The Crosstalk between the Gut Microbiota and Mitochondria during Exercise

Abstract

Many physiological changes occur in response to endurance exercise in order to adapt to the increasing energy needs, mitochondria biogenesis, increased reactive oxygen species (ROS) production and acute inflammatory responses. Mitochondria are organelles within each cell that are crucial for ATP production and are also a major producer of ROS and reactive nitrogen species during intense exercise. Recent evidence shows there is a bidirectional interaction between mitochondria and microbiota. The gut microbiota have been shown to regulate key transcriptional co-activators, transcription factors and enzymes involved in mitochondrial biogenesis such as PGC-1α, SIRT1, and AMPK genes. Furthermore, the gut microbiota and its metabolites, such as short chain fatty acids and secondary bile acids, also contribute to host energy production, ROS modulation and inflammation in the gut by attenuating TNFα- mediated immune responses and inflammasomes such as NLRP3. On the other hand, mitochondria, particularly mitochondrial ROS production, have a crucial role in regulating the gut microbiota via modulating intestinal barrier function and mucosal immune responses. Recently, it has also been shown that genetic variants within the mitochondrial genome, could affect mitochondrial function and therefore the intestinal microbiota composition and activity. Diet is also known to dramatically modulate the composition of the gut microbiota. Therefore, studies targeting the gut microbiota can be useful for managing mitochondrial related ROS production, pro-inflammatory signals and metabolic limits in endurance athletes.

Keywords: endurance; energy; gut microbiota; inflammation; mitochondria; oxidative stress.

Figure 1

The bidirectional crosstalk between the gut microbiota and mitochondria. Gut microbiota to mitochondria crosstalk: Recent evidence shows there is a bidirectional crosstalk between the gut microbiota and mitochondria. Microbiota and their byproducts (SCFA and secondary bile acids) regulate redox balance and energy production. Secondary bile acid metabolism might also directly modify mitochondrial biogenesis, inflammation and intestinal barrier function in different types of cells (Gao et al., ; Korecka et al., ; Alex et al., ; Caron et al., ; Kazgan et al., 2014). In the mitchondria of colonocytes, butyrate undergoes FAO which produces acetyl-CoA that enters the TCA cycle resulting in ATP and CO₂ (Donohoe et al., 2011). Among the SCFA, butyrate is a key regulator of energy production and mitochondrial function by inducing PGC-1α gene expression in skeletal muscles and brown adipose tissue (Gao et al., 2009) and improving respiratory capacity and FAO via AMPK-ACC pathway activation (Mollica et al., 2017). Mitochondria to microbiota crosstalk: Mitochondria regulate gut functions (Igarashi and Guarente, ; Wang et al., 2016), such as intestinal barrier protection (Peng et al., 2009) and mucosal immune response, which help maintain the mucus layer (Ma Y. et al., 2014) and intestinal microbiota (Shimada et al., ; Caron et al., 2014). SIRT1 maintains intestinal barrier function through various mechanisms such as enhancing crypt proliferation and suppressing villous apoptosis (Wang et al., 2012), stimulating intestinal stem cell expansion in the gut (Igarashi and Guarente, 2016), regulating tight junction expression of zonulin ocludin-1, occludin and claudin-1 during hypoxia (Ma Y. et al., 2014). Mitochondrial genome variants may affect the gut microbiota composition. For example, polymorphisms in the ND5, and CYTB genes or D- Loop region of mitochondrial genome have been associated with specific gut microbiota compositions like Eubacterium and Roseburia, which are butyrate producers (Ma Y. et al., 2014). Additionally, the European haplotype HV has been associated with decreased odds of severe sepsis, higher OXPHOS capacity and ROS and RONS production (Jiménez-Sousa et al., 2015) as well as elevated VO_2max and aerobic ATP production in response to exercise (Martinez et al., 2010).

Figure 2

The gut microbiota's regulation of mitochondrial energy production. Top left to right: In the colon, the gut microbiota ferment indigestible dietary fiber such as resistant starch and oligosaccharides to produce SCFA in the intestines that can account for up to 10% of human caloric requirements (den Besten et al., 2013). SCFA are key mediators of mitochondria energy metabolism and act as ligands for free fatty acid receptors 2 and 3 (FFAR2, FFAR3) that regulate glucose and fatty acid metabolism (den Besten et al., ; Kimura et al., 2014). SCFA regulate SIRT1 which plays a role in mitochondrial biogenesis via PGC-1α deacetylation, (Lakhan and Kirchgessner, ; Radak et al., 2013). In skeletal muscle cells, butyrate phosphorylates AMPK and p38 which then activates PGC-1α and thus FAO and ATP production. Butyrate also activates AMPK via UCP2-AMPK-ACC pathway (den Besten et al., 2015). Commensal bacteria such as Lactobacillus rhamnosus CNCMI–4317 has been associated with increased Fiaf expression (Jacouton et al., 2015). In lamina propia macrophages, SCFA also inhibit NF-κB activation that reducing inflammation associated with ulcerative colitis (Lührs et al., 2002). The result is increased mitochondrial biogenesis, FAO, OXPHOS, oxygen usage, glucose uptake, AMP, ATP ratio and glycogen breakdown and reduced apoptosis (Lantier et al., ; Canfora et al., ; den Besten et al., 2015). Bottom left to right: Anaerobic bacteria degrade 5–10% of bile acids (Gérard, 2013), and secondary bile acids regulate carbohydrate and lipid metabolism by modulating the transcription factor receptors farnesoid X receptor (FXR) and G-coupled membrane protein 5 (TGR5) resulting is increased FAO and OXPHOS (Nie et al., 2015). FXR mediates carbohydrate metabolism via regulating SIRT1 and Fiaf expression as well as SREBP-1c and ChREBP activation (Kuipers et al., ; Joyce and Gahn, 2016) and fatty acid metabolism via PPAR-α activation (Joyce and Gahn, 2016). There is increasing evidence that secondary bile acid metabolism might also directly modify mitochondrial biogenesis, inflammation and intestinal barrier function in different types of cells (Gao et al., ; Korecka et al., ; Alex et al., ; Caron et al., ; Kazgan et al., 2014). The result of SCFA and secondary bile acid's role in mitochondrial biogenesis is better overall athletic performance due to better oxygen uptake, energy availability and fatigue resistance.

Figure 3

The gut microbiota's regulation of mitochondrial ROS production. Top left to right: Athletes have two major sources of ROS and RONS: the mitochondrial electron transport chain and the intestinal epithelial cells and transmigrating neutrophils in the gut lumen (Holland et al., 2015) in which free radicals such as NO and superoxide are produced (Fisher-Wellman and Bloomer, ; Gomes et al., ; Radak et al., 2013). Poorly trained individuals and athletes who overtrain are at a higher risk of suffering from oxidative stress (Radak et al., 2008) causing ROS-induced DNA (Radak et al., 2013), which increases mutations in DNA (Green et al., 2011), shortens telomere length (Wallace et al., 2010) and alters mitochondrial biogenesis (Sahin et al., 2011). Bottom left to right: The excessive release of stress hormones overtrained athletes experience as well as increased body oxygen uptake can generate ROS and RONS in the tissues that undergo ischemia and hypoperfusion (Mach et al., 2017). Ischemia-induced intestinal hyperpermeability (Holland et al., 2015) can induce LPS translocation and an inflammatory cascade of TNFα (Clark and Mach, 2016), the ROS-triggering OXPHOS inhibitor and inflammasome NLRP3 which results in a mitochondria-mediated inflammatory responses (Green et al., ; de Zoete and Flavell, 2013) and mitophagy (Shimada et al., 2012), as well as NF-κB, IL-1β, IL- 6, and IL-8 expression (Liu et al., 2012). TNFα and IL-6 inhibit AMPK activation, which reduces glucose metabolism and FAO in mitochondria (Steinberg et al., ; Lim et al., ; Viollet et al., ; Andreasen et al., 2011). Reduced expression of uncoupling protein 2 (UPC2) can lead to partial uncoupling of mitochondrial OXPHOS (Crouser et al., 2002) and elevated ROS production (Saint-Georges-Chaumet et al., 2015). Furthermore, pathobionts (i.e., Fusobacterium, Veillonella, and Atopobium parvulum) can produce hydrogen sulfide (H₂S) and nitrogen oxide (NO) which favors infectious proliferation and inflammation (Mottawea et al., 2016), inhibition of COX activity and butyrate β-oxidation in the colon (Leschelle et al., ; Blachier et al., 2007) which negatively affects mitochondrial function and energy production (Blachier et al., ; Mottawea et al., 2016). On the other hand, SCFA such as N-butyrate and secondary bile acids, might influence mitochondrial functions related to energy production, mitochondrial biogenesis, redox balance and inflammatory cascades, making it a potential therapeutic target for endurance (Circu and Aw, ; Bär et al., ; den Besten et al., ; Mottawea et al., 2016).