Study Spotlight Take-Away with Chef Dr. Mike; Intermittent Fasting Versus Caloric Restriction: Effects on the Gut Microbiota

by Michael S. Fenster, MD

“Time is a fool’s enemy, but a sage’s friend.”

― Matshona Dhliwayo

Fast food is an interesting phrase.

What does it mean to you?

Perhaps it is convenience in the form of something ready to eat as soon as you ask for it; perhaps it is about transportability, food that you can take on the run; perhaps it is about multitasking, something to gobble mindlessly in a few bites whilst you concentrate on the other tasks at hand; perhaps it conjures up images of reproducibly satisfying foods so often associated with the standard American diet or SAD as it is known in many places around the world; or perhaps is some combination of some or all of these things. Whatever it may be, the images invariably link to time.

As several previous columns have touched upon, the time element in the food-health relationship—reflected in the emerging discipline of chrononutrition—is increasingly being recognized for its impact on our overall well-being. This, of course, includes effects on the gut microbiome. The gut microbiota is affected not only by food composition but also by feeding frequency and meal timing.

This week’s study spotlight examines the role of both what we eat and how we eat it – with respect to timing – and its consequences on our gut microbiota.

The Study:

  • The study examined two different dietary patterns with respect to time: calorie restriction (CR) and intermittent fasting (IF).
  • The intermittent fasting group (IF) incorporated protein pacing, which is defined as four meals per day consumed every four hours with 25-50 g of protein per meal.
  • The intermittent fasting group also incorporated caloric restriction from baseline.
  • Both groups were matched for weekly energy intake and expenditure.
  • The CR group employed continuous caloric restriction based on the current US dietary recommendation guidelines for a heart-healthy diet.[1]
  • The duration of the intervention was 8 weeks, involving a total of 41 participants: 21 in the IF group and 20 in the CR group.
  • Both dietary interventions reduced total fat, carbohydrate, sodium, sugar, and total energy intake by approximately 40% compared to baseline.
  • Whilst similarly matched in terms of energy (approximately 9000 cal per week), the IF regimen consisted of 35% carbohydrates, 30% fat, and 35% protein, compared to the CR regimen, which consisted of 41% carbohydrates, 38% fat, and 21% protein.
  • Physical energy expenditure was similar between the two groups.

The Take-Away:

  • Whilst both groups lost weight during the intervention period, the IF group lost significantly more total body weight, abdominal fat, and visceral fat mass.
  • The IF group experienced improved gut symptomatology and an increase in gut bacteria diversity.
  • The IF group also saw significant increases in cytokines associated with “lipolysis, weight loss, inflammation, and immune response.”

The Caveat:

One of the interesting observations of the study was how highly individualized the human gut microbiota was in response to the various dietary interventions. Despite that, there were some similarities between the groups as a whole. In the IF group, the type of bacteria that decreased as a result of the dietary changes were those species that produce butyrate, a short-chain fatty acid (SCFA). These short-chain fatty acids play an important role in proper good health, and while there was a decrease in these butyrate producers, the overall level of short-chain fatty acids, including acetate, propionate, and valerate, did not vary significantly. Such findings, when taken together show, “the complexity of dietary influences on [the] gut microbiome.”

In parallel, the dietary impacts on the immune system are likewise intricate. Many dietary approaches are sold and promoted on the basis of their “anti-inflammatory” effect, but this greatly oversimplifies the sophisticated nature of the immune response. Healthy immune function requires balance and avoidance of regressing to the extremes.

For example, the IF group experienced increases in the plasma cytokines interleukin (IL)-4, IL-6, IL-8, and IL-13. The diet was “pro-inflammatory” with respect to these particular inflammatory mediators. However, a closer look indicates potential benefits and potential pathways by which the intervention’s benefits manifest. IL-4 has lipolytic effects (meaning it breaks down fat into smaller particles). IL-8 is associated with both weight loss and maintenance of lost weight. IL-6 helps mobilize fat for use under fasting or exercise conditions. IL-13 appears to be important in maintaining a healthy gut microbiome due to the stimulation of mucus production from human cells that line the gastrointestinal tract. Whether these beneficial directional changes in cytokine production were due to changes in the gut microbiome or the changes in the gut microbiota were due to these changes in cytokine production – the classic chicken and egg conundrum – remains unanswered.

Another potential confounder of the study was that the IF group’s fiber intake was primarily in the form of fiber-rich shakes used as two of the daily meals versus the CR group’s primarily whole-food approach, thus introducing the food matrix as an additional variable. Despite the addition of shakes to the IF group’s diet, there were no changes in gut permeability (using the Lipopolysaccharide Binding Protein (LPB) assay) in either group. Gut permeability is a measure of “leaky gut” syndrome.

The larger context of this study’s results, beyond just looking for another weight loss mechanism, is that these associations “may reflect the direct impact of the dietary intervention [and its involvement] in the deeper crosstalk within the gut-immune axis.” Furthermore, as the highly individualized results within the IF group suggest, despite consuming the same diet, it is possible that it is the differences in the individual gut microbiome that are what determines an individual’s outcome in response to diet; adding yet another weave into the complex tapestry that is our individual food-health relationship.


[1] (U.S. Department of Agriculture and U.S. Department of Health and Human Services, 2020)


The Study:

Mohr, A.E., Sweazea, K.L., Bowes, D.A. et al. Gut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction. Nat Commun 15, 4155 (2024). https://doi.org/10.1038/s41467-024-48355-5.


Additional resources:

Li M, Wang S, Li Y, Zhao M, Kuang J, Liang D, Wang J, Wei M, Rajani C, Ma X, Tang Y, Ren Z, Chen T, Zhao A, Hu C, Shen C, Jia W, Liu P, Zheng X, Jia W. Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice. Nat Commun. 2022 Apr 19;13(1):2060. doi: 10.1038/s41467-022-29589-7.

Machado, A. C. D.; Brown, S.D.; Lingaraju, A.; Knight, R. diet and feeding pattern modulate diurnal dynamics of the ileal microbiome and transcriptome. Cell Rep.40, 111008 (2022).

U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025, 9th edn DietaryGuidelines.gov (2020).

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