Medical Bulletin 04/ March/ 2024

A study conducted by researchers from Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) and the Norwegian School of Sports Sciences revealed that the body undergoes significant, systematic changes across multiple organs during prolonged periods of fasting.

The findings published in the Journal Nature Metabolism demonstrated the health benefits of fasting beyond weight loss but also showed that any potentially health-altering changes appear to occur only after three days without food.

Over millennia, humans have developed the ability to survive without food for prolonged periods of time. Fasting is practised by millions of people throughout the world for different medical and cultural purposes, including health benefits and weight loss. During fasting, the body shifts from consuming calories to utilising its own fat stores for energy. However, the broader effects of prolonged fasting on health remain largely unknown. Advanced techniques for analysing circulating proteins in the blood help analyze how the body molecularly adapts to fasting in humans.

For the study, researchers recruited 12 healthy volunteers for a seven-day water-only fast. They closely monitored the volunteers daily to track changes in approximately 3,000 proteins in their blood before, during, and after the fast. By pinpointing the proteins involved in the body's response, researchers could forecast the potential health effects of prolonged fasting by integrating genetic data from extensive studies.

Researchers discovered that during fasting, the body shifted its energy source from glucose to stored fat within the first few days. Volunteers lost an average of 5.7 kg of fat and lean mass. After three days of refeeding, weight remained stable, with lean mass mostly restored but fat loss maintained. Protein levels underwent notable changes after three days of fasting, indicating a systemic response to calorie restriction. Approximately one-third of measured proteins changed significantly across major organs during fasting, with distinctive signatures beyond weight loss, including alterations in brain neuron-supporting proteins.

“For the first time, we’re able to see what’s happening on a molecular level across the body when we fast. Fasting, when done safely, is an effective weight loss intervention. Popular diets that incorporate fasting – such as intermittent fasting – claim to have health benefits beyond weight loss. Our results provide evidence for the health benefits of fasting beyond weight loss, but these were only visible after three days of total caloric restriction – later than we previously thought.” said Claudia Langenberg, Director of Queen Mary’s Precision Health University Research Institute (PHURI).

Reference: Journal: Nature Metabolism; Maik Pietzner, Burulça Uluvar, Kristoffer J. Kolnes, Per B. Jeppesen, S. Victoria Frivold, Øyvind Skattebo, Egil I. Johansen, Bjørn S. Skålhegg, Jørgen F. P. Wojtaszewski, Anders J. Kolnes, Giles S. H. Yeo, Stephen O’Rahilly, Jørgen Jensen & Claudia Langenberg; DOI: 10.1038/s42255-024-01008-9

New microbiome discovery may enhance immunotherapy for various rare cancers

Researchers from the Wellcome Sanger Institute, the Olivia Newton-John Cancer Research Institute in Australia have identified specific strains of bacteria that are linked with a positive response to combination immunotherapy in the largest study of its kind.

The study, published on 1st March 2024 in Nature Medicine, detailed a collection of microorganisms in an individual’s gut bacteria that may help identify those who would benefit from combination immunotherapy and help explain why the efficacy of this treatment is otherwise hard to predict.

Immunotherapy is a type of treatment that harnesses the body’s immune system to target the cancer. While it can be very effective, it only works in a proportion of recipients across a wide range of cancers. As with all cancer treatments, immunotherapy can have multiple side effects. Therefore, being able to predict who is most likely to respond to treatment helps ensure that patients do not endure these unnecessary side effects for no medical benefits.

In a large clinical trial targeting various advanced rare cancers, including gynaecological, neuro-endocrine, and upper gastrointestinal cancers, researchers utilized stool samples collected from patients. Employing deep shotgun metagenomic sequencing, they mapped the microbiomes of participants at the strain-level. The trial centered on immune checkpoint inhibitors, blocking PD-1 and CTLA-4 checkpoints to empower the immune system to combat cancer cells effectively. Additionally, the team used a machine learning model that could predict who would benefit from combination immunotherapy.

The findings showed multiple strains of bacteria in those who responded well to treatment, many of which had not been cultivated before. This allowed them to identify a microbiome signature that was found in patients who responded well to treatment. However, when applied to patients who received just one of the immunotherapy drugs, targeting the immune checkpoint receptor PD-1 only, the machine-learning model could not identify those who would respond to treatment.

The results suggested that the relationship between gut microbiota and treatment response is specific for particular therapeutic combinations. Therefore, the researchers suggest that future development of diagnostics tests or therapeutics that rely on the gut microbiome should be tailored to the immunotherapy regimen, regardless of cancer type.

“Rare cancers can be hard to study and treat and while immunotherapy treatment can be incredibly effective in some of these cases, it can also be unpredictable. Our research shows that the microbiome impacts how well someone responds to combination immunotherapy, but that monotherapy gives a different result. This suggests that the microbiome should be taken into account when developing therapeutics going forward. In addition to this, there is a possibility of developing live biotherapeutic products that could provide the bacteria shown to support immunotherapy, helping the microbiome work with the patient to give them the best odds of response possible.” said Dr David Adams, co-senior author from the Wellcome Sanger Institute.

Reference: A. Gunjur, Y. Shao, T. Rozday, et al. (2024) A gut microbial signature for combination immune checkpoint blockade across cancer types. Journal: Nature Medicine. DOI: 10.1038/s41591-024-02823-z

One in four pregnant women not receiving sufficient omega-3 fatty acids, finds study

A research published in the Journal of Public Health Nutrition revealed that despite strong recommendations advocating the consumption of omega-3 fatty acids for optimal pregnancy outcomes and offspring health, 25% of pregnant women rarely or never consume fish during pregnancy, and fewer still take omega-3 supplements.

Omega-3 fatty acids play a crucial role in the development of the fetus during pregnancy. Adequate intake of omega-3s, particularly DHA (docosahexaenoic acid), supports healthy cognitive function and vision in the growing fetus.

“Omega-3 fatty acids are essential nutrients for supporting positive health outcomes. Getting enough of these nutrients during pregnancy is vital for preventing preterm birth and promoting optimal child health and neurodevelopment,” said the study’s lead author Emily Oken, Harvard Medical School professor and chair of the Department of Population Medicine at the Harvard Pilgrim Health Care Institute.

The nationwide cohort study utilized data on fish consumption provided by 10,800 pregnant women, and supplement intake data from 12,646 pregnant women who were part of the Environmental Influences on Child Health Outcomes (ECHO) program.

The study results showed that nearly 25% of participants reported not eating fish or eating it less than once per month, and only 16% took supplements. Supplement use was less common among those who consumed less fish, putting the group at even higher risk for insufficient omega-3 fatty acid intake. Additionally, supplement use was less common among those at higher risk for adverse pregnancy outcomes or having a higher BMI.

“Current evidence shows that the benefits of maternal consumption of low-mercury fish, or in its place, omega-3 supplements, outweigh any potential risks,” said Dr. Oken. “Our study provides updated information to inform much-needed public health advice and resources to support clinical conversations to encourage consumption of low-mercury fish during pregnancy and intake of omega-3 supplements among those who do not consume fish.”

Reference: Emily Oken, Rashelle J. Musci, Matthew Westlake, Kennedy Gachigi, Judy L. Aschner, Kathrine L. Barnes, Theresa M. Bastain, Claudia Buss, Carlos A. Camargo Jr., Jose F. Cordero, Dana Dabelea, Anne L. Dunlop, Akhgar Ghassabian, Alison E. Hipwell, Christine W. Hockett, Margaret R. Karagas, Claudia Lugo-Candelas; Journal: Public Health Nutrition; DOI: 10.1017/S136898002400051X