainly consists of nitrogen, oxygen, carbon dioxide and water. The researchers thought that the mix of VOCs in the breath of patients with advanced non-small cell lung cancer (NSCLC) might indicate whether or not the patient would respond to anti-PD1 therapy; VOCs can vary depending on metabolic processes that occur in the whole body or in parts of it, such as the lungs.

Ms de Vries, who is also chief operating officer of Breathomix, which is currently producing the eNose, continued: “When using the eNose, the patient takes a deep breath, holds it for five seconds and then slowly exhales into the device. The eNose sensors respond to the complete mixture of VOCs in the exhaled breath; each sensor has its highest sensitivity to a different group of molecules. The sensor readings are sent directly to and stored at an online server for real-time processing of the data and for ambient air correction because the air that you exhale is influenced by the air that you inhale. The measurement takes less than a minute, and the results are compared to an online database where machine-learning algorithms immediately identify whether or not the patient is likely to respond to anti-PD1 therapy.”

Between March 2016 and February 2018, the researchers at The Netherlands Cancer Institute, Amsterdam, recruited 143 patients with advanced NSCLC. They used the eNose to take the breath profiles of the patients two weeks before they started treatment with nivolumab or pembrolizumab, and after three months they used standard criteria (Response Evaluation Criteria of Solid Tumours, RECIST) to assess whether the patients were responding to the treatment nor not. Results from the first 92 patients (who started treatment between March 2016 and February 2017) were validated by the results from the remaining 51 patients (who started treatment after April 2017).

The other first author of the study, Dr Mirte Muller, a PhD student in the department of thoracic oncology at The Netherlands Cancer Institute, said: “We found that before the start of treatment with immunotherapy, the eNose analysis of exhaled breath from the patients with non-small cell lung cancer could distinguish between responders and non-responders with an accuracy of 85%.

“Our findings show that breath analysis by eNose can potentially avoid application of ineffective treatment to patients that are identified by eNose as being non-responders to immunotherapy, which in our study was 24% of the patients. This means that in 24% of NSCLC patients this treatment could be avoided, without denying anyone effective treatment.

“ENose technology is cheap compared to other available medical technologies and diagnostic tests and biomarkers. The eNose qualifies as a non-invasive and rapid point-of-care test that provides feedback within seconds in the doctor’s office. Our results form a solid base for taking the next step to validate these findings in a large prospective multi-centre study.”

Although immunotherapy tends to have fewer side effects than chemotherapy, with fatigue being the most common, it can trigger more serious side effects in about 10% of patients. Organs such as the lungs, liver and bowel can become inflamed when the body’s immune system starts to attack its own cells. By correctly identifying patients who will not respond to immunotherapy, side effects related to the treatment can be avoided.

Prof van den Heuvel concluded: “We are convinced that this study merely scratches the surface. It represents the first introduction of modern precision medicine, namely that molecular fingerprints can be easily obtained and quickly analysed on the spot. This truly offers new possibilities for the individual patient and the doctor. The power of this eNose system is that it has been properly validated, both technically and clinically, which is essential. We believe that analysis of exhaled breath is going to become an important diagnostic tool and will guide future treatment in oncology as well as in many other diseases.”

Led by Dr Martin Zeidler, from the University of Sheffield’s Department of Biomedical Science and Dr Sebastian Francis from the Department of Haematology at the Royal Hallamshire Hospital, as well as the Universities of Oxford and Cambridge, the study results show that methotrexate (MTX) — a drug on the World Health Organisation list of essential medicines that is commonly used to treat rheumatoid arthritis — significantly reduces the symptoms associated with the disease.

Every year around 6,000 people in the UK are diagnosed with either PV or ET, related blood cancers that cause an overproduction of red blood cells (PV) or blood-clotting platelets (ET). Patients often suffer with itching, headaches, weight loss, fatigue and night sweats.

Although current treatments are usually able to control the increased blood counts, they provide little relief from sometimes debilitating symptoms that can often have a significant impact on quality of life.

Building on previous Medical Research Council-funded work in the Zeidler lab that identified methotrexate as an inhibitor of the JAK/STAT signalling pathway, this study examined hospital records to identify existing ET and PV patients already taking methotrexate for other diseases.

Despite the small numbers involved and the presence of background rheumatoid arthritis, these patients reported significantly lower symptom scores than patients not taking methotrexate.

The misregulation of the JAK/STAT signalling pathway in humans is central to the development of Myeloproliferative neoplasms (MPNs), the collective term for progressive blood cancers like ET and PV and is also central to many inflammatory processes such as those associated with rheumatoid arthritis.

Lab-based results showed that low doses of methotrexate acted as a powerful suppressor of JAK/STAT pathway activation — even in cells carrying the mutated gene responsible for MPNs in patients.

Dr Zeidler said: “While we still need to undertake a clinical trial to validate these findings, our results are very encouraging and suggest that a simple drug that has been used for nearly 40 years to treat arthritis can provide significant relief to blood cancer sufferers.

“Patients we tested showed a pronounced improvement in symptoms, something conventional treatments have been unable to provide.

“Given the very low cost of MTX, this research could offer an effective therapy on a budget accessible to healthcare systems throughout the world — marking a potentially substantial clinical and health economic benefit.”

An 81 year old PV patient based in California commented: “Methotrexate seemed to do a very nice job of controlling itching and night sweats. My subjective experience of MTX was of a PV holiday.”

MTX has been used for 40 years to treat inflammatory diseases including rheumatoid arthritis, Crohn’s disease and psoriasis. Even though the mechanisms by which MTX acts in these diseases had not previously been understood, the safety and effectiveness of MTX is well documented and many millions of patients regularly take the drug.

Diseases such as rheumatoid arthritis all feature inflammatory processes driven by JAK/STAT activity and the effectiveness of MTX in these inflammatory diseases may well be a consequence of its ability to dampen the JAK/STAT pathway.

The results of the study have today (17 September 2019) been published in the British Journal of Haematology.

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The Human Factors Research Group at the University of Nottingham, developed an immersive VR system to stimulate participants’ perception of temperature, and senses of smell, sight and hearing to explore how they behaved during two health and safety training scenarios: an emergency evacuation in the event of a fire and a fuel leak.

In one scenario, participants had to evacuate from a virtual fire in an office, seeing and hearing using a VR headset but could also feel heat from three 2kW heaters, and could smell smoke from a scent diffuser, creating a multisensory virtual environment. This group was compared against another group who were observed in this scenario using only audio-visual elements of VR.

Observing real life behaviours

Previous research on human behaviour during real-world fire incidents has shown that a lack of understanding of the spread and movement of fire often means that occupants are unprepared and misjudge appropriate actions. Immersive health and safety training enables employers to train people about hazards and hazardous environments without putting anyone at risk.

The Nottingham research, funded by the Institution of Occupational Safety and Health (IOSH), found contrasts between the groups in the way participants reacted to the scenario. Those in the multi-sensory group had a greater sense of urgency, reflecting a real-life scenario, and were more likely to avoid the virtual fires. Evidence from the audio-visual participants suggested that they were treating the experience more like a game and behaviours were less consistent with those expected in a real world situation.

Dr Glyn Lawson, Associate Professor in the Faculty of Engineering, University of Nottingham, said: “Health and safety training can fail to motivate and engage employees and can lack relevance to real-life contexts. Our research, which has been funded by the Institution of Occupational Safety and Health, suggests that virtual environments can help address these issues, by increasing trainees’ engagement and willingness to participate in further training. There are also business benefits associated with the use of virtual environment training, such as the ability to deliver training at or near the workplace and at a time that is convenient to the employee.”

Virtual Reality vs. PowerPoint

A further test was done, as part of the study, to measure the effectiveness of VR training versus traditional PowerPoint training. Participants took questionnaires, testing their knowledge on either fire safety or safe vehicle disassembly procedure, before and after training as well as one week later.

While those trained via PowerPoint appeared to have gained more knowledge when tested directly after training, there was a significantly larger decrease in knowledge scores when participants were retested one week later. In comparison, the VR group’s long term retention was better and reported higher levels of engagement; attitude to occupational safety and health; and willingness to undertake training in the future.

The research suggests that the increased cognitive engagement of learning in the virtual environment creates more established and comprehensive mental models which can improve recall, and implies that testing an employee’s knowledge immediately following health and safety training may not be an effective means of gaging long-term knowledge of health and safety.

Applications to the work place

Mary Ogungbeje, Research Manager at IOSH, said: “The wheels are turning so that virtual and smart learning is increasingly engrained in the workplace and everyday life.

“Technology is continuously advancing and in many cases becoming more affordable, so this study gives us a taste of what’s to come. By improving training strategies with the use of technology and stimulated sensory experiences, we are heading in a direction where the workforce will not just enjoy a more immersive and interesting training course but participate in an effective learning experience, so they are better prepared and equipped to stay safe, healthy and well at work.”

The researchers conducted meetings, discussions, and visits with partners including Rolls-Royce, for expert advice around fire safety and safe handling of hazardous chemicals. The University of Nottingham’s Health and Safety advisors also contributed to help the researchers better understand how the training may be implemented in industry.

The study aims to produce evidence-based guidance for the development and use of virtual environments in engaging and effective training using cost-effective and accessible solutions. The full study features in a report, titled ‘Immersive virtual worlds: Multisensory virtual environments for health and safety training’, to be released at the IOSH’s annual conference on Tuesday 17 September.

Further information: https://www.iosh.com/multisensoryVE