June 2021 Hot Topic: Fasting and Gut Microbiota

Vegetables on round chopping board shaped like a clock to represent intermittent fasting


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As part of the functional medicine year in review, fasting was a prominent topic in the literature. This is the Hot Topic article from June 2021. Hot topics highlight recent medical research findings and appear in IFM’s monthly Connections newsletter, exclusively for IFM members. Learn more about becoming an IFM member.

Studies have suggested a range of possible health benefits linked to therapeutic fasting routines, including the slowing or reversal of aging and disease processes and the improvement of overall physical and mental health.1 Specific to the intestinal microbiome, emerging research primarily based on animal models has highlighted the potential benefits of fasting on gut health, such as decreased intestinal inflammation, increased intestinal stem cells, and an expansion of protective gut bacteria.2-4 However, few human studies have investigated periodic fasting and its impact on gut microbiota composition. A recently published controlled clinical study completed such an investigation and found changes in gut microbial makeup and in longevity-related genes and signaling proteins.5

Fasting Impacts: Gut Microbiota, SIRT Expression, and Longevity

A small but first-of its-kind controlled clinical trial (n=51) enrolled male and female study participants either to a fasting group or a non-fasting control group to analyze changes to gut microbiota composition, sirtuin (SIRT) gene expression, and age-related pathways.5 The fasting group underwent five consecutive days of fasting following the Buchinger fasting protocol (daily energy intake of a maximum of 250 kcal).5 Blood and stool samples were collected from all participants for assessment. For the fasting group specifically, stool samples were collected before fasting and from the first stool after the fasting break, and blood ketone body levels were measured before and at the end of the fasting treatment.5

After analysis, the following results and suggested conclusions were found:

Gut Microbiota Composition: While the control group showed no phylum-level intestinal microbiota changes, the fasting group showed differences in microbial composition and an expansion of diversity at the phylum and species levels.5

  • At the species level, strong, statistically significant changes in microbiota composition before and after the fasting intervention were noted, with multiple species impacted.5
  • At the phylum level, TenericutesVerrucomicrobiaCyanobacteriaProteobacteriaTM7, and Fusobacteriawere affected by the treatment, with only the last three reported as statistically significant. In addition, no significant changes were seen for ActinobacteriaBacteroidetes, and and Firmicutes. After the fasting period, a positive correlation was seen between the noted abundance of Tenericutes and the increased amount of butyrate produced. Cyanobacteria was increased after the fasting intervention, whereas the level of Euryarchaeota was reduced.5
  • Of particular interest, after the fasting treatment, researchers noted a significant increase for Christensenella.5  This longevity-relevant gut microbiota has previously been associated with the gut microbial make-up of centenarians.6

Gene Expression (SIRTs): Comprehensive study results suggested that periodic fasting affects gene expression in blood cells.5

  • Compared to controls, after the fasting treatment, the blood levels of FoxO1SIRT1SIRT3, and miRlet7b-5p significantly increased, whereas miR34a-5p levels were reduced.5
  • SIRTs are signaling proteins involved in metabolic function and cellular health, including DNA repair, cell survival, and stress resistance. Animal studies have proposed that SIRT1 is associated with longevity, promoting mitochondrial biogenesis and functioning,7 and research indicates that SIRT3 regulates mitochondrial metabolism and homeostasis.8
  • For context, researchers from the Lilja et al study noted that mammalian forkhead box O (FoxO) proteins, such as FoxO1, stimulate the expression of many genes involved in autophagy, that miRlet7b-5p is believed to play a role in multiple metabolic regulatory processes, and that an overexpression of miR34a-5p may lead to mitochondrial dysfunction.5

Mitochondrial Content: Researchers found that mitochondrial (mt) DNA content in the blood was significantly higher in the fasting group compared to controls, with a positive trend noted between stool butyrate and mtDNA content in the fasting group.5

Ketone Bodies: As expected, ketone body production was increased during the fasting treatment. Of interest, one of the ketone bodies, beta-hydroxybutyrate (BHB), significantly increased from 0.2 to 5.7 mM after the treatment. According to investigators, BHB has been associated with cellular signaling, gene expression regulation, and the potential reduction of age-related neurological impairments.5

Study Conclusions: Results from this 2021 clinical study suggest that periodic fasting not only changes the composition of the intestinal microbiota, creating more diversity at the species level, but also increases both SIRT expression and the expression of those genes and microbiota relevant to aging and longevity in humans.5

Clinical Considerations: Mitochondrial Health

A 2021 review of 15 studies that investigated the effect of different types of fasting and caloric restriction on the intestinal microbiome and its metabolites affirmed that fasting interventions may positively influence the progression of chronic disease.4 In addition, a recent review published in The New England Journal of Medicine indicated that potential health benefits associated with therapeutic fasting treatments may be linked to several metabolic factors, including the optimization of mitochondrial quality and function, leading to improvement of energy metabolism and overall health.1 Lifestyle factors such as nutrition and exercise9 are effective strategies for supporting mitochondrial biogenesis. IFM’s Mitochondrial Food Plan, for example, is a nutritional approach to mitochondrial health that can be expanded with various levels of fasting, if appropriate for a patient’s treatment. Fasting-related research continues to evolve, with a focus on therapeutic applications for addressing chronic disease and optimizing a patient’s health trajectory.

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  1. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease [published correction appears in N Engl J Med. 2020;382(3):298; N Engl J Med. 2020;382(10):978]. N Engl J Med. 2019;381(26):2541-2551. doi:10.1056/NEJMra1905136
  2. Cignarella F, Cantoni C, Ghezzi L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab. 2018;27(6):1222-1235.e6. doi:10.1016/j.cmet.2018.05.006
  3. Rangan P, Choi I, Wei M, et al. Fasting-mimicking diet modulates microbiota and promotes intestinal regeneration to reduce inflammatory bowel disease pathology. Cell Rep. 2019;26(10):2704-2719.e6. doi:10.1016/j.celrep.2019.02.019
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  7. Chen C, Zhou M, Ge Y, Wang X. SIRT1 and aging related signaling pathways. Mech Ageing Dev. 2020;187:111215. doi:10.1016/j.mad.2020.111215
  8. Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B. Mitochondrial sirtuin 3: new emerging biological function and therapeutic target. Theranostics. 2020;10(18):8315-8342. doi:10.7150/thno.45922
  9. Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2021;599(3):803-817. doi:10.1113/JP278853