The Ancestral Link Between the Microbiome and Mitochondria

It is not news that mitochondria are not the ONLY powerhouses of our body. Indeed, our gut microbiome can metabolize foods that were thought to be undigestible and therefore didn’t provide energy to our body. Furthermore, this overlapping metabolic function between mitochondria and the microbiome is yet another form of symbiosis. Our evolution from a single-cell unit to a multi-cellular living creature is the foundational phenomenon of this microbiome-mitochondrial communication. Ultimately, the microbiome’s overlapping metabolic functions and the mitochondria directly affect our cardiometabolic and immunologic functions. Nevertheless, the microbiome surpasses our genetic and cellular content, and as a host, it is our responsibility to provide an environment in which beneficial bacteria can live and grow. In turn, microbiome-derived metabolites will contribute to supply energy to mitochondria in the skeletal muscle giving metabolic stability.

Nutrition: Mitochondria and the Microbiome

The connection between what we ingest, digest, and metabolize in our mitochondria has always been the classical way to understand energy production and tissue preservation. However, today we know that the microbiome can produce metabolites that promote mitochondrial function and biogenesis. 

Mitochondrial biogenesis describes mitochondrial replication and the capacity of these new mitochondria to increase ATP production. This biogenesis mechanism coincides with the growth of specific bacterial strains and the production of gut-derived metabolites. In particular, the interaction between bacterial diversity and nutritional components such as urolithin A, short-chain fatty acids (SCFA), and lactate is responsible for mitochondriogenesis.

Nutritional compounds like SCFA and ellagitannins are promoters of gut-derived metabolites butyrate and urolithin A, respectively. Nonetheless, butyrate is associated with bacterial strains like Clostridium and Butyvibrio, whereas urolithin is produced mainly by Lactobacilli and Bifidobacterium. Recently, urolithin A has been associated with the novel bacterial strain Akkermansia muciniphila.

Furthermore, the production of butyrate and urolithin A coincides with higher microbial diversity and abundance of other gut-derived metabolites that in turn favor the growth of beneficial bacteria. Besides this beneficial effect, butyrate increases AMP kinase activation leading to mitochondriogenesis, adding another layer of symbiosis to this axis.

Butyrate confers stability and reproducibility to colonocytes in germ-free mice. Therefore, it is only natural to hypothesize that the same bacterial strains that produce butyrate can induce metabolic homeostasis. 

Lactic acid also provides an environment promoted by lactobacilli and bifidobacteria (and possibly mitochondria). Indeed, lactic acid enhances the production of butyrate by microbiota and the production of ATP.

There is growing speculation of a connection between muscular lactic acid production and microbiome function. This theory could open the border of the gut microbiome to bacteria outside the gut in this interaction.

Consequently, the observations of the abundance of bacterial strains like Clostridiaceae and higher concentrations of lactic acid in blood after exercise can prove this metabolic-microbiome-muscle interaction.

Exercise, mobility, and mitochondrial health

Muscle represents the largest tissue mass in our body, and it also contains the highest amounts of mitochondria, which means it is the most metabolically active tissue. There is a coincidental interplay between the host’s fitness, muscle mass, and butyrate levels. This has been studied and measured, with the result being that a higher fitness level of the host associates with higher fecal butyrate levels. Also, higher levels of Clostridium spp and lactobacilli in feces exist in those patients with a good fitness level. 

Consequently, there is a clear link between the higher oxidative capacity and mitochondrial function and more elevated butyrate and urolithin A levels.

Aging, muscle, and microbiome

There is a clear association between aging, the loss of muscle mass, and microbiome dysbiosis. Indeed, this interaction plays a determinant role in the host’s metabolic function. Therefore, new therapeutic strategies encompassing probiotic supplementation in combination with prebiotics and a comprehensive physical activity guideline can be the cornerstone of anti-aging strategies.

A tale as old as time is the never-ending quest to keep youth and defeat the disease. However, the interaction between the cell mitochondria and the gut microbiome is not only old but ancient. There is a reason why these microbes are still living with us and through us, and how they have developed a way to benefit us by multiple pathways. The answer to what we need to “hack” aging is in the gut by promoting microbiome diversity and producing suitable gut-derived metabolites. In turn, we get new and better functioning mitochondria that create an environment of metabolic homeostasis and enhances body composition. – Ana Paola Rodríguez Arciniega

References:

Franco-Obregón, A., & Gilbert, J. A. (2017). The Microbiome-Mitochondrion Connection: Common Ancestries, Common Mechanisms, Common Goals. mSystems, 2(3), e00018-17. doi.org/10.1128/mSystems.00018-17

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