TABLE 1.

Critical mitochondrial metabolites with various signaling functions and their potential implication on the microbiota composition and function.

Mitochondrial metabolites	Function	Effect on the microbiome
Reactive Oxygen Species (ROS)	- Role in signaling and cellular balance at lower levels - Cell damage and interference in cell signaling (Ballard and Towarnicki, 2020)	- High levels contributes to microbial dysbiosis and reduced bacterial diversity in the gut microbiota - Facilitate mobilization of resident stem cells to support epithelial integrity (Ballard and Towarnicki, 2020)
Lactate	- Molecule used for glycogenesis and gluconeogenesis in the liver (acts as an energy source) - Signaling molecule in the brain that is associated with long-term memory in vivo - Lactate transport as a result of exercise regulates muscle acidosis (Ballou et al., 2016; Lee et al., 2021)	- Can inhibit the growth of some pathogens such as E. coli O157 (McWilliam Leitch and Stewart, 2002) - Lactate-utilizing bacteria can promote the growth of butyrate and propionate-producing bacteria (Sheridan et al., 2022) - However, it has also been reported that lactate of host origin can support the growth of certain pathogens such as Salmonella and C. albicans, which has been found to supress the production of butyrate (Gillis et al., 2018) - Increased levels of D-lactate can exacerbate symptoms of chronic fatigue syndrome (CFS) in patients due to its direct or indirect neurotoxic effects - High concentrations of lactate has been associated with some colonic disorders such as colitis and bowel syndromes (Taylor et al., 2022) - High concentrations of fecal lactic acid were related to lower risks of dementia (inverse association with the presence of dementia which indicates that lactic acid can be protective against dementia) (Wang et al., 2014)
Succinate	- A substrate in the citric acid cycle that plays a role in oxidative metabolism by interacting with mitochondrial electron transport chain to produce ATP (Matheoud et al., 2019) - Signaling molecule in thermogenesis (Matheoud et al., 2019) - Plays a role in maintaining gut homeostasis as it is produced by the microbiota and the host (Ferreyra et al., 2014) - Produced during bacterial fermentation of dietary fibers	- Plays a role in intestinal and extra-intestinal diseases that are associated with dysbiosis of the microbiota - Host and microbiome-derived - There is a link between dysbiosis, succinate accumulation and inflammation; Increased succinate can stimulate pro-inflammatory states by polarizing macrophages and increase intestinal inflammation (Wei et al., 2023) - Succinate can exacerbate some diarrheal diseases - Accumulation is associated with Inflammatory Bowel Disease (IBD) (Serena et al., 2018; Monfort-Ferré et al., 2022) - High levels of circulating succinate is associated with obesity, possibly by altering the gut microbiome composition. (Ferreyra et al., 2014) - Can be targeted for the treatment of obesity (Ferreyra et al., 2014); succinate can improve glucose utilization in the context of obesity (Canfora et al., 2019) - Succinate also indirectly promotes colonization resistance from other invading pathogens but some have reported succinate’s ability promote the growth of a variety of gut microbiota, both commensal and pathogenic such as Salmonella (Yan et al., 2022)
Cytochrome C	- Released into the cytosol from mitochondria and triggers apoptosis by activating caspase 3 (a protease that enables cell death) - Plays a key role in ATP synthesis by participating in electron transport (Martínez-Reyes and Chandel, 2020)	- Altered function of mitochondria of mucosal cells is associated with intestinal diseases such as colorectal cancer or inflammatory bowel disease - IBD patients demonstrate decreased activity of electron chain transport and thus decreased ATP levels - Mitochondrial dysfunction in the gut is associated with intestinal inflammation, bacterial invasion, and epithelial cell apoptosis as a result of a compromised epithelial barrier (Novak and Mollen, 2015)
Citrate	- Synthesized in astrocytes with high concentrations found in cerebrospinal fluid - Acts as a substrate in the TCA cycle which works to produce ATP (Wu et al., 2020)	- Changes to the microbiome occur when ferric citrate is prescribed to patients with chronic kidney disease (CKD) - Experimental CKD rats treated with ferric citrate showed increased bacterial diversity at levels comparable to normal control rats (specifically, tryptophanase-possessing families in the gut increased) - Administration of ferric citrate prevented further inflammatory states in patients with CKD by increasing gut microbial diversity (Xu et al., 2021a) - Ferric citrate can be used as a beneficial treatment in CKD patients to improve kidney and blood pressure - Citrate is able to trap and feed Fe III) to some Gram-negative bacteria, thus promoting their growth (Wu et al., 2020)
Fumarate	- Intermediate in the TCA cycle - Dimethyl fumarate (DMF), a fumarate derivative, is used as a treatment in patients with multiple sclerosis - DMF detoxifies mycotoxins (Araújo et al., 2011)	- Evidence suggests that DMF may play a role in normalizing the composition of the gut microbiome in an effort to prevent neuroinflammation however, further research is necessary - DMF decreases intestinal permeability and maintains the integrity of the gut epithelial barrier - DMF also increases the diversity and richness of microbiota - DMF was found to inhibit the growth of some pro-inflammatory bacteria and promote the abundance of commensal, albeit controversial, bacteria in patients with MS (Diebold et al., 2022) - DMF stimulated the growth of some commensal bacteria and attenuated gut inflammation (Fu et al., 2023) - In one study, DMF did not majorly affect the mycobiome composition and diversity (Yadav et al., 2022)