The Gut-Brain Axis in Alzheimer’s and Parkinson’s Diseases: The Catalytic Role of Mitochondria

Abstract

Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer’s and Parkinson’s diseases. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer’s and Parkinson’s disease strengthen by cellular, animal and clinical studies.

Keywords

Alzheimer’s disease gut-brain axis gut microbiome metabolites inflammation mitochondria Parkinson’s disease

HUMAN GUT IN HEALTH AND DISEASE

Gut homeostasis

Maintaining a harmonious relationship between the host and gut flora (eubiosis) is essential for overall health, while imbalances (dysbiosis) are linked to a range of diseases, such as inflammatory bowel disease, obesity, diabetes, hypertension, cardiovascular disorders, depression, anxiety, cancer, and neurodegenerative disorders. The diverse human microbiome has substantial benefits to the host, either in metabolic activities, epithelial homeostasis, or immune function [1, 2]. Current research have found the significant role of gut microbiota in generating short-chain fatty acids (SCFAs) (e.g., propionate, butyrate, and acetate), metabolizing phytochemicals (especially polyphenols) and synthesizing essential vitamins (biotin, nicotinic acid, panthotenic acid, folate, riboflavin, pyridoxine, thiamine, and vitamins K and B12) [3 –5]. All of these factors will influence host health, for instance, SCFAs play roles in cellular regulation, anti-inflammatory and anticancer activities, energy source for colonocytes, modulation of appetite regulation, glucose homeostasis and immune system modulation [6].

In addition, gut microbiota significantly impacts epithelial homeostasis, promoting cell renewal, wound healing, and modulating mucus properties [7]. It also contributes to the development of the intestinal mucosal and systemic immune system, influencing the expansion of CD4 + T-cell populations. Bacteria actively interact with pattern recognition receptors (PRRs) on epithelial cells, mediating distinct immune responses depending on whether they are commensals, pathobionts or even pathogens. [8]. The physical presence of the microbiota in the gastrointestinal (GI) tract influences microbial colonization through competition for resources, production of antimicrobial substances, and modulation of the host’s immune responses [9]. Indeed, microbiota induces the production of various antimicrobial compounds, such as antimicrobial peptides and secretory IgA, contributing to host protection against pathogens and maintaining a balanced relationship with commensals [10, 11]. On the other hand, antibiotics and dietary fiber deficiency can alter the gut microbiota, impacting the nutritional landscape and promoting the expansion of pathogenic populations [12]. Thus, and even though, a well-balanced gut microbial community is essential for the host and microbiome to maintain a mutually beneficial relationship, defining an appropriate composition for a healthy microbiome has been challenging due to inter-individualvariation.

Gut-brain axis

Instead of merely existing as passive inhabitants within our bodies, extensive research has unveiled the vital significance of the gut microbiota in influencing the functionality of our immune systems, metabolism, and the development of various organs. The dysbiosis of the gut microbiota is therefore linked to various impairments between this communication (gut-bladder axis, gut-kidney axis, gut-reproductive axis, gut-skin axis, gut-muscle axis, gut-bone axis, gut-pancreas axis, gut-liver axis, gut-lung axis, gut-heart axis, gut-brain endocrine axis, gut-brain axis), and may directly influence human health and the development of diseases [13].

Regarding the microbiota– gut-brain axis, this is a complex network facilitating bidirectional communication between gut bacteria and the brain, crucial for maintaining homeostasis in the GI, central nervous, and microbial systems. Communication pathways involve the autonomic nervous system (including the enteric nervous system (ENS) and the vagus nerve), the neuroendocrine system, the hypothalamic– pituitary– adrenal (HPA) axis, the immune system, and metabolic pathways [14]. As previously mentioned, the gut microbiota produces neuroactive compounds and metabolites that influence host immune responses, metabolism, and neuronal cells. Furthermore, disruption of gut barrier integrity, observed in several neurodegenerative diseases, can impact the passage of signaling molecules. In fact, stress, activating the HPA axis, releases hormones affecting intestinal barrier integrity and gut microbiota composition [15]. Overall, this axis highlights the intricate interplay between the gut microbiota and the nervous system, impacting human physiology. Thus, microbiota and microbial-derived molecules play a crucial role in influencing host behavior and nervous system function [14, 15].

Microorganisms can stimulate the production of metabolites and neurotransmitters that facilitate gut– brain signaling, either by directly producing these compounds or by modulating the host’s immune system. SCFAs play a role in regulating genes involved in microglia maturation and inducing morphologic changes in mice [16].

The gut microbiota also plays a crucial role in shaping the development and function of the peripheral immune system, as well as the development, maturation, and activation of microglia, the innate immune cells in the brain [17, 18]. Germ-free (GF) mice exhibit increased numbers of immature microglia, a condition restored by treatment with bacterial-derived SCFAs. Proper microglia function and development may require a complex microbiota, as the transfer of a full microbiota, but not a limited subset of commensal organisms, rescues microglia deficiencies in GF mice [19]. Gut bacteria, may influence microglia development and activation through transcriptional mechanisms in a sex and time-specific manner [20, 21]. The gut microbiota and the brain also interact through the systemic immune system, where changes in systemic immunity impact immune signaling within the brain [22]. Increased peripheral inflammation, observed in neurodegenerative diseases is associated with alterations in the microbiome, microbial substrates, circulating cytokines and the use of external factors like prebiotics, antibiotics, and probiotics [23]. Cytokines and chemokines can either be produced by brain-resident immune cells or access the central nervous system (CNS) through direct transport across the blood-brain barrier (BBB). Notably, the gut microbiota influences BBB permeability, and studies show that GF mice have increased BBB permeability, partially due to reduced expression of tight-junction proteins [24]. Disruptions in BBB integrity, such as those caused by infections, autoimmune diseases, or injury, may allow microbial products to enter the brain, potentially contributing to neuropathological conditions [25]. The interconnection between gut microbes, systemic immunity and brain outcomes underscores the potential impact of these interactions on neurologicaldiseases.

Gut– brain axis in Alzheimer’s and Parkinson’s diseases

Some cross-sectional studies have highlighted differences in gut microbiota composition between individuals with various neurological diseases and healthy counterparts [26]. Preclinical models of neurological diseases have successfully replicated these alterations in gut microbiota and demonstrated the potential impact of human gut bacteria on behavior and brain pathology in mice. Research have also identified potential probiotics that can alleviate disease symptoms, while others have pinpointed specific bacteria and factors influencing disease progression in mice [27]. Indeed, accumulating evidence demonstrates that communication along the gut microbiota– brain axis plays a role throughout life, influencing neurodevelopmental disorders (e.g., ASD), neurodegenerative conditions (e.g., Parkinson’s disease (PD) and Alzheimer’s disease (AD), and behavioral disorders (e.g., depression and anxiety) [28].

PD is the second most prevalent neurodegenerative disorder globally, affecting over 1% of the elderly population [29]. PD is characterized by progressive neurodegeneration, impacting voluntary movement control due to substantial changes in the nigrostriatal pathway. These changes involve dopaminergic neuron degeneration, α-synuclein (αSyn) aggregation, mitochondrial dysfunction, increased reactive oxygen species, and increased microglia activation. PD symptoms include tremors, difficulty walking, hunched posture, muscle rigidity, and often, GI issues such as constipation, which can precede PD diagnosis by many years [30]. The PD gut is underscored by inflammation, heightened intestinal permeability, and early accumulation of phosphorylated αSyn in the ENS and the dorsal motor nucleus of the vagus nerve [31]. Historical observations and Braak’s hypothesis support the idea that PD pathology might originate in the gut before affecting the brain [32]. Recent studies propose a link between the gut microbiota and PD, with distinctive microbial community composition and serum metabolic profiles in PD individuals [33]. As per meta-analyses and systematic reviews, individuals with PD exhibit a reduction in the abundance of SCFAs producers [34, 35] and individuals with Crohn’s disease face an increased risk of developing PD [36, 37]. Notably, those with Crohn’s disease treated with anti-inflammatory drugs, such has anti-TNFα, are partially protected from PD, suggesting a potential connection between gut inflammation and PD pathology [37]. Studies in mice indicate that GI infections can exacerbate PD-like symptoms, with motor symptoms worsened by intestinal inflammation in a PD mouse model [38]. The gut microbiota may contribute to PD symptomatology through both inflammatory and metabolic mechanisms. Individuals with PD exhibit distinct metabolic profiles compared to healthy individuals, showing changes in metabolites associated with the gut microbiota. Alterations in beta-glucuronate, bile acids, tryptophan, histamine, niacinamide, γ-aminobutyric (GABA) levels, and reduced concentrations of SCFAs are observed [39, 40]. Furthermore, the gut microbiota can impact PD treatments, potentially reducing the efficacy of anti-PD drugs, including standard levodopa treatment [41]. These findings, derived from both human and animal studies, suggest that the gut microbiota might worsen PD pathology by influencing inflammation, promoting αSyn misfolding, altering host metabolism, and compromising the effectiveness of approved PD treatments [42]. Interestingly, certain gut bacteria demonstrate neuroprotective effects and can alleviate symptoms, with potential benefits through the production of butyrate, supporting intestinal barrier integrity [33, 43]. On the other hand, the absence of bacteria that modulate mucin production can be involved in gut permeability. Additionally, the MitoPark PD mouse model, with mitochondrial dysfunction in dopamine neurons, shows that motor dysfunction and dopaminergic neurodegeneration can be mitigated by a probiotic mix administered over a 16-week period [44]. Moreover, work from our group demonstrated that in vivo administration of a microbial toxin induced the erosion of a group of bacteria with important roles in barrier integrity protection leading to an increase in gut inflammation and in αSyn aggregation [45].

AD, the leading cause of dementia, is characterized by brain pathology involving amyloid-β protein (Aβ) plaques and hyperphosphorylated tau protein [46]. The microbial origin of AD has been discussed for years, gaining support from emerging evidence. There is a growing case for a connection between pathogenic microbes and AD development and progression [47]. Experimental evidence suggests that Aβ may act as an antimicrobial peptide in the brain, although proving an infectious etiology is ethically challenging [48]. The relationship between gut proteins and brain health is gaining attention, since amyloid-like proteins expressed by certain gut bacteria can accelerate synuclein aggregation [49]. While the accumulation of Aβ peptide and abnormal tau protein is a traditional AD pathogenic hallmark, it does not imply causality. On the other hand, herpes simplex virus-1 (HSV-1), common in elderly brains can stay dormant in the CNS and contribute to AD. Indeed, examining the humoral response to HSV-1 suggests that virus reactivation, not persistence, may contribute to AD development. Evidence of AD transmission comes from inoculation studies, showing Aβ deposition and tau aberrations after infection with HSV-1 [50]. Studies using GF APP-PS1 mice indicate reduced Aβ pathology, suggesting a role for microbiota in Aβ biology and AD pathogenesis [51]. Aβ itself demonstrates antimicrobial properties in murine AD models [52]. The involvement of microorganisms at key points in the AD pathogenic cycle is evident, but questions remain about whether Aβ accumulation is a malfunctioning immune response or a disease driver [53]. Studies using 5XFAD transgenic mice, modeling human AD, reveal significant alterations in the gut microbiota and amino acid metabolism. Depleting the microbiota with antibiotics reduces inflammation and brain pathology in these mice, suggesting that the gut microbiota contributes to the severity of AD [54]. Recent research in 5XFAD mice also demonstrates microbiota effects on learning and memory, possibly through a mechanism involving microglia [55]. Individuals with AD show shifts in their gut microbiota composition that correlates with pathological Aβ and phosphorylated tau species [56]. Cognitively impaired older adults, especially those with a high Aβ load, exhibit distinct microbiota profiles [57]. However, these findings are observational, and further research is required to establish correlations orcausations.

MITOCHONDRIA AND BACTERIA: FRIENDS OR FOES?

Evolutionary friendship between mitochondria and bacteria

Mitochondria is a membrane-bound structure known as the “powerhouse” of the cell due to its role in cellular respiration [58]. The production of energy in the form of adenosine triphosphate (ATP) makes these organelles crucial in various metabolic functions including calcium storage and homeostasis, cell growth and apoptosis [58].

In 1890, Richard Altmann did the first description of these “elementary organisms”, mentioning their unique features: they are self-replicating and have their own circular DNA (mitochondrial DNA (mtDNA)) [59]. The autonomous metabolic and genetic properties of these multifaceted organelles sparked interest in understanding their evolutionary origins and their significance in health and disease. Remarkably, similarities between mitochondria and bacteria suggested that they share an evolutionary history. Starting with the structure, mitochondria and bacteria share the double-structure membrane and share the same phospholipid: cardiolipin [60]. Moreover, the genome of the mitochondria is circular, similar to bacterial DNA, and it is not associated to histone proteins, unlike the nuclear DNA [60]. Another mechanism inherited from the ancestral mitochondria is the oxidative phosphorylation (OXPHOS) system. The OXPHOS in eukaryotic cells is encoded by mitochondrial, but also nuclear DNA, showing the symbiosis between mitochondria and the host cell [58, 61]. Importantly, the mitochondrial genome encodes 13 proteins essential for mitochondria’s OXPHOS, 12S and 16S rRNAs and 22 tRNAs [62]. Over the years, the improvement of OXPHOS led to an increase of energy generation in the host cell, allowing eukaryotic cells to become more complex at cellular level [63, 64]. In addition, the study of the primary structure of rRNAs allowed the identification of the mitochondrial origin, revealing a close relationship to Alphaproteobacteria [65]. Overall, the identification of these similarities suggests a prokaryotic origin of mitochondria, which is in accordance with the endosymbiotic theory, stating that mitochondria were free-living bacteria that were engulfed by ancestral eukaryotic cells developing a symbiotic relationship with the host cell[66, 67].

Mitochondria as a cellular hub in inflammation

From different perspectives, mitochondria have a crucial role in the regulation of innate immunity and inflammation since its able to activate different PRRs [68]. These PRRs recognize pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS), mannose, flagellins, nuclei acids or damage-associated molecular patterns (DAMPs), molecules resulting from cell damage pathways [69]. There are several families of PRRs: toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and (NOD)-like receptors (NLRs) [69]. Each pathway is involved in the antimicrobial, antiviral or cellular damage response, respectively, and mitochondria is in the center of these pathways’ activation. This organelle is capable of triggering type I interferon and proinflammatory cytokines secretion via Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [58, 70]. In bacterial infections, PAMPs will activate the TLR pathway, which will lead to the increase of mitochondrial reactive oxygen species (mtROS). This increase in mtROS acts as a defense mechanism of host cells to impair the growth of intracellular bacteria by damaging its metabolism, lipid membrane or bacterial genome [71, 72]. On the other hand, some bacteria sustain balanced ROS homeostasis since they benefit from it to grow [72]. Mitochondrial dynamics, more specifically mitochondrial fission, is also a strategy against bacteria proliferation as it leads to the apoptosis of infected cells [73, 74]. In the case of viral infection, mitochondria can detect viral particles through the mitochondrial antiviral signaling protein (MAVS), a protein located in the outer membrane of mitochondria leading to the activation of the RLR pathway. This pathway will also lead to the translocation of NF-kB to the nucleus activating the expression of proinflammatory genes [75]. In this context, contrary to what occurs in the TLR pathway activation, it has been demonstrated that the interaction of MAVS with mitofusin proteins (MFNs), involved in mitochondrial fusion, is crucial for the activation of the RLR pathway [76, 77]. In the presence of cellular damage, mitochondria are also implicated in mounting a response through NLR pathway where NLR family pyrin domain containing 3 (NLRP3) inflammasome is activated [58]. The first step of this pathway is related to the activation of TLR and production of pro-IL1β, previously activated by PAMPs, which allow NLRP3 to interact to ASC and pro-Caspase-1 leading to (NLRP3) inflammasome activation. This will prompt caspase 1 activation that will cleave pro-IL-1β into IL-1β. This proinflammatory cytokine will be released in the circulation, leading to the recruitment of inflammatory cells to the infection site inducing a Th1 response and increased cytotoxic activity [78 –80]. Therefore, mitochondria emerge as an important trigger for innate immune responses against virus, bacteria or tissue damage.

Since mitochondria and bacteria share a common ancestor, some mitochondrial components can have a high DAMP potential [81]. The phospholipid cardiolipin is considered a mitochondrial DAMP since it can translocate from the inner to the outer membrane to bind NLRP3 [82, 83]. Another mitochondrial DAMP, capable of NLRP3 inflammasome activation, are mtROS. Several studies have shown that different factors, like the accumulation of damage mitochondria, ATP depletion or even fatty acid accumulation induced by a long-term high-fat diet, leads to increased mtROS production and, consequently, activation of NLRP3 inflammasome [84, 85]. Esteves and colleagues showed that β-N-methylamino-L-alanine (BMAA), a non-proteinogenic diamino acid produced by cyanobacteria, may be involved in neurodegeneration since it targets mitochondria leading to mitochondrial fragmentation and cardiolipin exposure, inducing the activation of innate immune responses. This study reveals the capacity of microbial molecules selectively targeting mitochondria as a bacterial competitor. Moreover, this study also corroborates that mitochondrial components exhibit a high DAMP potential, activating neuroinflammation pathways that ultimately contribute to neurodegeneration [86].

In 2011, Nakahira identified another mitochondrial DAMP, able to activate NLRP3 inflammasome: mtDNA [87]. After that, several studies have shown that mtDNA, released into the cytosol, can trigger immune responses like an antiviral immune response [88, 89] and its oxidation is capable of inflammasome activation [88, 90]. Moreover, MAVS is already known to be essential for the recruitment of NLRP3 to mitochondria [91]. Hence, understanding the intricate relationship between mitochondria and inflammation is crucial for unravelling the mechanisms underlying inflammatory diseases.

Mitochondria as a connector between neuroinflammation and neurodegeneration

Mitochondrial dysfunction, neuroinflammation and oxidative stress are highly associated to the neurodegenerative process of disorders such as AD and PD [92]. The correlation between mitochondrial dysfunction and neuroinflammation is well-established, as inflammatory factors can induce mitochondrial dysfunction, a known trigger of neuroinflammation. Despite the controversy, there are strong evidence showing that mitochondrial damage precedes neuroinflammation in these disorders, yet the underlying mechanisms remain to be elucidated.

Considering the important role of this organelle, a healthy mitochondrial network is crucial for cell survival and function. On the other hand, alterations in mitochondrial dynamics, increased ROS production, mutations on mtDNA and impaired mitochondrial membrane potential are strongly linked to abnormal innate immunity activation and cell death [93, 94].

When comparing various cell types, neurons have a higher energy demand. Consequently, they rely more on mitochondria bioenergetics, making them more susceptible to its dysfunction [95]. Knowing this, targeting mitochondria dysfunction and clarification of the process and its consequences seem to be an effective strategy against neurodegenerative diseases such as AD and PD.

Regarding AD, a study revealed that an AD mice model develops impaired mitochondrial energetics, 6 months prior to Aβ accumulation. This suggests that mitochondria dysfunction is one of the initial contributors to AD pathology [96]. Mitochondrial bioenergetics is also associated with the neurodegenerative process observed in PD since it starts in the long and extensively branched axons, characterized to have higher ATP demands. These neurons are particularly more affected by the presence of dysfunctional mitochondria [97]. Similarly, synapse degeneration is also compromised in AD due to disruptions in mitochondrial transport and function induced by the neuronal accumulation of AD-related proteins, namely Aβ and tau [98]. Interestingly, Parkin and PINK1, PD-related genes, are also mitochondrial quality control genes [99]. The upregulation of these genes prevents the neurodegeneration due to αSyn gene overexpression [100, 101].

Overall, throughout the progression of neurodegenerative pathways in AD or PD, there are shared points, all intricately related to mitochondrial dysfunction [95]. These include compromised metabolism [102 –104], increased oxidative stress [105, 106], alterations in mitochondrial dynamics [103, 107] and disrupted mitochondrial mechanisms like biogenesis [97, 102], transport [102, 108] and mitophagy [103, 109]. Ultimately, the accumulated dysfunctional mitochondria that was not eliminated by mitophagy will release their content, the mitochondrial-derived DAMPs, into the cytoplasm. As mentioned before, due to the common ancestrally of mitochondria with bacteria, these mitochondrial— derived DAMPs will be recognized as bacteria or a pathogen, triggering the innate immune mechanisms, enhancing the neuroinflammatory process.

Although neuroinflammation is considered a protective mechanism, excessive activation of these processes can result in tissue damage and disease. Microglia are the first mediators of neuroinflammation, able to respond to the presence of PAMPs and DAMPs, and responsible for the elimination of harmful molecules, dead cells and protein aggregates [110]. However, the release of mitochondrial-derived DAMPs from dysfunctional mitochondria exacerbates the activation of these cells, causing stress to heathy neurons leading to gradual neuronal loss [111].

Current research has shown that mitochondrial dysfunction is the primer for the neurodegenerative process where glial cells recognize mitochondrial-derived DAMPs as pathogenic molecules, triggering the onset of neuroinflammation. Overall, this interplay between mitochondria and inflammation contributes significantly to the progression of neurodegenerative diseases.

MITOCHONDRIA ROLE IN GUT MICROBIOME-HOST CROSSTALK IN ALZHEIMER’S AND PARKINSON’S DISEASES

A varied and healthy gut microbiome is crucial to maintain intestinal health. Mitochondria and ROS have been shown to play an important role in the preservation of gut epithelial homeostasis and to maintain the GI microbial community’s biodiversity. The gut epithelium protects itself against toxins, pathogens or other environmental factors by producing ROS, antimicrobial peptides and mucus. ROS, for instance, harbours an important microbicidal mechanism among innate immune cells [112]. Briefly, upon exposure to stress the gut epithelium can promote inflammation which is coupled with the production and release of ROS by mucosa-resident cells or by newly recruited innate immune cells being essential for antimicrobial responses [113]. Several reports indicate that mitochondrial function and metabolism have a crucial role in intestinal epithelium self-renewal, differentiation, and homeostasis, thereby establishing the mature intestinal crypt phenotype. Intestinal stem cells, located between terminally differentiated Paneth cells at the bottom of the intestinal crypt, are critical for small intestinal epithelium self-renewal. Importantly they show high mitochondrial activity and when mitochondrial function is inhibited stem cell function is affected [114]. Another study demonstrated that mitochondrial dysfunction reduces stemness and leads to dysfunctional Paneth cell phenotype [115]. Several reports also show that variations in mtDNA may also influence intestinal health trough alterations in gut microbiome profiles [116, 117]. In intestinal epithelial cell– specific mouse models, loss of Hsp60, a mitochondrial chaperone, results in mitochondria dysfunction which results in the loss of crypts stemness and cell proliferation [118]. Moreover, Hsp60 has been identified as a regulator of anti-bacterial immunity through p38 MAP kinase signaling [119].

Peroxisomal proliferator-activated receptor-α (PPARα) seems to display an important role in the cross-talk between microbial metabolism and epithelial repair as a potential mitochondrial target for restoring gut barrier function in gut inflammatory diseases [120]. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis, has been shown to be decreased in the intestinal epithelium of patients with inflammatory bowel disease. Also, PGC-1α activation was found to protect against gut inflammation by promoting mitochondrial homeostasis within the intestinal epithelium [121]. Remarkably, natural antioxidants (e.g. resveratrol), have been shown to reduce chronic intestinal inflammation [122].

Gut microbiota are able to alter cellular ROS and regulate oxidative stress by modulating mitochondrial activity [123]. Some gut bacteria can produce nitric oxide (NO) and influence host metabolism [124]. As previously mentioned, the gut microbiome can produce small metabolites, such as SCFAs, that can influence mitochondrial homeostasis, intestinal physiology, and host health [125]. Butyrate and propionate have been shown to enhance mitochondrial function in several reports [126 –128]. In addition, acetate was shown to improve intestinal defence mediated by epithelial cells [129]. SCFAs were also reported to reduce ROS production by inducing the production of the antioxidant glutathione [130]. Importantly, SCFA’s concentrations were found to be reduced in both PD and AD patients [131, 132]. Gut microbiota can also alter mitochondrial function by affecting host’s neurotransmitter levels, such as GABA, serotonin (5-HT), and dopamine (DA). For instance, excessive DA induces mitochondrial dysfunction through a decrease in mitochondrial respiratory control and loss of membrane potential [133].

Most interestingly, ROS act as a double-edged sword in the gut. Excessive ROS perpetuates mucosal inflammation which causes cellular and molecular damage [134]. Beltran and co-workers suggested that persistent mitochondrial dysfunction and oxidative damage may contribute to gut epithelial barrier disruption in several GI pathological disorders [135]. As previously mentioned, accumulating evidence shows the importance of the gut-brain axis contribution in AD and PD neurodegeneration positing the crucial role of oxidative stress and overall inflammation in which gut dysbiosis is also involved [136]. Work from our group demonstrated that a bacterial toxin induced gut inflammation and gut barrier disruption that potentiated BBB permeability and neuroinflammation, which culminated in nigrostriatal neuronal damage and PD-like motor dysfunction [45]. As formerly stated, this neurotoxin targeted the mitochondria. Moreover, gut microbiota dysbiosis and inflammation have been observed in mouse models of PD that are known to induce parkinsonism through mitochondrial dysfunction. Notably, MPTP-treated mice harbour a decrease in the abundance and diversity of the microbiota [137]. Similarly, gut microbiota in rotenone-treated mice is altered which caused systemic inflammation and neuroinflammation culminating in dopaminergic neurodegeneration [138]. In a PINK1 KO mice model bacterial infection aggravated PD symptoms by prompting gut inflammation [139]. On the other hand, different infectious agents and/or microbiota metabolites were shown to affect mitochondrial function. We demonstrated that bacterial infection induced αSyn oligomerization in the ileum, together with a local and systemic pro-inflammatory environment that ultimately culminated in neuronal mitochondria dysfunction [140]. Likewise, exposure of mesencephalic neurons to an environmental alphaproteobacterium contributed to innate immunity activation and to αSyn oligomers accumulation that interact with mitochondria, leading to their dysfunction [141]. Similarly to PD, LPS was also shown to induce mitochondrial dysfunction and activate neuronal innate immunity, ultimately culminating in tau and Aβ pathology [142]. As aforementioned, there has been a growing association between Aβ production and antimicrobial response. In fact, Aβ seems to act as an antimicrobial peptide being an important innate immune effector in preventing infections [143, 144]. On the other hand, acute and chronic exposure to Aβ results in gut microbiome dysbiosis [145] and leads to intestinal alterations [146]. Other metabolites produced by gut microbiota were reported to affect mitochondrial function. Urolithin A has been found to maintain mitochondrial Ca^2 + and ROS homeostasis, thereby preventing amyloidosis and cell death in a streptozotocin (STZ)-induced diabetic mouse model [147]. Likewise, ghrelin, an intestinal peptide hormone whose secretion is modulated by commensal bacteria [148] was reported to protect from Aβ-induced mitochondrial dysfunction [149].

Another interest reciprocal regulation is that of microRNAs (miRNAs) and gut microbiota. Remarkably, secreted microRNAs from intestinal epithelial cells are able to enter bacteria and regulate its gene expression, therefore shaping the gut microbiome [150]. On the other hand, gut microbiome can modulate host miRNA expression affecting gut homeostasis [151]. Accumulating evidence underscores the role of faecal miRNAs in modulating gut microbiota and keeping intestinal homeostasis [152]. Importantly, a report from 2019 examined potential interactions between miRNAs and the human gut metagenome and identified numerous miRNAs relevant for PD and AD that are key regulators to bacterial secretion system, LPS biosynthesis and biofilm formation [153]. In fact, miRNAs alterations have been implicated in the pathogenesis of several gut and brain disorders, including AD and PD, highlighting the importance of miRNAs in maintaining gut-brain axis homeostasis and as well in mitochondrial function [152, 154]. For instance, miRNA-155 which was found to be up-regulated in AD patient’s brains [155], is expressed in intestinal immune cells, controls gut immune homeostasis by regulating SOCS1 (suppressor of cytokine signalling 1) [156] and has been suggested to modulate mitochondrial dynamics [157]. miR-31, a key miRNA associated with the Hippo signalling pathway that was shown to improve cognition in AD triple-transgenic mice [158] was also shown to reduce inflammatory signalling and to promote epithelium regeneration [159]. Furthermore, miRNA-144 downregulation which is associated with PD [160] was found to cause occludin and zonula occludens loss in gut epithelial cells [161] and to be involved in Nrf2-antioxidant response element signalling pathway [162]. miR-93, which was also shown to be involved in PD [163], was associated with claudin-3 upregulation contributing to epithelial barrier integrity [164] and with cell metabolism through PI3K/Akt pathway [165].

MITOCHONDRIA ROLE IN GUT-BRAIN AXIS IN ALZHEIMER’S AND PARKINSON’S DISEASE

Recent findings suggest that disruptions in both mitochondrial function and the gut microbiome are fundamental features in various neurodevelopmental and neurodegenerative conditions. This association stems from the bidirectional communication between the gut and the CNS [166, 167] in which emerging discoveries emphasize the crucial role of mitochondria. Therefore, it is theoretically significant to elucidate the pathways through which gut microbiota impact brain function by modulating mitochondrial bioactivities.

Numerous gut microbiota metabolites, known to traverse the BBB, or act directly on the CNS through the vagus nerve [168], have been identified to modulate mitochondrial physiology in the brain [169]. These metabolites produced by commensal microorganisms, include glucagon-like peptide-1 (GLP-1), ghrelin, cholecystokinin, GABA, 5-HT, DA, acetylcholine, SCFAs, trimethylamines, amino acid metabolites, and vitamins. Their impact modulates mitochondrial function via the mammalian target of rapamycin (mTOR) signaling pathway, ROS signaling pathway, immune pathway, or direct interaction with neural mitochondria, thereby affecting brain functions. This modulation can contribute to neuronal survival by enhancing mitochondrial quality, promoting mitophagy, facilitating organelle biogenesis, or conversely, promoting neurodegeneration through mitochondrial hyperactivation, damage, and dysfunction [170 –172]. For instance, gut microbiome-derived metabolites can target mitochondria in both the ENS and the CNS [173].

Additionally, gut microbial metabolites can indirectly influence the epithelium’s permeability or alter the secretion of intestinal endocrine cells [174]. Moreover, these metabolites can stimulate mucosal immune cells to release cytokines or other immune signaling molecules, initiating inflammatory reactions upon the breach of the epithelial barrier. Notably, immune cells activated by microbial metabolites have been observed to enter the bloodstream and influence the brain through diverse mechanisms. Persistent or recurrent intestinal inflammation can contribute to a prolonged systemic inflammatory condition, fostering neurodegeneration [25 , 175].

Conversely, the nervous system can impact the intestinal microbiota by activating the mitochondrial unfolded protein response in gut epithelial cells, thereby weakening the epithelial barrier [166]. SCFAs have been identified as particularly influential in altering mitochondrial physiology not only in the gut but also in the brain. In the case of propionate, it has been implicated in directly enhancing mitochondrial function in neurons, potentially impeding the progression of multiple sclerosis and brain atrophy in human patients [176, 177]. Acetate, was observed to act on microglia cells, restoring mitochondrial morphology and activity, particularly in the absence of gut microbiota in mice. Moreover, acetate administration also demonstrates effects on microglial phagocytosis in an AD mouse model [16]. Butyrate can reach the brain through the bloodstream, increasing mitochondrial activity, ATP production, and cellular viability. Furthermore, butyrate serves as a histone deacetylase (HDAC) inhibitor, promoting mitochondrial biogenesis and countering mitochondrial impairment in rats treated with amphetamine [178, 179]. Additionally, butyrate reduces gut permeability, leading to lower blood levels of LPS, a factor known to trigger mitochondrial dysfunction and neuronal loss [180].

Interestingly, and apart from SCFAs, isoallolithocholic acid, a monohydroxy bile acid produced by intestinal flora, derivative of lithocholic acid and associated with nervous system diseases, induces the production of mitochondrial ROS [181]. In addition, folate, produced by gut flora, regulates mitochondrial respiration and plays a pivotal role in the early development of the nervous system by activating the mTOR signaling pathway [182]. Other gut metabolites such as 4-(trimethylammonio) pentanoate valerate and 3-methyl-4-(trimethylammonio) butanoate can enter brain tissue, inhibiting the oxidation of mitochondrial fatty acids and mediating gut-brain communication. Trimethylamine-N-oxide has been identified to increase mitochondrial damage and superoxide production in mice, accelerating neuronal aging in the hippocampus and exacerbating aging-related cognitive impairment [183].

As previously refereed some bacteria also produce bioactive neurotransmitters which are intricately linked to mitochondrial function. For instance, GABA can cross the mitochondrial membrane and modulate citric acid cycle reactions. Conversely, heightened mitochondrial activity has been associated with reduced GABAergic signaling, resulting in impaired social behavior [184]. Recent research has demonstrated that 5-HT can stimulate mitochondrial biogenesis, contributing to the reduction of toxic ROS in neurons. On the other hand, experimental evidence suggests that elevated DA concentrations induce dysfunction in striatal mitochondria by diminishing respiratory control and membrane potential, thereby promoting inhibition of mitochondrial complex I and contributing to the development of neuropsychiatric disorders [185, 186].

In AD, SCFAs produced by the gut microbiome influence microglia cells, and the absence of acetate in germ-free mice results in immature microglia with mitochondrial dysfunction, impacting phagocytosis and promoting Aβ deposition [187, 188]. As NAD + precursors, the gut produced urolithin A downregulates amyloid-related proteins and induces mitophagy, offering cytoprotection and cognitive improvement in AD models. [109]. Ghrelin, modulated by commensal bacteria, exhibits neuroprotective effects in AD models [148]. Antibiotics like doxycycline target Aβ aggregation, while their impact on mitochondrial structure or function in reducing neuroinflammation is currently unclear [189].

Toxins produced by human gut microbiota may induce mitochondrial dysfunction, contributing to PD neurodegeneration [45, 142]. Dysregulation of the incretin hormones GLP-1 and GLP-2, associated with gut microbiota dysbiosis, results in mitochondrial dysfunction via the NLRP3 inflammasome which is linked to PD [190]. In a C. elegans PD model, a screen of E. coli mutants identified curli amyloid fibril as a bacterial metabolite promoting αSyn-induced mitochondrial dysfunction. Inhibiting curli amyloid improved mitochondrial function, reducing αSyn-induced neuronal death and enhancing neuronal function [191]. Bacterial metabolites that enhance mitochondrial function demonstrate neuroprotective effects in PD. Nicotinamide (NAM) supplementation in Drosophila PD models enhances SIRT and PARP activity, protecting mitochondrial function and reducing neurodegeneration [192]. Ursodeoxycholic acid (UDCA) and tauroursodesoxycholic acid (TUDCA), secondary bile acids from commensal bacteria, improve motor function in PD models by promoting mitophagy through PINK1 and Parkin, reducing apoptosis, and maintaining mitochondrial quality [193, 194]. Similarly to AD, ghrelin protects against dopaminergic neuron loss in mouse PD models by restoring mitochondrial function and reducing apoptosis-related factors [195, 196]. Butyrate, with HDAC-inhibitor activity, may ameliorate PD symptoms through direct mitochondrial effects, counteracting ceramide-induced pathophysiology [39, 197].

CONCLUSION

Mitochondria behave as a gate keeper to a controlled immune system and to a healthy and balanced microbiome (Fig. 1). On the other hand, the gut microbiome can impact mitochondrial metabolism thereby interfering with intestinal homeostasis and gut-brain axis.

Fig. 1

The role of mitochondria in gut-brain axis. Mitochondria were free-living bacteria that were engulfed by ancestral eukaryotic cells developing a symbiotic relationship with the host cell (A). These organelles play a vital role in the two-way communication between the gut and brain. Communication pathways comprise the autonomic nervous system (including the ENS) and the vagus nerve), the neuroendocrine system, the HPA axis, the immune system, and metabolic pathways. Various harmful metabolites produced by gut microbiota may directly influence the epithelium’s permeability, modulating host immune responses, metabolism, and impairing mitochondria (B). Interestingly, microRNAs secreted by intestinal epithelial cells can enter bacteria and control their gene expression, thereby influencing the composition of the gut microbiome, which can also influence the expression of host microRNAs, thus impacting gut homeostasis (C). Bacterial metabolites travel to the brain, via the vagus nerve or by being capable of crossing the blood-brain barrier, may regulate mitochondrial function in the brain, leading to the accumulation of Aβ, tau-protein, and αSyn and induce neurodegeneration (D). On the other hand, stress, which activates the HPA axis, releases hormones that impact intestinal barrier integrity and gut microbiota composition (E). The neurodegenerative process is also closely linked to mitochondrial dysfunction, neuroinflammation, and oxidative stress, with inflammatory factors being capable of inducing mitochondrial dysfunction, which in turn triggers neuroinflammation (F).

Considering that oxidative stress and the gut-brain axis are a central component for AD and PD pathogenesis, clarifying the dynamic interactions between mitochondria and the host gut microbiome is imperative. It will also enable pioneering studies to be carried out and accelerate the development of therapies targeting intestinal mitochondria in human diseases in which intestinal dysbiosis is involved and, potentially, in aging. These novel avenues of research have the potential to uncover disease mechanisms associated with neurodegeneration, ultimately guiding the discovery and development of effective treatments to enhance the quality of life for millions worldwide.

AUTHOR CONTRIBUTIONS

Emanuel Candeias (Conceptualization; Writing – original draft); Ana Raquel Pereira-Santos (Conceptualization; Writing – original draft); Nuno Empadinhas (Writing – review & editing); Sandra Morais Cardoso (Funding acquisition; Writing – review & editing); Ana Raquel Fernandes Esteves (Conceptualization; Funding acquisition; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This work was supported by the European Regional Development Fund (ERDF), through the COMPETE 2020– Operational Programme for Competitiveness and Internationalization, and by Portuguese national funds via FCT— Fundação para a Ciência e a Tecnologia under projects EXPL/MED-NEU/1515/2021, PTDC/MED-NEU/3644/2020, UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

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