The investigators previously demonstrated that the gut microbiome can be remodeled by one month of intermittent fasting (OMIF) in healthy volunteers and animal models, with a notable alteration observed in its overall composition which could be linked to improvement in liver function. The blood microbiome, which mirrors the human ecosystem and includes all microbes mainly including bacteria, archaea, and viruses, is a new-identified human microbiome assessment tool that is assumed to be more stable and representative than the gut microbiome, with substantial potential for the diagnosis and prediction of liver cirrhosis and cancer. However, the effect of OMIF, which mimics lifestyle change typically advised in liver disease, on this blood microbiome remains elusive at best. The aim of this study is to explore whether OMIF remodels the composition and function of the blood microbiome in healthy volunteers, through a Randomized controlled cross-over trial, with secondary outcomes on the association of blood microbiome with the gut microbiome.

The major proportion of human blood DNA is mainly released from host cells or unborn babies, which is often used either as a unique material in testing for genomic variants associated with genetic disorders like trisomy or as a potential candidate in the diagnostic and prognostic approach to unveiling many inflammatory diseases, especially cancer. Nevertheless, a substantial proportion (~1%) of human blood cell-free DNA is non-human origin. This fraction has gained relatively little attention hitherto. With the development of next generation sequencing technology and bioinformatic tools, the origin of these ignored DNA fragments can be identified by alternatively assigning these non-human DNAs to genome of various microorganisms: such analysis reveals that this DNA is a collection of microbiome sequences and includes archaea and other bacteria, viruses, fungi, and even eukaryotes. Subsequently, the value of analyzing these microbial DNAs was illustrated by the discovery that they create unique microbiome signatures that deconvolute healthy controls, patients with cancers even between different cancer types. Further research showed that blood microbiome may even also direct pathogenic roles, mediating the development of acute decompensation of cirrhosis, for instance.

It is suggested that the blood microbiome may be an internal (blood) niche of overall external microbiome from either gastrointestinal tract, lung tract, oral cavity, or skin sites etc. These external microbiomes can be entirety or partially (e.g., DNA and LPS) transferred into the circulation by different transfer mechanisms, explaining the high sensitivity and specificity of using blood microbiome signature in mirroring disease in these tissues and tract sites. A novel example is the translocation of the gut microbiome via intestinal barrier into circulation by diffusion or transport during nutrition absorption, which is showed to be much faster especially under the injury of intestinal integrity (e.g., chronic stress and metabolic disease). Nevertheless, whether the gastrointestinal (oral and fecal) microbiome serves as a major source in general for blood microbiome remains unexplored so far.

Intermittent fasting is a popular dietary concept because of its perceived healthy benefits to weight loss. As a non-pharmacological dietary intervention strategy, intermittent fasting has been widely studied due to its significant healthy effect and applied for improving metabolic disease (liver function and lipid levels) and chronic stress, through a mechanism closely associated with the remodeling of the gut microbiome. Given the effect of intermittent fasting on the gut microbiome, intermittent fasting remains as a powerful strategy in exploring the effect of lifestyle change on the blood microbiome and especially its relationship with the gut microbiome as well as other health-associated parameters. This can provide insights into the origin of blood microbiome and its potential in serving as biomarker for disease prediction and therapeutic targets.

In this randomized controlled cross-over trial, the investigators aim to test the effect of one month of intermittent fasting (OMIF) on the blood microbiome in healthy volunteers. The specific aims are to 1) determine the effect of OMIF in shaping the blood microbiome, especially archaea; 2) evaluate whether the blood microbiome is associated with the gut microbiome. The investigators hypothesize that OMIF can influence the overall composition and function of blood microbiome. the investigators also hypothesize that the level of some taxa is stable over time, irrespective of lifestyle change, age, and gender.

Inclusion Criteria:

• Age 18-65 years
• 18.5 =< BMI < 25 kg/m2
• All genders are included.
• Have not fasted (go for a day without any food) for any amount of days in the month before the start of the study
• Being willing to provide App-derived movement data over the course of the study
• Participants are willing to and capable of providing written informed consent.

Exclusion Criteria:

• Regular use medications such as antibiotics, steroids, beta blockers, and adrenergic-stimulating agents (self-report)
• Regular use prebiotic and/or probiotics (self-report)
• Intake of antibiotic at least in previous 1 months (self-report)
• Daily consumption of >10 cigarettes, or >6 cups of coffee (the latter because of the effects on circadian rhythm). (self-report)
• Chronic diseases including type 2 diabetes, hypertension, fatty liver disease, cancer, or autoimmune disease (self-report and clinical chemistry)
• Internal diseases, including those of the gastrointestinal tract, lung, heart, vasculature, liver, and kidney (self-report and clinical chemistry)
• Eating disorder or unconventional eating habits (self-report)
• Have a clinically significant abnormality as measured by a blood test
• Participation in another study (self-report)
• Habit of performing regular fasting (self-report)
• Women: pregnancy and breastfeeding (self-report)