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Eicher, T.P.;  Mohajeri, M.H. Link of Microbiome–Gut–Brain Axis and Brain Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/26824 (accessed on 29 July 2024).
Eicher TP,  Mohajeri MH. Link of Microbiome–Gut–Brain Axis and Brain Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/26824. Accessed July 29, 2024.
Eicher, Tanja Patricia, M. Hasan Mohajeri. "Link of Microbiome–Gut–Brain Axis and Brain Disorders" Encyclopedia, https://encyclopedia.pub/entry/26824 (accessed July 29, 2024).
Eicher, T.P., & Mohajeri, M.H. (2022, September 02). Link of Microbiome–Gut–Brain Axis and Brain Disorders. In Encyclopedia. https://encyclopedia.pub/entry/26824
Eicher, Tanja Patricia and M. Hasan Mohajeri. "Link of Microbiome–Gut–Brain Axis and Brain Disorders." Encyclopedia. Web. 02 September, 2022.
Link of Microbiome–Gut–Brain Axis and Brain Disorders
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This entry is adapted from the peer-reviewed paper 10.3390/nu14132661

Neuropsychiatric diseases cover a wide spectrum of diseases affecting the brain, behaviour, and mood, affecting people of any age. Disruptions in microbial compositions have been implicated in diseases such as asthma, diabetes, inflammatory bowel disease, obesity, and autism. The microbiota–gut–brain axis (MGBA) is a bidirectional communication pathway between the gut bacteria and the central nervous system (CNS). It is an extension of the gut–brain axis, in which the enteric nervous system (ENS), CNS, and the GI-tract work together to affect physiological aspects of the gut: motility, secretion, and acid and mucus production. The bacteria may influence the brain via the production of neurotransmitters and bacterial metabolites via stimulation of the vagal nerve, the immune system, or the hypothalamic–pituitary–adrenal axis (HPA-axis). On the other hand, the brain’s effects on the gut in terms of secretion, peristalsis, and sensory are mainly transferred via the vagus nerve.

bacteria metabolites microbiota–gut–brain axis neuroinflammation neurodegeneration neurodevelopment neuropsychiatric disorder

1. Microbiome

The human body is densely populated with microbes, where each body site has an individual flora. The microbiota in the gut is the biggest, with approximately 1014 living microorganisms, including bacteria, viruses, archaea, eukaryotes, and fungi [1][2], which is equivalent to the number of human cells in the body [3]. Altogether these microorganisms are estimated to weigh around 2 kg. They encode over 232 million genes, suggesting that they may be able to exhibit a huge metabolic capacity [1][3].
Most bacteria of the intestinal microbiome are situated in the colon. Only relatively few can be found in the stomach or the small intestine due to unfavourable living conditions in these parts of the gastrointestinal (GI) tract (fast passage, gastric acid, bile, pancreas juices) [2][3]. Over the human lifespan, the microbiome continues to evolve: it first starts developing in the womb and during birth, stabilises and increases in diversity during childhood and adolescence [2][3], and is influenced by the ageing processes later on in life [4]. Furthermore, it is also highly susceptible to environmental and lifestyle factors such as drugs, antibiotics, toxins, stress, and diet [1][5][6][7], resulting in big interindividual and temporal differences [2][4][8].
Even though gut bacteria populations are highly dynamic, the mature microbiome after the age of three years is dominated by two phyla, namely Bacteroidetes and Firmicutes [3][4]. In addition, looking at the most abundant genus, three enterotypes could be distinguished: (i) Bacteroides, (ii) Prevotella, and (iii) Ruminococcus [9]. These enterotypes have been linked to different dietary patterns. Bacteroides enterotype, which has only little Pretovella, is found in individuals with Western diets (high in saturated fats, high in animal protein). Pretovella enterotype, in contrast, is present in people consuming a plant-based diet (high in fibres and carbohydrates) [8][10]. In addition to environmental influences, twin studies have shown that the composition of the microbiome may also be determined by genetic components [2][6].
A balance in the microbial composition is known as a state of eubiosis [5]. Bacteria and humans have evolved together, forming a symbiotic host–microbiome relationship [2]. Gut microbes are important for gut motility, barrier homeostasis, maintenance of gut integrity, regulation of the host immune system, absorption, and production of nutrients [2][11]. If the bacterial composition is altered, also recognised as dysbiosis, those beneficial mechanisms might be disrupted [2]. In dysbiosis, potentially harmful and inflammatory bacteria take overhand, leading to an imbalance in immune homeostasis and increased permeability in the gut. This, in turn, allows the migration of bacteria from the gut into blood circulation, which is a risk factor for systemic inflammation [5]. As a result, intestinal dysbiosis has been linked to the pathogenesis of different diseases and unfavourable health conditions such as obesity, asthma, diabetes, autism, and inflammatory bowel disease [11]. A disrupted microbiome has also been associated with different neuropsychiatric diseases, including depression, autistic disorder, Parkinson’s disease, and schizophrenia [6].

2. Microbiota–Gut–Brain Axis (MGBA)

2.1. Chemical Signalling

Certain types of bacteria can produce small molecules which influence the metabolism of the nervous system, either directly or indirectly. This path is referred to as chemical signalling [1].

Short-Chain Fatty Acids (SCFAs)

Short-chain fatty acids (SCFAs) are saturated fatty acids with a maximal chain length of six carbon atoms synthesised by colonic bacteria [12]. SCFAs derive from polysaccharides found in dietary fibres, which cannot be broken down by our own digestive enzymes. In contrast, bacteria in the intestines digest those through a process of anaerobic fermentation. The two most important bacteria in this SCFA production are Bacteroides spp. and Clostridiae spp. [13][14][15]. Acetate, propionate, and butyrate are the most abundant SCFAs in the colon [7][12].
After their synthesis, SCFAs might exert a direct impact on the gut and support local gut health, or they may be distributed by systemic blood circulation throughout the body, affecting other organs, including the brain. In the gut itself, SCFAs are quickly absorbed by colonocytes and act as the main source of energy for the intestinal lining. Absorbed SCFAs influence the cell’s metabolism. They play an important role in increasing mucous production within the GI tract and enhance the integrity of the gut barrier by upregulating the expression of tight junction proteins. Tight junctions are specific connections between cells (here gastrointestinal epithelial cells), contributing to a physical barrier. A functional gut barrier is crucial for preventing the entrance of pathogens and waste products into the body whilst enabling the uptake of important molecules and nutrients. It also prevents the body from systemic inflammation, which is associated with numerous diseases. Prevention of such systemic inflammation further reduces the risk for subsequent neuroinflammation because through systemic inflammation, the blood–brain barrier (BBB) might be impaired. Neuroinflammation, in turn, leads to compromised brain health [5][12][15]. This sums up the immune pathway of SCFA–brain interaction. In addition, tight junctions are an integral component of the BBB. A regulatory effect of SCFAs on the permeability of this barrier was shown in animal models [15].

Short-Chain Fatty Acids (SCFAs)

SCFAs might exert a direct impact on the gut and support local gut health, or they may be distributed by systemic blood circulation throughout the body, affecting other organs, including the brain. In the gut itself, SCFAs are quickly absorbed by colonocytes and act as the main source of energy for the intestinal lining. Absorbed SCFAs influence the cell’s metabolism. They play an important role in increasing mucous production within the GI tract and enhance the integrity of the gut barrier by upregulating the expression of tight junction proteins. Tight junctions are specific connections between cells (here gastrointestinal epithelial cells), contributing to a physical barrier. A functional gut barrier is crucial for preventing the entrance of pathogens and waste products into the body whilst enabling the uptake of important molecules and nutrients. It also prevents the body from systemic inflammation, which is associated with numerous diseases. Prevention of such systemic inflammation further reduces the risk for subsequent neuroinflammation because through systemic inflammation, the blood–brain barrier (BBB) might be impaired. Neuroinflammation, in turn, leads to compromised brain health [5][12][15].

Systemically, SCFAs can have direct or indirect effects on the MGBA. The indirect pathway is mediated by affecting the immune or the endocrine system, while direct signalling is the result of the neuroactive characteristics of SCFAs. Once SCFAs reach the brain through systemic circulation, they can cross the BBB and bind to specific G-protein-coupled receptors (GPCRs) expressed in CNS tissue. GPCR-activation may then influence the gene expression (epigenetic modulation) in the correspondent nerve cells. For example, the inhibition of histone deacetylation results in more transcriptionally active chromatin (hyperacetylated histones). The inhibited enzymes, histone deacetylases (HDACs), are thought to be associated with brain development and also with a variety of neuropsychiatric disorders such as depression, Alzheimer’s disease, or schizophrenia [5][7][12].

Amino Acids and Neurotransmitters

Some gut bacteria possess the ability to produce neuroactive substances, including amino acids and neurotransmitters [1]. The inhibitory neurotransmitter GABA can be produced by Lactobacillus spp. or Bifidobacterium spp. Acetylcholine is synthesised by Lactobacillus spp. Noradrenaline is produced by Bacillus spp., Escherichia spp., and Saccharomyces spp. Serotonin is produced by Streptococcus spp., Candida spp., Enterococcus spp., and Escherichia spp. Dopamine is produced by Bacillus spp. [5][7].
Those microbial neurotransmitters are thought to have a more local than peripheral effect. They might cross the intestinal epithelial cells, but their area of action is limited to the surrounding ENS. Even upon reaching the bloodstream, they will be unable to cross the BBB and therefore cannot enter the brain and are unable to influence brain chemistry. Indirect influences on the brain, by acting on the ENS, are possible.
In contrast, certain precursors of neurotransmitters, namely amino acids, are capable of crossing the BBB [16]. The levels of circulating tryptophan, the precursor for serotonin (5-HT), can be elevated by Bifidobacterium infantis [7]. Within the brain, tryptophan can then be further the bolized into 5-HT and impact brain chemistry [7][14][16]. Similarly, the genus Bifidobacterium increases the level of phenylalanine, the precursor for the amino acid tyrosine, which itself again is a precursor for the two neurotransmitters dopamine and noradrenaline in the brain [13]. Increased or decreased abundance of such precursor-producing bacteria shifts the availability of monoamine neurotransmitters in the brain and paves the way for related diseases and behavioural changes [16].

2.2. Immune System Signalling

Intestines harbour the largest number of immune cells in the human body, allowing the body to scan all the transitioning food and also the symbiotic gut-residing bacteria for potential pathogens or toxins [8]. With the help of pathogen-associated molecular pattern (PAMP) recognition receptors, intestinal cells can detect certain parts of bacteria such as lipopolysaccharide (LPS). LPS is a characteristic cell wall component of Gram-negative bacteria. Innate immune cells are equipped with Toll-like receptors (TLRs), which are the most studied family of PAMP recognition receptors. LPS activates TLRs. Through this activation, Gram-negative bacterial invasion is identified, and an innate immune response is triggered, which involves many signalling molecules, including cytokines and the recruitment of inflammatory cells [8][17]. Immune signalling (production and peripheral secretion of cytokines) is also mediated to the brain via the bloodstream. Recent research has suggested that in the area of the hypothalamus, cytokines can cross the locally more permeable BBB, although they are generally incapable of crossing the BBB. In the hypothalamus, the major physiological stress response system, the hypothalamus–pituitary–adrenal (HPA) axis, has its starting point. Originally from the gut-derived pro-inflammatory cytokines, interleukin (IL)-1 and IL-6 can activate the HPA axis. Subsequently, body cortisol levels rise, and the body enters the stress response mode [7][8]. Multiple neuropsychiatric diseases and pathological conditions have been linked to a dysregulated stress axis and altered immune signalling within the brain, of which depression and autism spectrum disorder are just two examples [1]. Peripheral systemic inflammation, which is driven by circulating immune signalling molecules such as cytokines, is also a major factor in the pathophysiology of many diseases, including brain disorders. Through systemic inflammation, the BBB becomes disrupted and more permeable for bacterial metabolic products. It is not surprising that the condition of a disrupted BBB facilitates the development of different neuropathologies due to the compromised protective barrier against toxic substances [1].

2.3. Neural Signalling

The intestines are innervated by both ENS and the autonomic nervous system (ANS), of which the vagus nerve (10th cranial nerve) is known to be the most direct connection between the CNS and the gut. Approximately 80% of all nerve fibres in the vagus nerve are afferent; the remaining 20% carry efferent signals from the CNS to the periphery. With both efferent and afferent fibres, the basis for bidirectional communication is already given, either bottom-up (gut to the brain via afferent fibres) or top-down (efferent fibres from the brain to the gut) [1][8]. ANS and ENS are both implicated in the physiological homeostasis of the gut and regulate motility, mucous production, and transition time [8]. The initial formation of the ENS takes place during embryogenesis, but differentiation and maturation processes occur later on after birth. These processes are thought to be influenced by gut microbial development, which takes place simultaneously [1][4][8]. ENS and CNS are functionally interconnected through the use of the same signalling molecules [4][8]. Hence, the identified effects that gut microbiota has on local neurons resemble those discussed earlier in the above paragraphs discussing chemical and immune signalling. Those mechanisms include activation of PAMP recognition receptors such as TLRs through LPS, SCFA signalling, and stimulation of mechanoreceptors or chemoreceptors, which sense neurotransmitters, hormones, or metabolic products. Local neuronal stimulation on the ENS level by bacterial metabolites is thought to be then transmitted to the brain via vagal nerve conduction [1]. Metabolites and neurotransmitters can either be directly produced by gut bacteria or secreted by enteroendocrine cells (EECs), which are also affected by gut microbes [1][8].

3. Changes in Gut Microbiota and Metabolites in Brain-Related Pathologies

3.1. Attention Deficit Disorder with Hyperactivity

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease with an early onset consisting of the three main symptoms inattentiveness, impulsivity, and/or hyperactivity [13][18]. With a worldwide prevalence of 5.29%, ADHD is one of the most common mental illnesses amongst children and adolescents [18][19]. In total, 70–80% of the risk for developing ADHD is made up of genetic components, whereas the remaining 20–30% has been linked to environmental risk factors such as premature birth, toxins, diet, and psychosocial distress [5][18][20][21]. The exact underlying mechanisms of aetiopathogenesis remain unclear [22]. Several known pathomechanisms in ADHD, both direct and indirect, have been linked to the gastrointestinal microbiota by three possible ways of interaction: (i) direct production of neuroactive metabolites/neurotransmitters, (ii) vagal nerve stimulation, (iii) interactions via the immune system [14][20][23].
One widely accepted hypothesis on the ADHD pathophysiology highlights the dysfunction of the monoamine neurotransmitters dopamine (DA), noradrenaline (NE), and serotonin (5-HT), which are involved in the rewarding and motivational processes in the brain. This hypothesis is further supported by the fact that the current medications treating ADHD target the monoaminergic system and increase the concentration of the neurotransmitters in the synaptic cleft by blocking their re-uptake [5][13][22][24]. The production of those neurotransmitters can be influenced by gut bacteria.
Bifidobacterium of the phylum Actinobacteria, for example, encodes an enzyme known as arogenate dehydratase (ADT), which is important for the production of phenylalanine an essential amino acid. The latter can pass the BBB and is metabolised into the amino acid tyrosine, which can further be turned into DA and then NE in the brain [13][16]. Aarts et al. compared faeces samples of ADHD patients (n = 19) to samples of a healthy control group (n = 66). They found that the relative abundance of Actinobacteria was increased in ADHD patients, whereas Firmicutes were slightly reduced compared to the control group. No changes in the phylum Bacteroidetes were observed. Within the phylum, Actinobacterium, especially the genus Bifidobacterium, marked a significant increase [16]. As mentioned above, Bifidobacterium is equipped with ADT and thus involved in dopamine synthesis, which is an important neurotransmitter within the brain reward response, which is dysfunctional in patients with ADHD. Therefore, these findings suggest that there is a link between the microbiome and ADHD [14][16].

3.2. Autistic Spectrum Disorder

Autism spectrum disorder (ASD) describes a heterogenous group of neurodevelopmental disorders, mainly affecting children [25][26]. The diagnosis is based on clinical observation of behavioural aberrations and diagnostic interviews [26][27]. The key characteristics of ASD are deficits in social interaction and communication, along with repetitive patterns of behaviours and cognitive difficulties [25][26]. ASD prevalence has increased in recent years, and 1–1.5% of the world’s population is affected [26]. Current estimations predict that 1 in 68 up to 1 in 36 children suffer from ASD [27][28]. Interestingly, compared to girls, boys show a four- to five-fold higher prevalence [25][28]. Brain development and reorganisation are altered in ASD patients [26]. Some of the findings are increased brain volume, which could be seen in neuroimages, and changes in brain connectivity compared to neurotypical children [26][28][29]. Aetiology is thought to be an interplay of genetics and environmental factors. Approximately 10–20% of ASD cases are attributed to genetic mechanisms [25][27]. Polluted air, maternal infections, high parental age, pesticides, preterm birth, and certain drug exposures during pregnancy are some of the environmental factors which have been associated with an increased risk for ASD [25][26].
Autistic patients often also suffer from GI symptoms such as diarrhoea, bloating, constipation, and abdominal pain. They appear more often in ASD patients than in healthy children, and constipation was found to be the most common GI symptom among them [30]. Thus, it is not surprising that researchers started investigating the role of the MGBA in ASD pathogenesis. Even more so, because the brain’s development, including synapse formation and growth, timely coincides with the maturation of the gut’s microbiome. Both processes mainly happen within a critical developmental time window until the age of two to three years [30].
Many studies revealed that the microbiome of ASD patients is different from those of healthy individuals. Some changes could be proven repeatedly by independent researchers, but also inconsistent and contradictory results were collected. Possible reasons for the discrepancy could lie in the patient’s origin, diet, lifestyle but also methodological differences [31]. Nevertheless, the data has shown that autistic children harbour a shifted ratio between the two phyla Bacteroidetes and Firmicutes in faecal and biopsy samples. Levels of Firmicutes were mostly increased, and those of Bacteroidetes decreased [25][30][31][32]. Additionally, several researchers measured a higher abundance of Clostridium spp. and lower levels of Bifidobacterium spp. and Enterococcus spp. [25][30]. SCFA-producing bacteria such as Bacteroides spp., Clostridia spp., and Desulfovibrio spp. could be found in higher abundance, which is consistent with higher SCFA levels in blood and stool of ASD patients [25][31]. Phylum Actinobacterium, class Betaproteobacteria, genera Dialister, Faecalibacterium, Lactobacillus, and Ruminococcus also marked an increased presence [31][32]. ASD patients had decreased levels of bacteria involved in degenerating and fermenting carbohydrates such as Coprococcus, Prevotella, and Veilonella [29][32]. In contrast, Suturella could be found in higher abundance, which is important for the regulation of mucosa metabolism and the integrity of the intestinal epithelium [29].

3.3. Schizophrenia

Schizophrenia is a psychiatric syndrome with a worldwide prevalence of 1% and is rated among the 10 most common causes of disability on a global level [33][34]. The psychotic symptoms range from delusions and hallucinations to disorganised speech. Other symptoms are a decrease in motivation, a diminishment in expressivity, and grossly disorganised or catatonic behaviour. Schizophrenic patients might also suffer from cognitive deficits such as reduced speed in mental processes or memory problems [33][34].
It has been suggested that schizophrenia is a low-grade chronic inflammatory disease. Neuroinflammation in the CNS and the periphery could be associated with schizophrenia, in which overly activated neuroimmune microglia cells play a crucial role [35]. Schizophrenia patients had altered activation of microglia compared to a healthy control group. Alterations in the microbiome, especially in early life, act as a predisposition to immune dysfunction, which has been associated with the development of schizophrenia [35][36].
Associations between changes in bacterial metabolites found in schizophrenia patients and the disease development are clearer. The impact of translocation biomarkers and cytokines on the pathology of schizophrenia has already been discussed above. Studying faecal samples revealed that schizophrenia patients show alterations in their gut glutamate metabolism. In the gut, the activity of glutamine oxoglutarate aminotransferase (GOGAT), which is involved in glutamate synthesis, was significantly higher than in healthy controls. This results in elevated levels of glutamate [37][38]. The neurotransmitter dopamine is seemingly important for psychosis symptoms such as delusions and hallucinations. In schizophrenia, overstimulation of dopamine receptors D2 in the striatum leading to these symptoms has been postulated. On a pharmacological level, these D2 receptors are blocked by antipsychotic drugs, reducing psychotic symptoms. Dopamine levels in the brain depend at least partly on gut microbiome metabolism, as discussed earlier [36][39]. Furthermore, changes in tryptophan metabolism could be identified, which are also thought to emerge from bacterial metabolism. In addition to being turned into serotonin, tryptophan can also be metabolised through the kynurenine pathway. In Schizophrenia, higher levels of kynurenine metabolites could be measured [36][38][39]. Within the brain, astrocytes metabolise kynurenine into kynurenic acid, which is an antagonist to acetylcholine and glutamate receptors. Those receptors are involved in brain development, behaviour, and cognition. Altered levels of kynurenine and kynurenic acid have therefore been linked to the pathophysiology of schizophrenia [36]. SCFAs are also thought to be of importance. Research findings suggest that their epigenetic modulation potential via decreasing HDAC activity could be crucial in the development of schizophrenia, keeping in mind that 80% of the risk for schizophrenia is attributed to genetics [38][39].

3.4. Alzheimer’s Disease

The cognitive impairment in AD is caused by irreversible neuronal death and synaptic loss. The accumulation of insoluble and misfolded amyloid-beta (Aβ) proteins is caused by a different secretase cleavage of the amyloid precursor protein (APP) or by reduced clearance of Aβ, where APOE is involved. Aβ then forms extracellular amyloid plaques and accelerates the hyperphosphorylation of tau protein, which forms intraneuronal neurofibrillary tangles (NFTs). Aβ and NFT activate a neurotoxic pathway leading to a loss of neurons and synapses, in which microglia activation and neuroinflammation are crucial [40][41]. At first, the acute neuroinflammatory response helps with Aβ-clearance, but the continuous microglial activation leads to a neurotoxic pathway [42]. In post-mortem AD brains, Aβ-plaques, NFTs, and brain atrophy can be observed with accentuation in the temporal lobe (including hippocampus) and parietal lobe [41].

Increasing evidence shows that the gut microbiota may be contributing to the pathogenesis of AD. As people age, the microbiome undergoes fundamental changes. In the elderly, a decrease in microbial diversity could be found, and they host more pro-inflammatory bacteria and less anti-inflammatory bacteria (Bacteroidetes, Bifidobacteria, Lactobacillus). Additionally, SCFA-producing bacteria species were found to be less abundant in the elderly. Decreased SCFA levels are thought to facilitate activation of microglial cells by inducing inflammatory processes, first on the gut leading to a leaky gut, but also on a systemic level, including the brain, as the inflammation signalling molecules spread throughout the body. In fact, elevated levels of circulating pro-inflammatory cytokines were found in AD patients [43][44][45][46][47][48]. This, in turn, also affects the permeability of the BBB [42][43][46][48]. The interrupted BBB facilitates neuroinflammation in the brain and neuronal death, as seen in AD [43][46].
Further, the gut microbiota is a source of amyloid proteins. Many bacteria strains are capable of producing amyloid. Bacillus subtilis, Escherichia coli, Mycobacterium tuberculosis, Salmonella enterica, Salmonella typhimurium, and Staphylococcus aureus are a few examples [15][43][48]. Those bacterial amyloids are thought to influence AD pathogenesis in three different ways. Firstly, they may act as an inducer of inflammation response against Aβ. Even though bacterial amyloids and Aβ differ in their amino acid sequence, they resemble each other in their folding structure. Therefore, they are recognised by the same TLRs [15][46][47][48]. TLR activation triggers the inflammatory immune response, which in turn might lead to further neuronal amyloid production inside the brain and reinforces the process of chronic neuroinflammation [46][48]. Secondly, through the concept of molecular mimicry, microbial amyloids could show a prion-like behaviour and cross-seed to the brain, where they promote the formation and accumulation of pathogenic β-sheet structure in other proteins, which leads to misfolded Aβ, as in AD [43][46][49]. Thirdly, an additional hypothesis suggests that bacterial amyloids might be leaking from the gut and find their way to the brain, where they contribute to the brain amyloid load. However, so far, this translocation has only been observed in animal studies with mice [43][48].

3.5. Parkinson Disease

Parkinson’s Disease (PD) is, after Alzheimer’s disease, the most prevailing neurodegenerative disease [50]. There is a strong association with age. Approximately 2–3% of people older than 65 are affected by PD, whereas, in the general population, the prevalence is approximately 0.3% [51]. With the increase in worldwide life expectancy, a dramatic increase in prevalence is expected in the future [52]. PD is the most common cause of clinical parkinsonism syndrome, which consists of brady-/hypokinesia, resting tremor, rigidity, and postural instability [50].

Gut microbial dysbiosis and its effects on the MGBA contribute to PD pathogenesis and progression on various pathways. Changes in bacteria and metabolite abundance, lost gut integrity, deficiency in BBB, and neuroinflammation are important players [53][54].

SCFAs are also relevant for PD pathogenesis. In multiple clinical studies, faecal samples of PD patients generally contained a reduced amount of SCFAs compared to healthy individuals [15][53]. This reduction is consistent with the lower abundance of SCFA-producing bacteria (including Bacteroides, Blautia, Coprococcus, Faecalibacterium prausnitzii, Lachnospiraceae, and Roseburia) in PD patients [15][53][54][55]. SCFA deficiencies may lead to intestinal and neuronal inflammation, gut leakage, microglial activation, and also Lewy body formation in the ENS, which are all important factors in PD pathogenesis [54][55][56].

3.6. Depression

In general, the taxonomic changes in bacteria were connected to a pro-inflammatory state, with a reduction in anti-inflammatory bacteria (Faecalibacterium, Firmicutes, and Subdoligranulum) and an increase in pro-inflammatory ones (Alistipes, Bacteroidetes, Eggerthella, Flavonifractor, and Gammaproteobacteria). These changes go hand in hand with metabolite alterations. Within the group of anti-inflammatory bacteria, SCFA-producing bacteria were reduced (e.g., Faecalibacterium and Prevotella) [57][58][59][60]. Accordingly, faecal samples of MDD patients contained lower levels of total SCFAs compared to healthy controls [15]. SCFAs are known to have various interactions with the host’s physiology. In the pathophysiology of depression, their influence ranges from epigenetic mechanisms via HDAC inhibition to downregulation of pro-inflammatory cytokine production, vagus nerve stimulation, microglia maturation, and BDNF production [57][61]. The neurotrophic factor BDNF, which stimulates neurogenesis, was found to be reduced in patients with MDD [62]. The importance of SCFAs is further supported by different clinical trials, where after the intake of probiotics, including SCFA-producing strains, MDD patients experienced a reduction in depressive symptoms, and healthy individuals reported improved mood and cognition [57].
Altogether, the above-mentioned factors lead to local inflammation, which impairs the gut epithelial integrity. This is followed by an increase in systemic inflammation [58][60]. LPS from Gram-negative bacteria could translocate and, via PAMP-activation, stimulate microglia cells and cytokine production in depressive patients [61]. In animals, such an inflammation-associated MDD model could be confirmed. Intravenous LPS injections in rats promoted depression-like behaviour [57]. Additionally, in patients with MDD, an upregulated genetic pathway for the metabolism of LPS was found [57]. Meta-analyses reported elevated cytokine levels in MDD patients, including IL-1β, IL-6, and TNF-α. The low-grade systemic inflammation can also be seen in elevated levels of C-reactive protein (CRP) [53][57][58][61]. Post-mortem studies of depressive patients’ brains found evidence for increased microglial activation and neuroinflammation [62].
Furthermore, disturbances in gut microbiota are thought to affect the production of neurotransmitters, including glutamate and tryptophan metabolism [58]. Changes in GABA metabolism and signalling have been associated with an increased risk for depression and anxiety. In MMD patients, elevated blood levels of GABA were shown. Additionally, its precursor glutamate was found in higher abundance in depressive patients [58]. A depletion in Bacteroides in MDD patients might be a contributing factor to GABA alterations [58].

3.7. Bipolar Disorder

Bipolar disorders (BD) are a group of chronic affective disorders and include bipolar disorders I and II. BD I can be diagnosed if recurring manic episodes are present, which may be alternating with depressive episodes. Manic symptoms should be present for a minimum of one week and include reduced need for sleep, general disinhibition, elevated mood, logorrhoea, grandiosity, increased confidence, increased energy, and activity. The depressive episodes fulfil the criteria of a major depressive episode for at least two weeks (depressed mood, loss of interest, anhedonia, fatigue). If the diagnostic threshold for a manic episode is not reached, the episode is classified as hypomania. Recurring hypomanic episodes with or without depressive episodes define BD II [63][64].

Some studies observed a reduction in SCFA-producing bacteria in BD patients’ microbiota composition. Especially butyrate-producing bacteria, including Coproccus, Faecalibacterium, and Roseburia, were found in lower abundance. Butyrate is thought to have a crucial impact on brain plasticity because it can stimulate BDNF production in the CNS. Lower BDNF levels, in turn, could contribute to BD development [65][66]. Serum levels of BDNF were lower compared to healthy controls during depressive episodes [67].

Secondly, inflammation in the periphery and the CNS seems to be connected to BD pathogenesis. In BD patients, elevated levels of inflammatory markers such as C-reactive protein (CRP), IL-1, IL-6, and TNF-α were reported [64][68]. The elevation was further accentuated during mood episodes [68][69]. There are multiple factors contributing to this pro-inflammatory state: microglial activation, leaky gut, and HPA-axis activation being three of them [68]. A leaky gut is a result of intestinal inflammation deriving from pro-inflammatory microbiota (e.g., a reduction in Faecalibacterium and Ruminococcaceae). As already discussed, the combination of a leaky gut and pro-inflammatory bacteria can promote systemic and central inflammation through bacteria migration, LPS increase, TLR-activation, and cytokine release [65][66][68][69]. As a result, the BBB permeability increases and the inflammation can spread to the CNS [65].

References

  1. Morais, L.H.; Schreiber, H.L.; Mazmanian, S.K. The gut microbiota–brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 2021, 19, 241–255.
  2. Thursby, E.; Juge, N. Introduction to the human gut microbiota. Biochem. J. 2017, 474, 1823–1836.
  3. Sidhu, M.; van der Poorten, D. The gut microbiome. Aust. Fam. Physician 2017, 46, 206–211.
  4. Quigley, E.M.M. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr. Neurol. Neurosci. Rep. 2017, 17, 94.
  5. Cenit, M.C.; Nuevo, I.C.; Codoñer-Franch, P.; Dinan, T.G.; Sanz, Y. Gut microbiota and attention deficit hyperactivity disorder: New perspectives for a challenging condition. Eur. Child Adolesc. Psychiatry 2017, 26, 1081–1092.
  6. Capuco, A.; Urits, I.; Hasoon, J.; Chun, R.; Gerald, B.; Wang, J.K.; Kassem, H.; Ngo, A.L.; Abd-Elsayed, A.; Simopoulos, T.; et al. Current Perspectives on Gut Microbiome Dysbiosis and Depression. Adv. Ther. 2020, 37, 1328–1346.
  7. Dinan, T.G.; Cryan, J.F. The Microbiome-Gut-Brain Axis in Health and Disease. Gastroenterol. Clin. N. Am. 2017, 46, 77–89.
  8. Cryan, J.F.; O’Riordan, K.J.; Cowan, C.S.; Sandhu, K.V.; Bastiaanssen, T.F.; Boehme, M.; Codagnone, M.G.; Cussotto, S.; Fulling, C.; Golubeva, A.V.; et al. The Microbiota-Gut-Brain Axis. Physiol. Rev. 2019, 99, 1877–2013.
  9. Costea, P.I.; Hildebrand, F.; Arumugam, M.; Bäckhed, F.; Blaser, M.J.; Bushman, F.D.; De Vos, W.M.; Ehrlich, S.D.; Fraser, C.M.; Hattori, M.; et al. Enterotypes in the landscape of gut microbial community composition. Nat. Microbiol. 2017, 3, 8–16.
  10. Hills, R.D., Jr.; Pontefract, B.A.; Mishcon, H.R.; Black, C.A.; Sutton, S.C.; Theberge, C.R. Gut Microbiome: Profound Implications for Diet and Disease. Nutrients 2019, 11, 1613.
  11. Rieder, R.; Wisniewski, P.J.; Alderman, B.L.; Campbell, S.C. Microbes and mental health: A review. Brain Behav. Immun. 2017, 66, 9–17.
  12. Dalile, B.; Van Oudenhove, L.; Vervliet, B.; Verbeke, K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 461–478.
  13. Bull-Larsen, S.; Mohajeri, M.H. The Potential Influence of the Bacterial Microbiome on the Development and Progression of ADHD. Nutrients 2019, 11, 2805.
  14. Boonchooduang, N.; Louthrenoo, O.; Chattipakorn, N.; Chattipakorn, S.C. Possible links between gut–microbiota and attention-deficit/hyperactivity disorders in children and adolescents. Eur. J. Nutr. 2020, 59, 3391–3403.
  15. Tran, S.M.-S.; Mohajeri, M.H. The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease. Nutrients 2021, 13, 732.
  16. Aarts, E.; Ederveen, T.; Naaijen, J.; Zwiers, M.P.; Boekhorst, J.; Timmerman, H.M.; Smeekens, S.P.; Netea, M.G.; Buitelaar, J.K.; Franke, B.; et al. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS ONE 2017, 12, e0183509.
  17. Yoo, J.Y.; Groer, M.; Dutra, S.V.O.; Sarkar, A.; McSkimming, D.I. Gut Microbiota and Immune System Interactions. Microorganisms 2020, 8, 2046.
  18. Banaschewski, T.; Becker, K.; Döpfner, M.; Holtmann, M.; Rösler, M.; Romanos, M. Attention-Deficit/Hyperactivity Disorder. Dtsch. Arztebl. Int. 2017, 114, 149–159.
  19. Polanczyk, G. The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. Am. J. Psychiatry 2007, 164, 942.
  20. Bundgaard-Nielsen, C.; Knudsen, J.; Leutscher, P.D.C.; Lauritsen, M.B.; Nyegaard, M.; Hagstrøm, S.; Sørensen, S. Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic literature review. Gut Microbes 2020, 11, 1172–1187.
  21. Posner, J.; Polanczyk, G.V.; Sonuga-Barke, E. Attention-deficit hyperactivity disorder. Lancet 2020, 395, 450–462.
  22. Sharma, A.; Couture, J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann. Pharmacother. 2014, 48, 209–225.
  23. Dam, S.A.; Mostert, J.C.; Szopinska-Tokov, J.W.; Bloemendaal, M.; Amato, M.; Arias-Vasquez, A. The Role of the Gut-Brain Axis in Attention-Deficit/Hyperactivity Disorder. Gastroenterol. Clin. N. Am. 2019, 48, 407–431.
  24. Drechsler, R.; Brem, S.; Brandeis, D.; Grünblatt, E.; Berger, G.; Walitza, S. ADHD: Current Concepts and Treatments in Children and Adolescents. Neuropediatrics 2020, 51, 315–335.
  25. Hughes, H.K.; Rose, D.; Ashwood, P. The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. Curr. Neurol. Neurosci. Rep. 2018, 18, 81.
  26. Lord, C.; Elsabbagh, M.; Baird, G.; Veenstra-Vanderweele, J. Autism spectrum disorder. Lancet 2018, 392, 508–520.
  27. Masi, A.; DeMayo, M.M.; Glozier, N.; Guastella, A.J. An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options. Neurosci. Bull. 2017, 33, 183–193.
  28. Sharma, S.R.; Gonda, X.; Tarazi, F.I. Autism Spectrum Disorder: Classification, diagnosis and therapy. J. Pharmacol. Ther. 2018, 190, 91–104.
  29. Vuong, H.E.; Hsiao, E.Y. Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder. Biol. Psychiatry 2017, 81, 411–423.
  30. Srikantha, P.; Mohajeri, M.H. The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder. Int. J. Mol. Sci. 2019, 20, 2115.
  31. Settanni, C.R.; Bibbò, S.; Ianiro, G.; Rinninella, E.; Cintoni, M.; Mele, M.C.; Cammarota, G.; Gasbarrini, A. Gastrointestinal involvement of autism spectrum disorder: Focus on gut microbiota. Expert Rev. Gastroenterol. Hepatol. 2021, 15, 599–622.
  32. Peralta-Marzal, L.N.; Prince, N.; Bajic, D.; Roussin, L.; Naudon, L.; Rabot, S.; Garssen, J.; Kraneveld, A.D.; Perez-Pardo, P. The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders. Int. J. Mol. Sci. 2021, 22, 10052.
  33. McCutcheon, R.A.; Reis Marques, T.; Howes, O.D. Schizophrenia-An Overview. JAMA Psychiatry 2020, 77, 201–210.
  34. Marder, S.R.; Cannon, T.D. Schizophrenia. N. Engl. J. Med. 2019, 381, 1753–1761.
  35. Yuan, X.; Kang, Y.; Zhuo, C.; Huang, X.-F.; Song, X. The gut microbiota promotes the pathogenesis of schizophrenia via multiple pathways. Biochem. Biophys. Res. Commun. 2019, 512, 373–380.
  36. Kelly, J.R.; Minuto, C.; Cryan, J.F.; Clarke, G.; Dinan, T.G. The role of the gut microbiome in the development of schizophrenia. Schizophr. Res. 2021, 234, 4–23.
  37. Xu, R.; Wu, B.; Liang, J.; He, F.; Gu, W.; Li, K.; Luo, Y.; Chen, J.; Gao, Y.; Wu, Z.; et al. Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav. Immun. 2020, 85, 120–127.
  38. Zhu, F.; Ju, Y.; Wang, W.; Wang, Q.; Guo, R.; Ma, Q.; Sun, Q.; Fan, Y.; Xie, Y.; Yang, Z.; et al. Metagenome-wide association of gut microbiome features for schizophrenia. Nat. Commun. 2020, 11, 1612.
  39. Rodrigues-Amorim, D.; Rivera-Baltanás, T.; Regueiro, B.; Spuch, C.; Heras, M.E.D.L.; Méndez, R.V.-N.; Nieto-Araujo, M.; Barreiro-Villar, C.; Olivares, J.M.; Agís-Balboa, R.C. The role of the gut microbiota in schizophrenia: Current and future perspectives. World J. Biol. Psychiatry 2018, 19, 571–585.
  40. Grøntvedt, G.R.; Schroder, T.N.; Sando, S.B.; White, L.; Brathen, G.; Doeller, C.F. Alzheimer’s disease. Curr. Biol. 2018, 28, R645–R649.
  41. Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol. 2018, 25, 59–70.
  42. Sochocka, M.; Donskow-Łysoniewska, K.; Diniz, B.S.; Kurpas, D.; Brzozowska, E.; Leszek, J. The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer’s Disease—A Critical Review. Mol. Neurobiol. 2019, 56, 1841–1851.
  43. Jiang, C.; Li, G.; Huang, P.; Liu, Z.; Bin Zhao, B. The Gut Microbiota and Alzheimer’s Disease. J. Alzheimer’s Dis. 2017, 58, 1–15.
  44. Bostanciklioğlu, M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J. Appl. Microbiol. 2019, 127, 954–967.
  45. De la Fuente, M. The Role of the Microbiota-Gut-Brain Axis in the Health and Illness Condition: A Focus on Alzheimer’s Disease. J. Alzheimers Dis. 2021, 81, 1345–1360.
  46. Kesika, P.; Suganthy, N.; Sivamaruthi, B.S.; Chaiyasut, C. Role of gut-brain axis, gut microbial composition, and probiotic intervention in Alzheimer’s disease. Life Sci. 2021, 264, 118627.
  47. Leblhuber, F.; Ehrlich, D.; Steiner, K.; Geisler, S.; Fuchs, D.; Lanser, L.; Kurz, K. The Immunopathogenesis of Alzheimer’s Disease Is Related to the Composition of Gut Microbiota. Nutrients 2021, 13, 361.
  48. Megur, A.; Baltriukienė, D.; Bukelskienė, V.; Burokas, A. The Microbiota-Gut-Brain Axis and Alzheimer’s Disease: Neuroinflammation Is to Blame? Nutrients 2020, 13, 37.
  49. Liu, S.; Gao, J.; Zhu, M.; Liu, K.; Zhang, H.-L. Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment. Mol. Neurobiol. 2020, 57, 5026–5043.
  50. Reich, S.G.; Savitt, J.M. Parkinson’s Disease. Med. Clin. N. Am. 2019, 103, 337–350.
  51. Raza, C.; Anjum, R.; Shakeel, N.U.A. Parkinson’s disease: Mechanisms, translational models and management strategies. Life Sci. 2019, 226, 77–90.
  52. Simon, D.K.; Tanner, C.M.; Brundin, P. Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clin. Geriatr. Med. 2019, 36, 1–12.
  53. Sun, M.-F.; Shen, Y.-Q. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease. Ageing Res. Rev. 2018, 45, 53–61.
  54. Zheng, S.-Y.; Li, H.-X.; Xu, R.-C.; Miao, W.-T.; Dai, M.-Y.; Ding, S.-T.; Liu, H.-D. Potential roles of gut microbiota and microbial metabolites in Parkinson’s disease. Ageing Res. Rev. 2021, 69, 101347.
  55. Rani, L.; Mondal, A.C. Unravelling the role of gut microbiota in Parkinson’s disease progression: Pathogenic and therapeutic implications. Neurosci. Res. 2021, 168, 100–112.
  56. Wang, Q.; Luo, Y.; Chaudhuri, K.R.; Reynolds, R.; Tan, E.-K.; Pettersson, S. The role of gut dysbiosis in Parkinson’s disease: Mechanistic insights and therapeutic options. Brain 2021, 144, 2571–2593.
  57. Knudsen, J.K.; Bundgaard-Nielsen, C.; Hjerrild, S.; Nielsen, R.E.; Leutscher, P.; Sørensen, S. Gut microbiota variations in patients diagnosed with major depressive disorder—A systematic review. Brain Behav. 2021, 11, e02177.
  58. Łoniewski, I.; Misera, A.; Skonieczna-Żydecka, K.; Kaczmarczyk, M.; Kaźmierczak-Siedlecka, K.; Misiak, B.; Marlicz, W.; Samochowiec, J. Major Depressive Disorder and gut microbiota—Association not causation. A scoping review. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 106, 110111.
  59. Bastiaanssen, T.F.S.; Cussotto, S.; Claesson, M.; Clarke, G.; Dinan, T.G.; Cryan, J.F. Gutted! Unraveling the Role of the Microbiome in Major Depressive Disorder. Harv. Rev. Psychiatry 2020, 28, 26–39.
  60. Knuesel, T.; Mohajeri, M.H. The Role of the Gut Microbiota in the Development and Progression of Major Depressive and Bipolar Disorder. Nutrients 2021, 14, 37.
  61. Athira, K.V.; Bandopadhyay, S.; Samudrala, P.K.; Naidu, V.; Lahkar, M.; Chakravarty, S. An Overview of the Heterogeneity of Major Depressive Disorder: Current Knowledge and Future Prospective. Curr. Neuropharmacol. 2020, 18, 168–187.
  62. Malhi, G.S.; Mann, J.J. Depression. Lancet 2018, 392, 2299–2312.
  63. Carvalho, A.F.; Firth, J.; Vieta, E. Bipolar Disorder. N. Engl. J. Med. 2020, 383, 58–66.
  64. McIntyre, R.S.; Berk, M.; Brietzke, E.; Goldstein, B.I.; López-Jaramillo, C.; Kessing, L.V.; Malhi, G.S.; Nierenberg, A.A.; Rosenblat, J.D.; Majeed, A.; et al. Bipolar disorders. Lancet 2020, 396, 1841–1856.
  65. Lucidi, L.; Pettorruso, M.; Vellante, F.; Di Carlo, F.; Ceci, F.; Santovito, M.; Di Muzio, I.; Fornaro, M.; Ventriglio, A.; Tomasetti, C.; et al. Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment. Int. J. Mol. Sci. 2021, 22, 3723.
  66. Sublette, M.E.; Cheung, S.; Lieberman, E.; Hu, S.; Mann, J.J.; Uhlemann, A.; Miller, J.M. Bipolar disorder and the gut microbiome: A systematic review. Bipolar Disord. 2021, 23, 544–564.
  67. Freund, N.; Juckel, G. Bipolar Disorder: Its Etiology and How to Model in Rodents. Methods Mol. Biol. 2019, 2011, 61–77.
  68. Fries, G.R.; Walss-Bass, C.; Bauer, M.E.; Teixeira, A.L. Revisiting inflammation in bipolar disorder. Pharmacol. Biochem. Behav. 2019, 177, 12–19.
  69. Flowers, S.A.; Ward, K.M.; Clark, C.T. The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management. Neuropsychobiology 2019, 79, 43–49.
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