One approach that has drawn growing interest is intermittent energy restriction (IER), a form of dieting in which periods of reduced calorie intake are followed by periods of more typical eating. Research published in 2023 suggests that this strategy may do more than reduce body weight. It may also shift the relationship between gut bacteria and brain activity in ways that are closely tied to appetite and food behavior.

“Here we show that an IER diet changes the human brain-gut-microbiome axis. The observed changes in the gut microbiome and in the activity in addition-related brain regions during and after weight loss are highly dynamic and coupled over time,” said last author Dr. Qiang Zeng, a researcher at the Health Management Institute of the PLA General Hospital in Beijing.

Intermittent fasting and the brain

To explore what happens inside the body during weight loss, the researchers studied 25 adults with obesity in China. The volunteers, who were about 27 years old on average, had a BMI between 28 and 45.

The team used several tools to track changes over time. Stool samples were analyzed with metagenomics to measure the composition of the gut microbiome. Blood tests were used to monitor metabolic and physiological changes. The researchers also used functional magnetic resonance imaging (fMRI) to examine activity in brain regions involved in appetite, emotion, attention, learning, inhibition, and reward.

“A healthy, balanced gut microbiome is critical for energy homeostasis and maintaining normal weight. In contrast, an abnormal gut microbiome can change our eating behavior by affecting certain brain area involved in addiction,” explained coauthor Dr. Yongli Li from the Department of Health Management of Henan Provincial People’s Hospital in Henan, China.

A carefully controlled weight loss program

The study began with a 32 day high controlled fasting phase. During this period, participants received meals designed by a dietitian. Their calorie intake was gradually reduced in steps until it reached about one quarter of their basic energy needs.

This was followed by a 30 day low controlled fasting phase. During this stage, participants were given a list of recommended foods rather than fully prepared meals. Those who followed the plan exactly would consume 500 calories per day for women and 600 calories per day for men.

By the end of the intervention, participants had lost an average of 7.6 kilograms, equal to about 7.8% of their starting body weight. They also had reductions in body fat and waist circumference.

The metabolic improvements extended beyond weight. Blood pressure fell, as did fasting plasma glucose, total cholesterol, HDL, LDL, and the activity of key liver enzymes. According to the researchers, these changes suggest that intermittent energy restriction may help reduce obesity related problems such as hypertension, hyperlipidemia, and liver dysfunction.

Brain and gut changes moved together

The researchers found that the weight loss program was linked to lower activity in several brain regions involved in appetite and addiction related behavior. These changes may help explain why dieting affects not only body size, but also food cravings, self control, and the drive to eat.

At the same time, the gut microbiome shifted. The abundance of Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis rose sharply. Escherichia coli decreased.

Further analysis suggested that certain microbes were connected with activity in specific brain areas. The abundance of E. coli, Coprococcus comes, and Eubacterium hallii was negatively associated with activity in the brain’s left orbital inferior frontal gyrus, a region involved in executive function and willpower during weight loss.

Other bacteria showed the opposite pattern. P. distasonis and Flavonifractor plautii were positively linked with brain regions involved in attention, motor inhibition, emotion, and learning.

These findings point to a striking possibility: as people lose weight, the gut microbiome and the brain may change together. The study cannot prove whether gut bacteria drive the brain changes, whether the brain drives microbial changes, or whether another factor influences both. Still, the results add to evidence that weight control is not just a matter of willpower or calories. It may involve a changing biological conversation between the gut and the brain.

A two way conversation inside the body

“The gut microbiome is thought to communicate with the brain in a complex, two-directional way. The microbiome produces neurotransmitters and neurotoxins which access the brain through nerves and the blood circulation. In return the brain controls eating behavior, while nutrients from our diet change the composition of the gut microbiome,” said coauthor Dr. Xiaoning Wang from the Institute of Geriatrics of the PLA General Hospital.

This two way communication may help explain why obesity is so difficult to treat. Hunger, cravings, mood, reward, and metabolism are all shaped by biological signals. The gut microbiome can produce compounds that influence inflammation, metabolism, and nervous system activity. The brain, in turn, helps regulate food choices and eating behavior.

The 2023 findings suggest that successful weight loss may involve changes across this entire system rather than in one isolated organ.

What later research adds

Research published after the 2023 study has continued to support the idea that fasting can influence the gut microbiome, although the evidence remains complex. A 2024 systematic review of human studies found that intermittent fasting appears to affect gut microbial richness, diversity, and composition. However, the authors also noted that results varied widely between studies, and more research is needed to determine which changes are truly beneficial for health.

Another 2024 clinical study compared intermittent fasting combined with protein pacing to continuous calorie restriction in adults with overweight or obesity. Both diets reduced calorie intake, but the fasting and protein pacing group showed greater weight loss and more pronounced shifts in the gut microbiome. The researchers reported increases in microbes and metabolic signals associated with improved body composition and fat loss.

Together, these later findings strengthen the broader picture: fasting based interventions may reshape the gut microbiome in meaningful ways. However, they also show that the details matter. The type of fasting, calorie intake, protein intake, fiber intake, meal timing, and individual biology may all influence the outcome.

The next question for weight loss research

The original 2023 study was small and correlational, so it cannot show cause and effect. It also focused on a specific group of participants and a short term intervention. Larger and longer studies will be needed to determine whether certain microbes or brain regions can reliably predict who will lose weight, who will keep it off, and which diets work best for different people.

Coauthor Dr. Liming Wang, likewise from the Health Management Institute in Beijing, said: “The next question to be answered is the precise mechanism by which the gut microbiome and the brain communicate in obese people, including during weight loss. What specific gut microbiome and brain regions are critical for successful weight loss and maintaining a healthy weight?”

For now, the research offers a more detailed view of what may happen during intermittent fasting. Weight loss may not be limited to shrinking fat stores. It may also involve a synchronized shift in gut bacteria, metabolism, and brain activity that changes how the body responds to food.

The work was funded by FAPESP and focused on Goto-Kakizaki rats, a well established animal model used to study non-obese type 2 diabetes. Type 2 diabetes is marked by high blood sugar that occurs when insulin, the hormone that helps move glucose from the blood into cells, does not work effectively.

Fish Oil and Insulin Resistance

Omega-3 supplements, including fish oil, are often used by people with cardiovascular disease and type 2 diabetes. However, scientists still know much less about how these fatty acids affect insulin resistance when obesity is not involved.

That question matters because obesity is one of the strongest risk factors for type 2 diabetes, but it is not the whole story. An estimated 10% to 20% of people with type 2 diabetes worldwide are not obese. For these patients, the biological roots of insulin resistance may differ from the better known obesity-linked pathways.

In the study, researchers gave the rats fish oil at a dose of 2 grams per kilogram of body weight (equivalent to 540 mg/g of eicosapentaenoic acid, or EPA, and 100 mg/g of docosahexaenoic acid, or DHA) three times weekly for eight weeks. By the end of the experiment, the treated animals showed lower insulin resistance, better blood sugar control, reduced inflammatory markers, and improvements in several lipid measures, including total cholesterol, LDL (“bad cholesterol”) and triglycerides.

The results came from preclinical experiments, so they do not prove that fish oil will have the same effects in people. Still, the findings point to inflammation as a powerful target in non-obese diabetes and suggest that omega-3 fatty acids deserve closer study in this group.

A Shift in Immune Cells

“Our experiments involved Goto-Kakizaki [GK] rats, an animal model for non-obese type 2 diabetes. We found that insulin resistance can be reduced in these animals by modulating the inflammatory response so as to change the profile of defense cells [lymphocytes] from a pro-inflammatory state to an anti-inflammatory state. This process parallels the response of obese individuals with insulin resistance to omega-3 fatty acid supplementation,” said Rui Curi, Director of Butantan Institute’s Education Center, Professor of Interdisciplinary Graduate Studies in Health Sciences at Cruzeiro do Sul University (UNICSUL), and coordinator of the study.

Lymphocytes are white blood cells that help direct the adaptive immune response. When their behavior changes, the effects can spread through the immune system and influence other cells involved in inflammation.

“In previous studies, we observed alterations in both lymphocytes and macrophages [large white blood cells that often reside in adipose tissue and are part of the innate immune system, engulfing and destroying pathogens] in non-obese rats with insulin resistance. In such cases, these cells produce more pro-inflammatory cytokines, as is central in obese people with diabetes,” Curi explained.

“The main aim of the study, therefore, was to find out whether supplementation with fish oil [rich in omega-3] could reverse specific alterations in lymphocytes that had been observed in previous research. Our findings increased our knowledge of the link between inflammation and insulin resistance in non-obese animals, confirming that this is a key factor in diabetes even in the absence of obesity,” said Renata Gorjão, last author of the article, and Co-Director of UNICSUL’s Program of Graduate Studies in Health Sciences.

Inflammation Without Obesity

The Nutrients study, conducted during the PhD candidacy of Tiago Bertola Lobato, was part of a broader FAPESP-supported project exploring how insulin resistance develops in non-obese animals.

Curi noted that obesity is a major diabetes risk factor, but not the only one. In people who develop diabetes without obesity, one leading hypothesis is that genetic factors may play an important role. In another study published in Cells, Curi, Gorjão, and colleagues investigated whether delayed intestinal transit might also contribute to insulin resistance in non-obese individuals.

“Most obese people have chronic low-level inflammation, which is known to affect the insulin signaling pathways. Adipose tissue, which is augmented in obesity, releases pro-inflammatory cytokines that affect the insulin signaling pathways, promoting insulin resistance. In the non-obese model, this impactful characteristic of adipose tissue is absent, but systemic inflammation is present,” Curi said.

The group had previously shown systemic inflammation in non-obese GK rats with insulin resistance in a study published in the International Journal of Molecular Sciences.

Another paper from the same project reported that anti-inflammatory defenses appear to break down early in non-obese GK rats with insulin resistance. Lymph nodes (part of the immune system) from newly weaned 21-day-old GK pups already showed reduced markers of regulatory T-cells (Tregs, cells with anti-inflammatory characteristics). The researchers also detected other early inflammatory changes. That work was published in FEBS Letters, a journal of the Federation of European Biochemical Societies.

How Omega-3s May Help

The Nutrients study suggests that fish oil may work by moving immune activity away from a damaging inflammatory pattern and toward a more protective one.

“Fish oil supplementation reversed this pro-inflammatory profile, displaying a significant anti-inflammatory effect and reducing polarization of Th1 and Th17 cells [lymphocyte subtypes that perform crucial functions in inflammation], followed by a rise in the percentage of Tregs, which can inhibit the activation of pro-inflammatory lymphocytes. Thus the action of omega-3 fatty acids on lymphocytes, modulating them from a pro-inflammatory state to an anti-inflammatory state, may have triggered the reduction in insulin resistance in these animals,” Lobato said.

That immune shift is important because insulin resistance is not only a problem of sugar metabolism. It is also deeply connected to inflammation. When inflammatory signals remain elevated, they can interfere with insulin signaling and make it harder for cells to respond to the hormone.

The study adds to a growing view of type 2 diabetes as a disease shaped by both metabolism and the immune system. In this case, fish oil appeared to improve blood sugar regulation not simply by changing fat levels, but by changing the inflammatory environment that helps drive insulin resistance.

What Later Studies Add

Since the Nutrients paper was published, related human research has continued to examine how omega-3 fatty acids may influence early diabetes risk and metabolic health.

A 2025 double blind randomized controlled trial in Food and Function tested fish oil supplementation in healthy middle aged and older adults. Over 12 weeks, the fish oil groups had dose related increases in serum EPA and DHA. The researchers also reported decreases in fasting insulin and the HOMA-IR index, a common marker of insulin resistance. Fasting blood glucose trended downward across groups, and several lipid related measures also improved.

Another 2024 analysis in Nutrition and Diabetes used modeling data from 161 patients with type 2 diabetes to explore the relationship between omega-3 levels and HbA1c, a longer term marker of blood sugar control. The authors reported a dose related association and proposed that omega-3 intake could be studied in a more individualized way, while also noting that the role of omega-3s in type 2 diabetes remains debated.

Together, these studies do not settle the question of whether fish oil should be used to manage diabetes. Human evidence remains mixed, and the Brazilian study was conducted in animals, not people. However, the newer findings are consistent with the idea that omega-3 fatty acids may affect insulin resistance and inflammation in ways worth testing more carefully.

More Research Still Needed

Despite the promising findings, the researchers stressed that the results should be interpreted cautiously. Animal studies are useful for uncovering biological mechanisms, but clinical trials are needed before scientists can know whether the same strategy works in people with non-obese type 2 diabetes.

“These studies involved well-established experimental models that mimic insulin resistance in non-obese individuals. Trials in humans are needed to estimate the ideal dose and the most indicated type of omega-3 fatty acid,” Curi said.

For now, the study offers a compelling clue: in diabetes, body weight may not be the only driver of insulin resistance. Inflammation can play a central role even without obesity, and fish oil may help reveal how that hidden process can be changed.