The findings may be particularly important for children and teenagers. Because their bodies are still developing, younger generations are expected to experience the greatest lifetime exposure to elevated atmospheric CO₂.

Decades of Blood Data Reveal a Shift

In a study published in Air Quality, Atmosphere and Health, scientists from The Kids Research Institute Australia, Curtin University and The Australian National University (ANU) examined more than 20 years of U.S. population health data. They found persistent changes in several measures of blood chemistry that closely followed the upward trend in atmospheric CO₂.

The researchers used information from the U.S. National Health and Nutrition Examination Survey (NHANES), analyzing blood test results from roughly 7,000 people at two-year intervals between 1999 and 2020.

Since 1999, average serum bicarbonate levels have increased by about 7 percent. Bicarbonate is a blood marker closely associated with carbon dioxide in the body. During the same period, average levels of calcium and phosphorus decreased.

Those biological trends occurred as atmospheric CO₂ climbed from about 369 parts per million (ppm) in 2000 to more than 420 ppm today.

Study author Associate Professor Alexander Larcombe said the results indicate that the body may already be adjusting to changes in the composition of the atmosphere.

“What we’re seeing is a gradual shift in blood chemistry that mirrors the rise in atmospheric carbon dioxide, which is driving climate change,” A/Prof Larcombe said.

How the Body Responds to More CO₂

Bicarbonate is essential for regulating the body’s acid-base balance. As CO₂ increases, the body can retain additional bicarbonate to help keep blood pH stable. Although this response helps preserve that balance, maintaining it over long periods could have physiological effects.

“If current trends continue, modeling indicates average bicarbonate levels could approach the upper limit of today’s accepted healthy range within 50 years,” A/Prof Larcombe said

“Calcium and phosphorus levels could also reach the lower end of their healthy ranges later this century.”

Humans evolved when atmospheric CO₂ concentrations were approximately 280 to 300 ppm. During the past decade, atmospheric levels have risen by an average of about 2.6 ppm each year, while 2024 alone saw an increase of 3.5 ppm.

Fellow Author Dr Phil Bierwirth, a retired environmental geoscientist affiliated with the ANU Emeritus Faculty, emphasized that the study does not establish a direct cause-and-effect relationship. However, he said the consistency of the changes across a large population warrants attention.

“I actually think that what we are seeing is because our bodies are not adapting,” Dr Bierwirth said.

“It appears we are adapted to a range of CO₂ in the air that may now have been surpassed.

“The normal range maintains a delicate balance between how much CO₂ is in the air, our blood pH, our breathing rate and bicarbonate levels in the blood.

“As CO₂ in the air is now higher than humans have ever experienced, it appears to be building up in our bodies. Maybe we can never adapt such that it is vitally important to limit atmospheric levels of CO₂.”

A Potential New Dimension of Climate Risk

The researchers say the results suggest that rising atmospheric CO₂ could represent a form of climate-related risk that is different from more familiar threats such as heatwaves, extreme weather and sea-level rise.

According to A/Prof Larcombe, increasing CO₂ may need to be considered not only as an environmental concern, but also as a long-term public health factor that should be monitored.

“We’re not saying people are suddenly going to become unwell when we cross a certain threshold,” he said.

“But this suggests there may be gradual physiological changes occurring at a population level, and that’s something we should be monitoring as part of future climate change policy.”

The researchers recommend monitoring the composition of the atmosphere together with biological markers across populations. Tracking both alongside established climate indicators could help scientists determine how slow environmental changes affect human biology over periods of decades.

CO₂ Reduction Could Have Health Implications

Cutting CO₂ emissions remains essential for limiting global warming. The findings also raise the possibility that lowering emissions could have an additional role in protecting long-term human health.

The researchers argue that potential physiological effects from rising CO₂ should therefore be considered in future discussions about climate policy, alongside its established environmental consequences.

Associate Professor Larcombe is part of the Wal-yan Respiratory Research Centre, a partnership between The Kids Research Institute Australia, Perth Children’s Hospital and Perth Children’s Hospital Foundation.

Two studies led by Ludwig Princeton’s Jenna AbuSalim and Director Joshua Rabinowitz offer new insight into that process. One appears in the current issue of the Proceedings of the National Academy of Sciences, while the other was published in Nature Metabolism in June. The first study found that plant fiber and certain plant proteins can change microbial metabolism in ways that increase beneficial metabolites while reducing harmful ones. The second showed that several biologically important metabolites usually credited to gut microbes can also be produced in substantial amounts by mammalian metabolism.

“There’s growing interest across medical disciplines in manipulating the human microbiome or using its metabolic products themselves for therapy,” said Rabinowitz. “Diet holds great promise for controlling the microbiome and its outputs. But to devise effective therapeutic interventions, we need to understand what aspects of the diet control which microbial outputs.”

How Plant Foods Shift Gut Metabolites

In the PNAS study, Rabinowitz, AbuSalim and their colleagues examined how plant based foods influence phenol metabolites. Gut bacteria create these compounds when they digest the amino acids tyrosine and phenylalanine, but the resulting metabolites can have very different effects on health.

Phenylpropionate and hippuric acid are produced when bacteria process phenylalanine, and they are associated with gut health and healthy body weight. By contrast, p-cresol sulfate and phenol sulfate come from tyrosine and have been linked to worse outcomes in cancer patients as well as systemic toxicity in people with kidney disease.

“Our studies showed that both the fiber and indigestible proteins from plants — which we call ‘proteins imitating fiber,’ or Prif — shift the balance of phenol metabolites from the harmful kind made from tyrosine to the healthful variety derived from phenylalanine,” said AbuSalim.

Fiber has long been recognized as an important part of a healthy diet, but indigestible plant proteins have received far less attention. AbuSalim, Rabinowitz and their colleagues found that these proteins are processed by gut microbes and can alter both the makeup of the microbiome and the host’s metabolism. Working together with indigestible plant fiber, they can also change the metabolic activity of gut bacteria in ways that favor the production of beneficial phenols.

When Gut Bacteria Turn to the Gut Lining

To trace where these compounds came from, the researchers labeled proteins with stable (non-radioactive) isotopes and followed their digestion in the mouse gut. They found that the “bad” phenols were produced when bacteria consumed proteins from the host, including proteins found in the mucus lining of the gut. The good phenols, in contrast, came almost entirely from indigestible proteins in the diet (Prif).

Fiber reduced the bacterial breakdown of the gut’s mucus lining, which in turn lowered production of the harmful phenols. Prif increased the amount of dietary protein that reached gut microbes, giving them more material to produce the beneficial phenols.

“We think Prifs represent an emerging class of dietary nutrients that shape the composition of the gut microbiome and could have a far-reaching influence on metabolic health,” said AbuSalim.

“Food packaging may eventually list Prif right below fiber,” said Rabinowitz.

Rethinking Where Gut Metabolites Come From

The Nature Metabolism study focused on the origins of phenol metabolites as well as indole metabolites, which are produced from the amino acid tryptophan. Like phenols, indoles are being studied for their possible therapeutic value.

Indole metabolites have been connected to a wide range of diseases, including inflammatory bowel disease, neurodegenerative disorders, and cancer. In cancer research, they have been found to affect processes that include cancer metastasis and anti-tumor immune responses.

Scientists had generally assumed that phenols and indoles were produced only by gut bacteria. AbuSalim, Rabinowitz and their colleagues decided to test that assumption. Researchers have been especially interested in dietary and probiotic approaches that might increase beneficial indole metabolites. But those strategies may need to be reconsidered if mammalian metabolism, rather than microbes, is responsible for much of what circulates in the body.

Using isotope tracing in mice, rats and human cells, the researchers found that mammalian metabolism can produce many indole and phenol metabolites on its own. These included important compounds such as indole-3-lactate and indole-3-acetate.

In mice, circulating levels of these metabolites remained high even after antibiotic treatment disrupted the microbiome. A similar pattern appeared in samples from patients taking antibiotics, including cancer patients. At the same time, metabolites made exclusively by microbes, including indole-3-propionate and p-cresol sulfate, declined after antibiotic treatment.

New Clues for Diet and Microbiome Therapies

Together, the two studies provide a clearer picture of where phenol and indole metabolites come from and how they are produced. The findings could influence the development of therapies designed to raise or lower specific metabolites.

They also add important detail to scientists’ understanding of how diet interacts with the microbiome. Knowing which foods influence particular microbial products could eventually help researchers design more precise dietary, probiotic, or metabolic interventions.

“Beyond that,” said Rabinowitz, “a clearer picture of how different foods interact with the microbiome to modulate the production of bacterial metabolites will help sharpen the guidance nutritionists and doctors can give to people for disease prevention and therapy.”

These studies were funded by the Ludwig Institute for Cancer Research, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the Princeton Alliance for Collaborative Research and Innovation, Princeton University.

Aside from his post as Director of the Princeton Branch of the Ludwig Institute for Cancer Research, Joshua Rabinowitz is Professor in the Department of Chemistry & Lewis-Sigler Institute for Integrative Genomics and a member of the Rutgers Cancer Institute.

The mouse study, published in Nature Metabolism, found that the outcome depends on which part of the brain is targeted. Activating the receptor in the brainstem reduced appetite, while blocking the same receptor in the hypothalamus produced a similar weight loss effect through a different mechanism.

More than a billion people around the world are living with obesity, a condition that raises the risk of diseases including type 2 diabetes, cardiovascular disease and cancer. Losing weight can reduce some of these risks, but achieving substantial weight loss through diet and exercise alone can be difficult.

How Modern Weight Loss Drugs Target the Brain

A new generation of weight loss medications has emerged in recent years that act on specific receptors involved in appetite. By influencing these receptors, the drugs can reduce food intake, promote weight loss, and help regulate blood sugar.

Several widely used medications, including Wegovy and Ozempic, activate a protein receptor called the glucagon-like peptide 1 receptor (GLP-1R).

Other obesity treatments act on both GLP-1R and another receptor known as the glucose-dependent insulinotropic polypeptide receptor (GIPR). This second target has presented scientists with an unusual puzzle.

Some medications, including Mounjaro and Zepbound, activate GIPR. Others, such as MariTide, block it. Despite producing opposite effects on the same receptor, both approaches can help promote weight loss.

Researchers at the Institute of Metabolic Science, University of Cambridge, set out to understand why. Their experiments in mice revealed that the two types of GIPR drugs work through different regions of the brain. The researchers also found that these approaches can increase weight loss when paired with certain GLP-1-based weight loss medicines.

Tracking GIPR Activity in Different Brain Regions

To identify the brain regions responsible for these effects, the team used genetically engineered mice in which GIPR had been selectively removed from specific areas.

One group lacked GIPR in the brainstem, the region at the base of the brain just above the spinal cord that is involved in appetite and nausea. Another group lacked the receptor in the hypothalamus, an important brain region involved in regulating hunger and body weight. A third group consisted of normal, unmodified mice that served as controls.

The scientists treated the animals with different combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor) and a GLP-1 drug. They then monitored food consumption, body weight, fat mass, blood sugar control and brain activity.

Comparing the different groups allowed the team to pinpoint where each treatment was acting.

The results showed that GIPR agonists primarily work through the brainstem. Activating GIPR in this region reduced appetite and led to lower body weight.

Blocking a Brain Brake on Fullness

GIPR antagonists followed a different route.

Instead of acting primarily through the brainstem, the researchers found that blocking GIPR promoted weight loss through the hypothalamus. In this region, GIPR appears to function as a kind of ‘brake’ that limits how strongly the brainstem responds to signals indicating that the body is full.

Blocking the receptor effectively releases that ‘brake’, allowing fullness signals to have a stronger effect.

The researchers also found evidence that blocking GIPR could enhance the effects of emerging medicines that target the amylin receptor. This suggests that GIPR antagonists might eventually be useful for strengthening several different classes of obesity treatments.

Clues to More Powerful Obesity Drug Combinations

The results help explain why treatments such as MariTide can be effective. MariTide, currently in phase 3 clinical trials, combines GIPR antagonism with GLP-1 receptor agonism.

Understanding how these separate pathways interact could also help researchers design more effective combinations of obesity medicines in the future.

Dr. Jo Lewis, the study’s first author from the Institute of Metabolic Science at the University of Cambridge, said: “Understanding which brain circuits respond to these medications – and how they do so – could help us design better drugs that produce more weight loss with fewer side effects, and which might work in combination with other obesity medicines to even greater effect.

“Our work also strengthens the idea that the brain is central to obesity treatment. Obesity drugs are not acting simply on the gut or pancreas. Instead, they have important effects on specific, identifiable brain circuits that regulate appetite and food intake.”

The research was funded by the Medical Research Council and Wellcome.