Circadian Health and the Microbiome: A New Frontier in Chrononutrition

We often think of nutrition as fuel and the gut as its processing center. But what if the gut also helps set the body’s internal clock?

Emerging research suggests that microbial metabolites may play a powerful role in aligning our biological rhythms and short-chain fatty acids are leading the conversation.

Table of Contents:

1. It Started With a Pattern

2. What We Found and Why It Matters

3. A New Lens on Chrononutrition

4. What Clinicians Can Do Now

5. Where We Go From Here

6. Let’s Keep Exploring Together

It Started With a Pattern

In clinical practice, I’ve seen a recurring theme. Individuals do everything right: they optimize their sleep, follow time-restricted eating, and prioritize whole foods, yet still struggle with fatigue, blood sugar swings, or poor sleep. Their labs often look fine. Their effort is never the issue.

What’s off is timing.

The body is rhythmic. And when that rhythm falls out of sync with our environment or behavior, even the best protocols can backfire.

That realization brought me back to a long-standing question. Could microbial metabolites such as short-chain fatty acids (SCFAs) have a direct role in supporting our circadian clocks?

To explore this, we conducted a systematic review titled The modulatory role of short-chain fatty acids on peripheral circadian gene expression: a systematic review, which examined how SCFAs influence the expression of core clock genes like BMAL1, PER1, and CRY1 in peripheral tissues. To our knowledge, it is the first review to synthesize data from both preclinical and clinical studies on this topic (dos Santos A. & Vasylyshyn A. 2025).

What We Found and Why It Matters

Our review, published as The modulatory role of short-chain fatty acids on peripheral circadian gene expression: a systematic review, included eight studies, seven in animal models and one in humans. Across these studies, SCFA supplementation resulted in measurable changes in circadian gene expression in tissues like the liver, kidney, and intestinal epithelium (dos Santos A. & Vasylyshyn A. 2025). It is my latest published article, and it offers new insight into how microbial metabolites can act as biochemical timekeepers across peripheral tissues.

In the only human trial included, sodium butyrate supplementation (600 mg daily) over 12 weeks led to a more than threefold increase in CRY1 expression, with significant rises in PER1, CRY2, and BMAL1 as well (dos Santos A. & Vasylyshyn A. 2025).

This confirms what many of us have suspected. Gut-derived molecules do not just support digestion or immunity. They can help coordinate systemic biological rhythms.

A New Lens on Chrononutrition

This finding gains more depth when viewed alongside emerging data in the field of chrono-nutrition. It is not just what you eat that matters. It is when you eat and how that timing interacts with microbial activity and gene expression.

Recent research shows that SCFAs can influence epigenetic regulators like histone deacetylases (HDACs), which in turn shape the accessibility of circadian gene sequences (de Oliveira Melo N.C. et al., 2024). Butyrate, a major SCFA, is one of the most potent HDAC inhibitors known in nutritional science. In the gut epithelium, this helps regulate inflammation and barrier function. But the same mechanism may also promote circadian gene activation in tissues beyond the gut (dos Santos A. & Vasylyshyn A. 2025).

There is growing evidence that meal timing, microbiota rhythms, and gene expression are deeply interconnected. A misaligned eating schedule can disrupt microbiota composition and SCFA production. That, in turn, may interfere with core circadian processes tied to glucose metabolism, hormone release, and immune signaling (Franzago M. et al., 2023).

In other words, SCFAs may be one of the missing links between nutritional timing and systemic circadian alignment.

What Clinicians Can Do Now

While more human data is needed, these findings are already informing how I approach circadian disruption in practice. Here are four strategies to consider:

• Prioritize fermentable fibers. Encourage foods like inulin, flaxseed, legumes, and cooked-and-cooled potatoes to promote SCFA production (dos Santos A. & Vasylyshyn A. 2025)

• Align fiber intake with the active phase. SCFAs follow a diurnal rhythm and exert their strongest effects when produced during the body's daytime feeding window (Franzago M. et al., 2023)

• Support gut barrier function. Nutraceuticals like butyrate, glutamine, and polyphenols reinforce epithelial health while also modulating circadian genes through epigenetic signaling (de Oliveira Melo N.C. et al., 2024)

• Personalize by chronotype. Evening types or shift workers may have altered microbial rhythms and different responses to SCFA-based strategies. Consider tailoring timing interventions accordingly (Franzago M. et al., 2023)

This is not just gut health. It is clock health. And it may be one of the most modifiable levers we have.

Additional Systemic Benefits of SCFAs

Beyond gene expression, our review also noted that SCFA supplementation influenced key metabolic and inflammatory pathways. For example, studies showed reductions in TNF-α and improvements in insulin sensitivity alongside circadian gene changes (dos Santos A. & Vasylyshyn A. 2025).

One study reported enhanced glucose tolerance following butyrate administration, suggesting a potential therapeutic role in metabolic disorders (dos Santos A. & Vasylyshyn A. 2025). Other findings included decreased expression of pro-inflammatory genes and improved gut barrier function.

This suggests that SCFAs may offer dual benefits, both as molecular clock modulators and as regulators of systemic health (dos Santos A. & Vasylyshyn A. 2025).

Where We Go From Here

Our review represents a first step. The human data is limited, and the ideal dose, timing, and type of SCFAs remain unclear. We need more studies to determine whether dietary or supplemental SCFAs can improve metabolic markers, sleep quality, and inflammation by restoring circadian rhythm alignment (dos Santos A. & Vasylyshyn A. 2025).

What is also clear is that timing matters. Introducing SCFAs outside of circadian context, especially in misaligned schedules like shift work, could diminish or even reverse their benefits (Franzago M. et al., 2023).

Still, the path forward is exciting. We are entering an era where nutrition and timing are no longer separate variables but part of the same therapeutic equation.

Let’s Keep Exploring Together

If this article resonated with your clinical perspective or your personal curiosity, I invite you to share it with your colleagues. The connection between gut health, gene expression, and circadian rhythm is still emerging, and your insight could help expand the conversation.

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References:

1. dos Santos A. & Vasylyshyn A. (2025). The modulatory role of short-chain fatty acids on peripheral circadian gene expression: a systematic review. Frontiers in Physiology. https://doi.org/10.3389/fphys.2025.1595057

2. de Oliveira Melo N.C., Cuevas-Sierra A., Felício Souto V., Martínez A. (2024). Biological Rhythms, Chrono-Nutrition, and Gut Microbiota: Epigenomics Insights for Precision Nutrition and Metabolic Health. MDPI. Biomolecules. https://doi.org/10.3390/biom14050559

3. Franzago M., Alessandrelli E., Notarangelo S., Stuppia L., Vitacolonna E. (2023). Chrono-Nutrition: Circadian Rhythm and Personalized Nutrition. MDPI. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms24032571