In affluent Western cultures, where constant meals and snacking have become the norm—often leading to habits that contribute to poor health—researchers are discovering that an alternative approach to eating may offer significant benefits.
Intermittent fasting is emerging as a potent tool for improving health, most specifically in age-related chronic diseases. Although the mechanisms are varied, research indicates that intermittent fasting has a notable impact on the gut microbiome.
This blog will explore the physiological effects of intermittent fasting and its interplay with the gut microbiome. In addition, the potential benefit of adjacent probiotic treatment will be investigated.
Intermittent fasting, in brief
Intermittent fasting (IF) encompasses various patterns of eating that alternate between periods of fasting and eating (or feeding in animals). Three main variants are:
- Time-restricted eating (TRE)—time window of eating of 6-12 hours a day
- Alternate day fasting (ADF) — alternating between days of no or minimal caloric intake (usually about 500 calories) and days of regular eating
- 5:2 diet—abstinence or restricted eating two days a week and unrestricted eating the other five days
You may come across several other types in the IF toolbox:
- Periodic fasting (PF) — fasting for several consecutive days (e.g., 3-7 days) every few weeks or months.
- Fasting-Mimicking Diet (FMD) — reduced calorie intake (with low protein and carbohydrates) mimics the effects of fasting without complete abstinence from food.
- Religious or cultural fasting—such as in Ramadan where eating is restricted to nighttime hours.
NOTE: Research on intermittent fasting focuses on the timing of eating rather than the absolute reduction in calorie intake whereas calorie restriction (CR) research assesses the effects of reduced caloric intake (with adequate nutrition) without specific changes to meal timing. Each differs in patterns of food consumption and specific mechanisms being investigated. This blog addresses the former.
Both animal and human studies have employed different types of IF to explore its effects on health, metabolism, and disease.
A successful extension of lifespan in the nematode Caenorhabditis elegans and the common fruit fly Drosophila melanogaster has been demonstrated through IF.
In rodents, IF has shown mixed effects on longevity, with some studies demonstrating lifespan extension, improved cognitive performance, reduced cancer risk, and enhanced immune system function, while others have reported no significant or even negative effects depending on timing, diet, and genetic factors.
However, research in humans suggests that IF may have significant protective benefits against metabolic diseases (obesity and diabetes), cardiovascular, and neurodegenerative diseases.
Mechanisms of action
The effect of starvation on humans is well documented. In essence, the body undergoes dramatic adaptations to preserve lean body mass and protect the essential organs. Energy output slows in a complex refiguring of the metabolism.
In an abridged version, IF appears to parlay the initial adaptations to the lack of nourishment for the body’s benefit. In humans, 12 to 24 hours of fasting, depending on activity level, typically leads to a 20% or more drop in blood sugar and the depletion of liver glycogen, prompting the body to switch to using fats, non-liver glucose, and ketones for energy.
Numerous mechanisms are thought to explain the beneficial outcomes of IF:
- Improvements in insulin sensitivity and blood glucose levels, key factors in metabolic disorders like type 2 diabetes.
- Lower inflammation—linked to many chronic diseases
- May activate autophagy, the body’s way of clearing out damaged cells and proteins to protect against further harm, especially during stress.
- Induces lower levels of IGF-1 (insulin-like growth factor 1), a hormone linked to aging and cancer. Reduced IGF-1 levels improve cellular stress resistance and enhance the body’s ability to repair itself.
- Improves mitochondrial efficiency promoting more energy and cardiovascular efficiency
- Promotes brain-derived neurotrophic factor (BDNF), which supports brain function and may protect against age-related cognitive decline.
By impacting key factors in metabolic regulation, inflammation, cellular repair, and hormonal balance, IF shows promise in improving metabolic health and delaying aspects of aging.
However, it must be considered that adherence to an IF regimen can be challenging given the social aspects and very human proclivity for nourishment. In addition, adverse effects— dehydration, nausea, headache, dizziness and more— are manageable but not uncommon. When compared to calorie restriction, clear superiority of IF over CR in health outcomes cannot be established, according to a 2024 review that analyzed over 50 clinical studies. Further research may give a clearer picture.
Intermittent fasting and the microbiome
Researchers have posited that some of the beneficial effects observed in IF may be the result of synergistic changes mediated by the gut microbiome.
Several studies have explored how the gut microbiome is altered in IF. As noted, IF takes many forms; please refer to each study to ascertain variants and methods.
Animal studies
In a study with fruit flies (Drosophila melanogaster), IF resulted in long-term improvements in gut health, including enhanced gut barrier function, reduced age-related pathologies, and lower bacterial abundance.
In a rat study, IF led to an increase in bacterial diversity and the stabilization of Firmicutes and Bacteroidetes ratios in the cecum of the intestinal tissue.
In experimental autoimmune encephalomyelitis (EAE) —a commonly used mouse model for studying multiple sclerosis— IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families, and enhanced antioxidative microbial metabolic pathways. IF reduced pro-inflammatory T cells, and increased regulatory T cells. In addition, transplanting fecal microbiota from mice on an IF regimen alleviated EAE in immunized recipient mice on a normal diet, suggesting that the benefits of IF are at least partly mediated by gut microbiota.
In a mouse model of inflammatory bowel disease IF reduced inflammation, increased stem cell production, and stimulated protective gut microbiota. Notably, fecal transplants from IF-treated mice restored healthy gut conditions in diseased mice, highlighting the microbiome’s involvement.
In db/db mice (a mouse model of Type 2 diabetes), long-term IF improved survival and reduced diabetic retinopathy (DR) markers, thought to be due to microbiota changes that increased beneficial metabolites reducing inflammation and preventing DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia.
IF significantly changed the gut microbiome composition in a study with mice, notably increasing the production of acetate and lactate metabolites. Additionally, transplanting microbiota from IF-treated subjects effectively improved metabolic dysfunctions linked to obesity.
Human studies
In a 2024 review, the authors looked at eight clinical studies that explored the impact of IF on the gut microbiota.
For example, in a study with metabolic syndrome patients, IF altered gut microbiota by increasing short-chain fatty acid production, reducing lipopolysaccharides, and shifting gut carbohydrate metabolism, which was linked to improvements in cardiovascular risk factors.
In another example from the above review, a pilot study in multiple sclerosis (MS) patients found that IF for 15 days led to changes in gut microbiota, including increased Faecalibacterium and Blautia, which may help counterbalance dysbiosis in MS and potentially influence inflammation-related biomarkers, though larger studies are needed to confirm these findings.
After analyzing the data in the eight studies, the reviewers suggested that IF may increase gut microbiota richness and diversity, with changes in the abundances of specific bacteria like Proteobacteria and Faecalibacterium. However, the evidence is inconclusive due to heterogeneity in study designs and populations, and more research is needed to understand the health impacts of these microbial shifts.
Probiotics and intermittent fasting
The evidence for the benefit of using probiotics in conjunction with IF to improve outcomes is limited. However, two recent clinical trials tested the hypothesis.
One study found that probiotics supplementation (type not stated) during an IF program significantly improved histopathology in the ileum and colon of aged rats, with combined interventions yielding greater protective effects against age-related intestinal damage and inflammation.
In another study, probiotic supplementation with a strain of Lacticaseibacillus rhamnosus during IF showed psychological benefits, but no significant additional effects on glycemic improvement or weight loss compared to placebo in individuals with prediabetes.
Takeaway
Intermittent fasting (IF) shows promise in improving metabolic health and longevity by regulating blood sugar, reducing inflammation, and enhancing cellular repair processes. However, adherence to intermittent fasting (IF) can be difficult due to social factors and common side effects like dehydration and headaches, and while it shows potential, a 2024 review of over 50 studies found no clear health superiority of IF over calorie restriction (CR).
Regarding the gut microbiota, IF has been shown to improve diversity and promote beneficial bacteria in some studies with animals and humans, potentially playing a role in gut health and reducing inflammation-related diseases.
Probiotic supplementation alongside IF may offer additional benefits, such as reducing intestinal damage and inflammation, as seen in an animal study, though human trials show limited evidence for added effects on glycemic control or weight loss. Further research is needed to clarify the synergistic effects of probiotics and IF on health outcomes.
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