Role of Akkermansia in Human Diseases: From Causation to Therapeutic Properties

The gut microbiota plays a critical role in the modulation of host metabolism and immune response, and its impairment has been implicated in many gastrointestinal and extraintestinal diseases. Current evidence shows the well-documented role of A. muciniphila in maintaining the integrity of the intestinal barrier, modulating the host immune response, and improving several metabolic pathways, making it a key element in the pathogenesis of several human diseases. In this scenario, A. muciniphila is the most promising next-generation probiotic and one of the first microbial species suitable for specific clinical use when compared with traditional probiotics. Further studies are needed to provide more accurate insight into its mechanisms of action and to better elucidate its properties in several major areas, paving the way for a more integrated and personalized therapeutic approach that finally makes the most of our knowledge of the gut microbiota.


Introduction
In 2004, Muriel Derrien isolated for the first time a bacterium capable of growing on a viscous substrate, such as mucin, and using it as its sole source of energy; as a tribute to the Dutch microbiologist Antoon DL Akkermans and given its ability to grow on a mucin substrate, this bacterium was named Akkermansia muciniphila. A. muciniphila represents approximately 1-3% of the total gut microbiota in healthy people; it is a non-motile, Gramnegative, non-spore-forming, oval-shaped bacterium belonging to the Verrucomicrobia phylum, and it is the first and only member of the phylum Verrucomicrobia found in the human gut [1][2][3]. A. muciniphila was originally considered a strict anaerobe, but it was recently proved to tolerate small amounts of oxygen and was therefore reclassified as an aerotolerant anaerobe [4].One of the distinguishing features of A. muciniphila is its ability to degrade intestinal mucin glycoproteins via enzymes, such as glycosyl hydrolases, proteases, sulphatases, and sialidase, and to use them as a sole source of carbon and nitrogen; this process leads to the production of the short-chain fatty acids (SCFAs) acetate, propionate, and 1,2-propanediol, as well as succinate and sulfate. Due to this process of degradation, A. muciniphila promotes mucin turnover and thickening, thereby reinforcing the intestinal barrier and reducing gut permeability to microbial products. A further barrierreinforcing mechanism is the A. muciniphila-induced production of antimicrobial peptides from Paneth cells. SCFAs derived from gut mucin glycoproteins are absorbed in the colon and serve as an energy source for colonocytes, inducing regulatory T cells and exerting anti-inflammatory effects [4][5][6][7][8]. Figure 1. Potential beneficial mechanisms of Akkermansia muciniphila in humans. Through the dir and indirect regulation of immune system response, inflammatory, and endocrine pathways, as w as its substantial influence on gut ecology, Akkermansia muciniphila has been proven to have beneficial role in modulating intestinal and extraintestinal diseases. HSCs-hepatic stellate ce GLP-1-glucagon-like peptide-1; SCFAs-short-chain fatty acids. Potential beneficial mechanisms of Akkermansia muciniphila in humans. Through the direct and indirect regulation of immune system response, inflammatory, and endocrine pathways, as well as its substantial influence on gut ecology, Akkermansia muciniphila has been proven to have a beneficial role in modulating intestinal and extraintestinal diseases. HSCs-hepatic stellate cells; GLP-1-glucagon-like peptide-1; SCFAs-short-chain fatty acids.
This review aims to analyze the mechanisms by which A. municiphila is involved in the development and progression of human diseases, with a focus on its potential therapeutic use as a novel probiotic.  [13] HFD-fed mice Akk-EVs • Reduced body weight; • Improved glucose tolerance.
• Reduced gut permeability with increased tissue expression of tight junction proteins in an AMPK-dependent manner.
Plovier H. et al. 2017 [14] HFD-fed mice Live and pasteurized A. muciniphila and the outer membrane protein Amuc_1100 • Reduced body and fat mass, insulin resistance, and lipid levels (>in mice treated with the pasteurized bacterium or with Amuc_1100).
Wang L. et al. 2020 [22] Mice with DSS-induced colitis and CAC Pasteurized A. muciniphila or the outer membrane protein Amuc_1110

Akkermansia muciniphila and Inflammatory Bowel Diseases
The gut microbiota plays an undeniable role in the pathogenesis of inflammatory bowel diseases (IBD), and the modulation of the gut microbiota represents one of the most promising challenges in IBD therapy [52][53][54][55][56].
Many case-control studies have documented a significant decrease in the relative abundance of A. muciniphila both in ulcerative colitis (UC) and Crohn's disease (CD) compared to healthy controls [32,[57][58][59], with only one study showing an opposite trend in a group of patients affected by CD [60].
As previously mentioned, A. muciniphila exerts an anti-inflammatory effect within the intestinal microecology, which was the object of exploratory analyses in the setting of IBD. Among the underlying mechanisms proposed, the production of SCFAs is the most deeply investigated; the production of SCFAs has been demonstrated to protect against colitis by increasing the number of forkhead box P3 (Foxp3+) regulatory T cells in the colon and through the activation of the G-protein coupled receptor 43 (GPR43) expressed by immune cells and colonic epithelium [33,61,62]. Wang et al. observed that the administration of A. muciniphila could improve dextran sulfate sodium (DSS)-induced colitis in mice by reducing macrophage and CD8+ cytotoxic T lymphocyte levels in the colon [22], while Bian et al. reported a downregulation of pro-inflammatory cytokines and chemokines [34]. Additionally, the administration of A. muciniphila enhances intestinal stem cell proliferation and Paneth and goblet cell differentiation in the small intestine and colon of both healthy mice and mice with gut damage [35].
A. muciniphila also restored the mRNA expression of tight junction proteins such as zonulin-1, occludin, and claudin-1 in mouse models of DSS-induced colitis, thereby reducing gut permeability and reshaping the intestinal microbiota, leading it toward eubiosis; these effects are related to the administration of Amuc:2109, a β-acetylaminohexosidase secreted by this microorganism [23].
On the other hand, an increased abundance of A. muciniphila was also reported in preclinical models of IBD [63][64][65]. Interestingly, when administered to mice with non-DSSinduced colitis, A. muciniphila was associated with symptoms worsening; A. muciniphila administration also exacerbated the symptoms of Salmonella-typhimurium-induced gut inflammation in a mouse model with a background microbiota of eight bacterial species [66], and it was possibly implicated in the worsening of colitis in IL10 −/− mice.
The discrepancy in the effects of this bacterial species could allow for several interpretations, being possibly biased by the different mouse models used; moreover, it can be speculated that the increased abundance of A. muciniphila in colitis models could represent a causative factor or rather, a reactive response. When A. muciniphila was administered in the IL-10 −/− mice colonized with a simplified human gut microbiota, it did not promote inflammation, suggesting that other environmental conditions could be involved [67,68].
Finally, there are few studies on the predictive effect of Akkermansia after FMT in patients with IBD. Zhang et al. demonstrated that washed microbiota transplantation (WMT) significantly increased the colonization rate of Akkermansia and that there was a positive correlation between the abundance of patient's and donor's Akkermansia abundance after WMT, speculating its possible role as a predictive factor of WMT efficacy [32]. Similar results were obtained by Kump et al. in treatment-refractory patients with UC; indeed, the stool of donors with a higher bacterial richness and a higher relative abundance of A. muciniphila, Ruminococcaceae, and Ruminococcus spp. were more likely to induce remission in these patients. In particular, A. muciniphila was nearly absent in baseline samples but was significantly increased the day after FMT in patients achieving remission [36].
In conclusion, current evidence, although conflicting to some degree, paves the way for a potential role of A. muciniphila in IBD treatment [69].

Akkermansia muciniphila and Cancer
Colorectal cancer (CRC) is one of the most common and lethal cancers in the world. Although being overweight and obese, Western dietary habits, smoking, and heavy alcohol consumption are the better-known risk factors for CRC, the intestinal environment has also received widespread attention in this field. It has been demonstrated in humans and in animal models that gut dysbiosis may promote colon carcinogenesis via multiple mechanisms, including the development of chronic inflammation and the production of genotoxins and other microbial products [70][71][72][73].
A. muciniphila depletion is also a feature of CRC-associated dysbiosis. In models of colitis-associated CRC (CAC), the administration of pasteurized A. muciniphila or Amuc_1100 alone improved symptoms, delayed tumor development, and decreased the number and area of tumor lesions by attenuating DNA damage, cell apoptosis, and abnormal proliferation; the beneficial effects of A. muciniphila were associated with the expansion of cytotoxic T-lymphocytes in the colon and mesenteric lymph nodes and with the modulation of macrophages subpopulations, thus explaining how A. muciniphila influences inflammation-associated tumorigenesis [22].
Another study further confirmed that the abundance of A. muciniphila is significantly reduced in humans with CRC and that its supplementation can inhibit colonic tumorigenesis in ApcMin/+ mice via the expansion of M1-like macrophages in colonic tissue. Tumor-associated macrophages (TAMs) can assume a pro-inflammatory polarization (M1) or an anti-inflammatory polarization (M2), with only the former helping to suppress cancer cells. This effect is mediated by the interaction between A. muciniphila and the TLR2 expressed by macrophages, with the subsequent activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) intracellular pathway [37,74,75].
Apart from its immunomodulatory effects, A. muciniphila can also directly interfere with colon carcinogenesis through the production of Amuc_1434, an enzyme that can degrade Mucin2, the main component of the intestinal mucus layer, which is highly expressed in mucinous CRC. Amuc_1434 showed a protective effect on tumor protein 53 (p53) expression in vitro, resulting in the blockade of the G0/G1 cell cycle phase and the promotion of CRC cells apoptosis [24,76].
Conversely, it was observed that A. muciniphila abundance was heavily increased in two different cohorts of patients affected by CRC, as well as in a cohort of patients with esophageal and gastric cancers compared with healthy controls [77,78]. However, according to Weil et al., this observation can be related to an increased substrate availability rather than to a detrimental role of this bacterium, considering the overexpression of MUC1 and MUC5AC in CRCs [78].
Besides CRC, A. muciniphila was found to be more abundant in patients with nonsmall-cell lung cancer (NSCLC) and to gradually decrease during the progression from cirrhosis to hepatocellular carcinoma [79][80][81].
In recent years, gut microbiota modulation applied to cancer therapy is certainly a topic of growing interest in either treatment efficacy or tolerability [38,82,83].
There are some data regarding the possible role of A. muciniphila in both conventional and targeted anticancer therapy. For instance, A. muciniphila could improve the antitumor effect of cisplatin; in mouse models of lung cancer, the administration of A. muciniphila in combination with cis-diamminedichloroplatinum (CDDP) was associated with reduced tumor growth, the downregulation of ki-67, p53, factor-associated suicide (Fas) ligand proteins, and the upregulation of Fas proteins [38]. Moreover, the administration of A. muciniphila in this setting positively affected the production of cytokines toward a pro-inflammatory profile, suppressing the development of T-reg lymphocytes. This suggests that A. muciniphila could modulate the immune microenvironment toward an inflammatory response, counteracting tumor immune escape. A. muciniphila has been proven to enhance the antitumor efficacy of interleukin (IL)-2; in murine models of melanoma and CRC, the combined administration of IL-2 and A. muciniphila reduced the tumor burden and improved survival compared with IL-2 treatment alone, primarily by stimulating the response of CD4+ and CD8+ T cells against cancer cells and by decreasing the number and the activity of T-regs. These beneficial effects were at least partially mediated by TLR2 signaling activated by a specific membrane protein [39]. The current literature also shows a peculiar interplay between A. muciniphila and abiraterone acetate (AA), an inhibitor of androgen biosynthesis for the treatment of prostate cancer (PCa) refractory to androgen deprivation therapy (ADT). In a cohort of PCa patients, AA administration increased the abundance of A. muciniphila. This was independent of immunological modulation and possibly resulted from the interaction between the conjugated acetate portion of AA and A. muciniphila [84][85][86]. Unfortunately, the authors did not explore the contribution of A. muciniphila to the efficacy of AA. In a later study, the intravenous administration of A. muciniphila-derived extracellular vesicles in PCa-bearing, immune-competent mice operated as an immune modulator; it was associated with the increased activation of CD8+ T cells and tumor-killing M1 macrophages, resulting in a reduced tumor mass [25].
To further clarify the role of Akkermansia in cancer immunotherapy, Xu et al. evaluated the effects of the modulation of the gut microbiome on the response to immune checkpoint inhibitors (ICIs). In CRC mouse models, the exposure to several broad-spectrum antibiotics interfered with the efficacy of programmed cell death protein 1 (PD-1) antibodies, depending on the type of antibiotic and the resulting changes in the gut microbiota composition. In particular, the authors conducted a metagenomic analysis to assess the correlation between specific bacterial taxa and metabolic and immunologic changes. A. muciniphila was found to be enriched in the vancomycin-treated group and associated with a better outcome; according to the authors, Akkermansia could preserve the efficacy of anti-PD-1 therapy by modulating the metabolism of glycerophospholipids, which influence the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment [87]. Other published studies in patients with hepatocellular carcinoma and melanoma highlighted the contribution of the gut microbiome to the response to immunotherapy, and A. muciniphila emerged as a key element associated with treatment efficacy [40,[88][89][90][91].
Finally, in patients with NSCLC and renal cell carcinoma (RCC) undergoing immunotherapy with ICIs, FMT from treatment responders to germ-free mice resulted in increased efficacy of immunotherapy. A. muciniphila was found to be more abundant and associated with treatment response, and the oral administration of A. muciniphila improved PD-1 blockade effectiveness, once again through the modulation of the immune response, specifically by promoting the recruitment of CD4+ T cells [40].

Akkermansia muciniphila and Metabolic Diseases
The prevalence of obesity is increasing worldwide, with growing concerns about the healthcare burden associated with its complications. Obesity is a risk factor for cardiovascular disease, diabetes mellitus, chronic kidney disease, several cancers, and musculoskeletal disorders [92,93]. Current evidence shows that obesity is associated with specific changes in the gut microbiota, and A. muciniphila is negatively correlated with body weight in both humans and in mouse models [94][95][96][97][98][99][100][101]. However, to date, the mechanisms by which A. muciniphila can modulate body weight and metabolism have not been completely clarified. A. muciniphila can increase the secretion of glucagon-like peptide-1 (GLP-1), a hormone able to increase insulin secretion by reducing postprandial glucose spikes, to reduce the expression of glucose and fructose transporters in the jejunum, with a consequent reduction in carbohydrate absorption, and to modulate the expression of proteins involved in adipose cell differentiation, thus influencing body weight and composition [41,102,103]. These beneficial effects of the host-microbe interaction could be also mediated by the endocannabinoid system, which stimulates the secretion of metabolically active molecules such as glucagon-like peptides [20,104]. Moreover, it has been suggested that the protective effect of A. muciniphila on the intestinal barrier can reduce systemic inflammation, resulting in an overall improved metabolism [13,26,42].
Since there is an inverse correlation between the abundance of A. muciniphila and metabolic diseases, its therapeutic potential has been widely explored in several studies. Plovier et al. demonstrated that in a murine model of obesity induced by high-fat diet (HFD), the administration of pasteurized A. muciniphila reduced body weight gain and the accumulation of white adipose tissue while improving insulin resistance and dyslipidemia; these effects were ascribed to the interaction between Amuc_1100 and TLR2. The latter has been implicated in the pathogenesis of metabolic disorders such as obesity and type 2 diabetes mellitus [14,105,106]. Another preclinical study reported a similar result, demonstrating an association with the restoration of the integrity of the intestinal barrier damaged by HFD, and that A. muciniphila administration in mice could prevent liver steatosis and improve hepatic function [27].
Depommier et al. confirmed that the oral administration of pasteurized A. muciniphila mitigates diet-induced obesity due to an increased fecal energy excretion, which is likely dependent on a reduction of carbohydrate absorption. This study also evidenced a reduced expression of perilipin 2, a protein associated with lipid storage, in brown and white adipose tissues, induced by the administration of A. muciniphila [28].
As opposed to the previously mentioned studies, A. muciniphila treatment reversed HFD-induced metabolic disorders in mice by increasing intestinal levels of endocannabinoids, which control inflammation, the integrity of the gut barrier, and gut peptide secretion. However, this only occurred after the administration of the viable microorganism, as the heat-killed forms did not achieve the same positive results [5]. Another study obtained an amelioration of metabolic parameters with either viable or heat-killed A. muciniphila [43].
A remarkable effect on glucose metabolism has been also highlighted, as treatment with metformin increases the abundance of A. muciniphila in HFD-fed mice by improving the glycemic profile. However, oral administration of A. muciniphila alone also significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by locally recruiting T-regs [44]. Even in T2DM patients, metformin increased the levels of A. muciniphila in feces, thus suggesting another possible mechanism of action of this drug. Furthermore, patients with T2DM who did not achieve optimal glycemic control using metformin or other hypoglycemic agents had a lower relative abundance of A. muciniphila compared to responders [44,[107][108][109].
Considering the promising effects of A. muciniphila on metabolic disorders in animal studies, some clinical trials have been conducted. Two of them have already been completed and published, with one specifically regarding patients with metabolic syndrome [102]. Depommier et al. conducted a randomized, controlled, double-blind clinical trial enrolling a total of 32 participants with a diagnosis of metabolic syndrome to assess the beneficial effects of A. muciniphila. After a 3-month treatment with pasteurized A. muciniphila, the authors observed a significant improvement in insulin resistance and plasma cholesterol levels, with a slight decrease in weight, fat mass, and hip circumference, and a good safety and tolerability profile [29]. Two other ongoing clinical trials are currently assessing the effects of A. muciniphila administration in obesity and type 2 diabetes mellitus (T2DM) (NCT: NCT04797442) and on insulin resistance in healthy individuals with dysglycemia (NCT: NCT05114018) [102].
Akkermansia is also a promising predictive factor of the success of dietary interventions; indeed, it was shown that the baseline abundance of A. muciniphila positively correlated with an improvement in blood glucose and lipid levels and body fat distribution following the dietary intervention [85]. Conversely, several dietary interventions have been tested in human and animal studies to enhance the intestinal abundance of A. muciniphila. Various types of dietary fibers, calorie restriction, and polyphenol-rich foods such as wild blueberry polyphenolic extract, cranberry extract, and grape polyphenols, appear to be the most effective [85,103,[110][111][112][113]. Moreover, the administration of prebiotics such as fructooligosaccharides and inulin has been reported to increase A. muciniphila abundance in mice [114,115]. In contrast, A. muciniphila abundance has been negatively affected by energy-rich diets, such as a high-fat diet (HFD), high-fat, high-sugar diet (HFHS), or highfat, high-cholesterol diet (HFHC) [116]; some of these studies also reported an improvement in metabolic parameters after nutritional interventions that was found to correlate with an increase in A. muciniphila abundance [111,117].
A. muciniphila has also been used for the treatment or prevention of diabetes in mouse models. In experimental models of diabetes induced by streptozotocin, the administration of A. muciniphila improved liver function, reduced glucotoxicity and lipotoxicity, alleviated oxidative stress, and suppressed inflammation [30]. In non-obese diabetic (NOD) mice, vancomycin treatment increased A. muciniphila intestinal abundance and at the same time, reduced the incidence of T1DM, thus suggesting a protective role of A. muciniphila against T1DM development [125]. Furthermore, NOD mouse colonies with a lower incidence of T1DM exhibited a greater abundance of A. muciniphila, and its administration to animals with a high incidence of T1DM was able to delay disease development [45]. Beyond the promising effects of A. muciniphila on diabetes in animal models, consistent findings have also emerged in humans. Perraudeau et al. showed that T2DM patients treated with WBF-011 (a product containing inulin, Akkermansia muciniphila, Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis, and Anaerobutyricum hallii) for 12 weeks significantly improved postprandial glucose control and glycated hemoglobin compared with a placebo, with no issues about safety or tolerability. The probiotic strains in this formulation interacted mutually to form butyrate, which further stimulates GLP-1 release, thus explaining the results [46,103].
Recently, the gut microbiome has been gaining extensive attention for the treatment of metabolic-associated fatty liver disease (MAFLD) as well [103,126]. MAFLD (previously known as non-alcoholic fatty liver disease, NAFLD) is a metabolic syndrome characterized by lipid accumulation in the liver and subsequent oxidative stress, inflammation, apoptosis, and various degrees of fibrosis [127][128][129]. Obese mice treated with A. muciniphila reported the regression of MAFLD in association with the enhancement of lipid oxidation in the liver and by strengthening the gut mucosal barrier [47]. Similarly, Kim et al. observed that the oral administration of A. muciniphila significantly improved hepatic steatosis in obese mice by reducing the synthesis of triglycerides in the liver; additionally, A. muciniphila administration improved gut integrity and mitigated liver inflammation in these models [42]. Another study aimed to assess the beneficial effects of A. muciniphila treatment on the prevention of liver fibrosis showed that it significantly correlated with a reduction in both hepatic stellate cell (HSC) activation and fibrosis stage in mice fed with HFD after the administration of carbon tetrachloride (CCl4) [31].
There are currently two other ongoing clinical trials in the recruitment phase that are assessing the effects of A. muciniphila administration in patients affected by obesity and T2DM (NCT: NCT04797442) and in healthy individuals with dysglycemia (NCT: NCT05114018) [102].

Akkermansia muciniphila and Atherosclerosis
A significant association between atherosclerosis and specific components of the gut microbiota has been reported by several human studies, prompting the reconsideration this condition as a microbiota-associated disease [130][131][132][133]. Given this evidence, some authors tried to address the exact role of A. muciniphila in this condition; in a study by Li et al., Apolipoprotein E (ApoE)−/− mice prone to the atherosclerotic disease on a normal or Western diet were treated with live A. muciniphila. The treatment significantly reduced the dimensions of the atherosclerotic lesions of the aorta induced by the Western diet and reduced local and systemic inflammation as well. Changes were associated with a marked attenuation in metabolic endotoxemia and gut permeability, suggesting that A. muciniphila could attenuate atherosclerotic lesions through the restoration of gut barrier function [21]. On the contrary, A. muciniphila has also been associated with the production of trimethylamine n-oxide (TMAO), a metabolite of L-carnitine that was reported to accelerate atherosclerosis through the impairment of the reverse cholesterol transport and the shift of the phenotype of artery wall macrophages [134]; however, the authors did not investigate whether A. muciniphila was associated with enhanced atherogenesis [135,136].

Parkinson's Disease
Colonic inflammation and increased gut permeability have been shown to be associated with Parkinson's disease (PD) [137][138][139]. It has been demonstrated in animal models that neuronal injury and the aggregation of the protein α-synuclein (aSyn), which is responsible for neuronal loss in the substantia nigra in patients with PD, can be triggered by toxins or the translocation of bacterial proteins or can even start in the enteric nervous system and spread to the central nervous system [137][138][139][140][141]. For these reasons, there is a growing interest in characterizing changes in the intestinal bacterial populations associated with PD. Several studies reported an increased abundance of A. muciniphila in the fecal samples of patients with PD compared with healthy donors [142][143][144][145][146][147][148][149], and these observations were confirmed by a recent meta-analysis which also took into account possible confounding factors, such as constipation, BMI, sex, age, and drug intake [150]. The hypothesis functionally related to this observation is that A. muciniphila, being involved in mucus turnover, can increase gut permeability in these patients via the production of hydrogen sulfide, altering the integrity of the intestinal barrier and enhancing the absorption of bacterial toxins [151]. Further studies are needed to confirm these mechanisms.

Multiple Sclerosis
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system whose etiology is still unknown [152,153]. In mouse models, commensal bacteria can trigger a spontaneous form of experimental autoimmune encephalomyelitis (EAE) after exposure to myelin oligodendrocyte glycoprotein [154,155]; nevertheless, germ-free mice prone to brain autoimmunity who received FMT from patients with MS showed more severe symptoms of EAE than mice who received FMT from healthy controls [156]. This suggests the role of the gut microbiota in the pathogenesis of MS.
Several studies and systematic reviews report an overabundance of A. muciniphila in the gut microbiota of patients affected by MS, either in the untreated ones or in those receiving various disease-modifying therapies [156][157][158][159][160][161]. These data were also confirmed by comparing patients with their genetically unrelated household healthy controls, thus minimizing the effects of diet and environmental factors on the gut microbiome composition [162].
In a particular observational study comparing the gut microbiota composition of 34 monozygotic twin pairs discordant for MS, an increased abundance of A. muciniphila was reported in the untreated twins affected by MS compared with either the healthy twins or those affected by MS who were receiving treatment; FMT from twins with MS induced a significantly higher incidence of disease in transgenic mouse models of spontaneous brain autoimmunity, with IL-10 being involved in preventing disease development [157].
Notably, cannabinoids, which are used to counteract muscle spasticity, reduced the abundance of A. muciniphila in stools, systemic inflammation, and LPS levels in a mouse brain, improving clinical conditions. Antibiotic treatment resulted in reduced disease severity in EAE mice, while FMT from EAE mice exposed to cannabinoids to those treated with antibiotics resulted in an even better outcome, confirming the critical role of cannabinoids play in attenuating EAE through the modulation of the gut microbiome [163].
To explain these findings, it was suggested that A. muciniphila might be involved in the activation/expansion of autoreactive memory CD4+ T cells or the production of cross-reactive antibodies via molecular mimicry in predisposed individuals [164][165][166]. Otherwise, A. muciniphila may induce dysfunction of the intestinal barrier under certain circumstances, e.g., in case of nutritional deficiencies or through interaction with other bacterial species [167][168][169][170][171].
However, there is also evidence regarding the protective role of A. muciniphila in central nervous system autoimmunity. Some authors hypothesized that the increased abundance of A. muciniphila in the early stage of the disease could be a compensatory mechanism aimed at preventing disease progression [172][173][174]. This makes it challenging to conclude the exact role of A. muciniphila in MS pathogenesis, even in animal models.

Alzheimer's Disease
The gut microbiota can release a significant quantity of amyloids and lipopolysaccharides, which might influence signaling pathways and lead to the production of proinflammatory cytokines related to the pathogenesis of Alzheimer's disease (AD) [175][176][177]. Colonization of germ-free amyloid β precursor protein (APP) transgenic mice with gut microbiota from conventionally raised APP transgenic mice increased cerebral levels of the amyloid β-protein (Aβ), while colonization with the gut microbiota from wild-type mice was less effective in inducing these changes, indicating a role of the gut microbiota in AD development [178].
Significant depletion of A. muciniphila was found in fecal samples from APP transgenic mice prone to developing AD when compared to wild-type mice and was negatively correlated with the amount of the pathogenic Aβ 42 in the brain.
A later study confirmed that the abundance of A. muciniphila decreased in mouse models of AD alongside a reduction in the number of colonic mucus cells and an increase in serum levels of diamine oxidase (DAO), which reflects an impairment of intestinal barrier function; the administration of A. muciniphila effectively reduced serum DAO, reverted the loss of colonic mucus cells, promoted the reduction of pathogenic Aβ 40-42 levels in the cerebral cortex, and improved cognitive abilities in AD mouse models [48].
Recent evidence indicated that metabolic disorders, including obesity and insulin resistance, are risk factors for cognitive impairment and dementia [176,[179][180][181]. The linkage between metabolic impairment and the course of AD was also explored. Early-life feeding with a HFD lead to microgliosis in mice and the expression of proinflammatory cytokines in the hippocampus: this resulted in impairment in neuronal development, spatial learning, and memory, which was associated with an alteration of the gut microbiota composition, again characterized by the depletion of A. muciniphila [49]. Oral supplementation with A. muciniphila improved gut permeability and reduced hippocampal microgliosis and the expression of proinflammatory cytokines, restoring neuronal development and defects in learning and memory.
Human studies on the topic are lacking. It is worth mentioning that it has been observed that a modified Mediterranean-ketogenic diet could ameliorate cerebrospinal fluid markers of AD in patients with mild cognitive impairment and is associated with an increased fecal abundance of A. muciniphila [182].

Amyotrophic Lateral Sclerosis
Environmental factors have been proposed as modulators of the clinical course of amyotrophic lateral sclerosis (ALS), in particular by influencing the composition of circulat-ing low-molecular-mass metabolites that originate from the gastrointestinal tract and enter the blood-brain barrier to modulate metabolic, transcriptional, and epigenetic programs in neurons and other resident cells [183,184]. The gut microbiome is a potential source of these bioactive molecules and has been linked to ALS in animal and human studies [50,[185][186][187]. Blacher et al. showed that A. muciniphila is less abundant in ALS-prone superoxide dismutase transgenic mice and that its administration ameliorates disease symptoms, prolongs the lifespan of these animals, reduces brain atrophy, and increases spinal cord cellularity. Supplemented mice accumulated nicotinamide (NAM) in the central nervous system, and the systemic supplementation of NAM itself improved motor symptoms and gene expression patterns in the spinal cord. Therefore, A. muciniphila could act via NAM to ameliorate mitochondrial function, NAM adenine dinucleotide (NAD) homeostasis, and the clearance of superoxide radicals, functions known to be impaired in ALS [50].
However, it should be taken into account that gut dysbiosis could be a consequence of altered feeding or rather of the use of food supplements or exposure to antibiotics, which are frequent in these patients [188]. Therefore, strong evidence is still required to confirm the role of gut microbiota in ALS.

Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a neuro-developmental disorder of children, characterized by a specific behavioral phenotype of impaired social communication and stereotypic behavior. Once considered uncommon, it is now recognized to involve 1% of the population worldwide [189].
Although still uncertain, the etiology of autism spectrum disorder (ASD) is assumed to reside in the interplay of genetic, epigenetic, and environmental factors, leading to an imbalance in neurotransmitters, dysfunctional neuronal pathways, and abnormal synaptogenesis and neuronal connectivity. Strong associations were found with several genetic and metabolic disorders [190]; gastrointestinal disturbances are also very common in patients with ASD, with significant differences in the gut microbiota profile compared with non-affected children [191][192][193][194].
A statistically significant decreased abundance of A. muciniphila in patients with ASD and their siblings compared to healthy controls was reported [195]. Notably, the modulation of the gut microbiota with antibiotics and probiotics improves behavior and bowel health outcomes [196,197].
In a recent study, FMT from normal mice to a mouse model of fragile X syndrome, which is associated with ASD, ameliorated autistic-like behavior, especially memory deficit and social withdrawal, and normalized A. muciniphila intestinal abundance, which was low at baseline. The increase in A. muciniphila was correlated with a reduction in TNFα and Iba1 (a marker of microglial activation) and with an increased expression of MUC2, suggesting that A. muciniphila can improve the course of the disease by restoring intestinal barrier integrity through the stimulation of mucin production and release [51].

Conclusions
A. muciniphila has been gaining increasing attention in recent years, with consistent evidence suggesting its crucial role in the homeostasis of the gut ecosystem and beyond. Indeed, the production of small metabolites and mediators, the influence on microbial diversity and the preservation of the gut barrier integrity promoted by A. muciniphila have been proven to exert a beneficial effect not only on the gut but also on a series of diseases involving the metabolic, cardiovascular, neurological, and even oncological fields. The administration of A. muciniphila could exert a significant effect on metabolic syndrome and T2DM, being able to affect significantly the course of the disease, thus representing an intriguing adjuvant intervention. On the other hand, data regarding neurodegenerative diseases and anticancer therapy are still lacking and inconclusive, partially due to a series of confounding factors persistently associated with these cohorts of patients. However, further studies are needed to address the precise role of this bacterial species in these topics, specifically in analyzing the administration of live, pasteurized, and single components of A. muciniphila in order to make the most of its promising features.
Author Contributions: A.P., F.S., G.C. and F.R.P. developed the concept, revised the literature, and wrote the manuscript; A.G. developed the concept, supervised the research, and revised the manuscript. All investigators participated in data interpretation and contributed to the revision of the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.