TABLE 2.

Metabolites produced by the gut microbiota that have reported modulations on mitochondrial function.

Microbial metabolites	General function	Effect on the mitochondria
SCFAs (Butyrate)	- Butyrate is an energy source for colonocytes resulting from fermentation in the large intestine by gut microbiota - Butyrate is a fatty acid oxidized in the mitochondria - Increases oxidative phosphorylation - Protects from insulin resistance and fatty liver - SCFAs modulate lipid and glucose metabolism and display antidiabetic effects (Monfort-Ferré et al., 2022)	- Targets hepatic mitochondria to revert insulin resistance in diet-induced obese mice - Improves fatty acid oxidation - Improves mitochondrial cell energy metabolism - Indirectly combats obesity, fat accumulation and insulin resistance (Zhao et al., 2021; Monfort-Ferré et al., 2022)
Phytoestrogens (isoflavones and flavonoids)	- Shown to have estrogenic and antiestrogenic effects (Kossoff et al., 2009) - Flavonoids are plant secondary metabolites known for their benefits on human health: antioxidants, anticarcinogenic, antibacterial, anti-inflammatory, and antidiabetic (Kyriazis et al., 2022) - Consumption of flavonoids significantly decreases risk of cardiovascular diseases, breast cancer, and osteoporosis (Patterson and Sears, 2017)	- Flavonoids can modulate and ameliorate mitochondrial function to contribute to cytoprotection (Kossoff et al., 2009) - Interacts with potassium channels of the inner mitochondrial membrane to increase K+ ions in the mitochondria - Flavonoids regulate apoptosis, reduce ROS which are usually a byproduct of mitochondrial oxidation cycles - Flavonoids stimulate mitochondrial biogenesis - Overall decrease in mitochondrial dysfunction which can be applied to human diseases (Kim, 2018)
Bile acids	- Regulate gut microbiome and lead to microbial/bacterial dysbiosis when levels in the intestine are low (Rietjens et al., 2016) - Facilitate digestion and absorption of lipids in the small intestine as well as regulate cholesterol, energy, and triglyceride homeostasis (Stojanov and Kreft, 2020) - Bile acids have antimicrobial properties that impact gut microbes (Rietjens et al., 2016) - Activate the innate immune system to regulate the composition of the gut microbiome (Rasbach and Schnellmann, 2008)	- Increased bile acid concentration can lead to apoptosis or necrosis by damaging mitochondria - Bile acids can induce mitochondrial toxicity by making the membrane more permeable and eventually leading to cell death (Park et al., 2022)
TMAO (trimethylamine N-oxide)	- Potent pro-inflammatory factor associated with mortality in patients with chronic kidney disease - Alters cholesterol metabolism (increases deposition in artery walls) by promoting atherosclerosis (Vidali et al., 2015) - Plays a role in CVD and neurological disorders (Srivastava et al., 2012) - Implicated in the prognosis of patients with heart failure (Zhang et al., 2018)	- Increased levels of TMAO found in patients with mitochondrial dysfunction when supplemented with L-carnitine (Vanhauwaert et al., 2015) - TMAO impairs mitochondrial energy metabolism in the heart - Increased levels of TMAO impair pyruvate and fatty acid oxidation in cardiac mitochondria and this can further exacerbate cardiovascular events (Marriage et al., 2004) - TMAO inhibits fatty acid oxidation in cardiac mitochondria which in turn decreases the energy produced by cardiac cell (Voicescu et al., 2016; Zhang et al., 2018)
Curcumin	- Influences the microbiota-gut-brain axis by indirectly acting on the CNS - Antioxidant and anti-inflammatory properties aid in prevention and treatment of neurodegenerative diseases (Diebold et al., 2022)	- Curcumin can scavenge ROS, retains mitochondrial membrane potential, enhances mitochondrial biogenesis and fusion activity (Peters et al., 2022) - Can attenuate mitochondrial respiration and biogenesis (Hao et al., 2021) - Can be used to treat neurodegenerative diseases by protecting CNS cells from mitochondrial dysfunction (Peters et al., 2022)