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From energy metabolism to vital cell signaling, mitochondria have multiple functions in human physiology, and mitochondrial quality impacts the performance of multiple body systems and tissues. Research continues to explore these mitochondria-body system relationships, with recent studies focused on the mitochondria and gut microbiome connection.

Hypotheses suggest the presence of a gut microbiome-mitochondria axis and that the balance and health of this axis may contribute to the prevention or the development of disease.^1-5 Research studies indicate that dysbiosis of the gut microbiota or mitochondrial impairments may play important roles in the pathophysiology of conditions such as chronic intestinal inflammation, inflammatory bowel disease, colorectal cancer, neurodegenerative disease, and depression.^6-10 Recent perspectives suggest that cross-talk interactions occur between gut microbes and the mitochondria of the intestinal epithelial cells, mucosal cells, immune cells, and even neural cells, and that dysfunctional cross-talk in these interactions may be associated with disease.^3,6,11-13

Mechanisms involved in this microbiome-mitochondria connection are not fully understood; however, developments in this area of research continue to clarify the interactions involved and to offer new hypotheses on bidirectional communication pathways. In addition, the expanding field continues to investigate how optimizing a robust mitochondria-gut microbiome relationship may effectively support disease treatments and therapeutic approaches for optimal health.

Bidirectional Pathways: Mechanisms of the Mitochondria-Gut Relationship

While this area of research continues to evolve, the latest literature suggests that the mitochondria-gut microbiome connection is bidirectional, rooted in reactive oxygen species (ROS) and metabolite interactions.^2,14 Mitochondria, through the production of ROS, are believed to have a crucial role in modulating gut functions such as intestinal barrier function and mucosal immune responses.¹⁵ Gut microbiota are believed to regulate key transcriptional co-activators involved in mitochondrial biogenesis, such as PGC-1-alpha.¹⁵ Further, metabolites such as short-chain fatty acids (SCFAs) have been shown to reduce intestinal inflammation¹⁶ and impact mitochondrial gene expression,¹⁷ and may contribute to ROS modulation as well as balance mitochondrial functioning^3,14,17 by reducing the effects of inflammasomes and TNF-alpha-mediated responses.¹⁵

Emerging evidence has also focused on how microbial signaling to mitochondria for the regulation of intestinal epithelial function is impacted by gut dysbiosis. Initial studies suggest that signaling from commensal bacteria to mitochondria enhances epithelial homeostasis, while signaling from pathogenic bacteria results in mitochondrial responses that may impair gut epithelial cell function.⁶ A 2020 in-vitro study investigated a concerning pathogen, adherent-invasive Escherichia coli, implicated in inflammatory bowel disease, and observed its effect on the form and function of colon-derived epithelial cell mitochondria after exposure.¹⁸ Researchers found that the pathogen significantly affected epithelial expression of thousands of genes, many relating to mitochondrial function.¹⁸ The exposed mitochondria appeared swollen, with reduced membrane potential and a fragmented network.¹⁸ Of note, mitochondrial fragmentation indicates excessive division or fission, which has been associated with mitochondrial functional defects that may lead to multiple disease states.¹⁹

Experimental evidence continues to lead to new perspectives on the system-wide impact of the gut microbiome-mitochondria connection. Most recently, researchers have investigated the direct interactions between microbes in the intestines and mitochondria in the brain, prompting new gut-brain axis hypotheses focused on communication pathways and remote functional regulation.^10,13

Clinical Applications: Optimal Mitochondrial Function and Improved Gut Health

The emerging research described above illustrates the interconnectedness of systems throughout the body and demonstrates the importance of a systems biology approach to understand disease and optimize health. Within the gut microbiome-mitochondria connection context, therapies that simultaneously support gut health for optimal mitochondrial function while also specifically supporting mitochondrial health for gut homeostasis may together constitute a synergistic approach to ensuring a robust and healthy gut microbiome-mitochondria relationship.

As an example, the antioxidant and anti-inflammatory benefits from plant-based nutrients, such as polyphenols, have been reported many times, and recent research suggests these plant-based nutrients may also be supportive of mitochondrial biogenesis and function,^20,21 potentially due to the previously mentioned benefit of metabolites such as SCFAs. Further, diets that emphasize the consumption of plants such as the Mediterranean diet have been shown to benefit the gut microbiome,²² with a recent cross-over study of patients with ulcerative colitis finding that a diet of increased fiber intake and low fat decreased markers of inflammation and reduced intestinal dysbiosis.²³ In addition, while one of the suggested benefits of intermittent fasting is the optimization of mitochondrial health,^24,25 a recent randomized controlled trial also indicated that in adults with metabolic syndrome, eight weeks of modified intermittent fasting induced changes in the participants’ gut microbiota communities and increased the production of SCFAs.²⁶

As this research field expands, new preclinical and clinical studies will help document those effective therapeutic approaches, including nutrition, that bridge research avenues to specifically target the microbiota-mitochondria connection for disease treatment and prevention.^3,5 At IFM’s upcoming Bioenergetics Advanced Practice Module (APM), hear more about the latest mitochondria-related research and learn how personalized nutrition strategies and therapeutic food plans can help enhance your patient’s mitochondrial function, energy metabolism, and overall health.

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References

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