The role of the probiotic Akkermansia muciniphila in brain functions: insights underpinning therapeutic potential

Figures & data

Table 1. Akkermansia muciniphila and its association with different neuropsychiatric diseases.

Neuropsychiatric Disorders	Subjects and sample size	Changes in the microbiome of subjects compared with that in healthy controls	Changes in other organ systems	A. muciniphila intervention and its effect	Citation
Depression and anxiety	Infants aged 2.5 months (n = 446)	After maternal prenatal psychological distress: ↑ Proteobacteria ↓ Akkermansia	↑ levels of depression and anxiety (Score of chronic EPDS, PRAQ-R2, SCL, and Daily Hassles negative subscale)	NA	(Aatsinki et al. 2020)
	Male C57BL/6J mice, n = 20; wild-type mice treated with minocycline, n = 27.	After genetic deficiency or pharmacological inhibition of caspase-1: ↑Akkermansia ↑ Blautia spp. ↑ Lachnospiracea	After genetic deficiency or pharmacological inhibition of caspase-1: Ameliorated stress-induced depressive-like behaviour, increased locomotor activity and skills	NA	(Wong et al. 2016)
	Male C57BL/6J mice n = 69 administered prebiotics FOS, GOS, FOS + GOS.	GOS and FOS + GOS treatment: ↑ Lachnospiraceae ↑Akkermansia ↑ Oscillibacter ↓ Lactobacillus ↓ Bifidobacterium	GOS and FOS + GOS treatment: ↓ Stress-induced corticosterone release	NA	(Burokas et al. 2017)
	Male C57BL/6J mice Social defeat, n = 20; Control, n = 19.	Group with social defeat: ↓Overall diversity ↓Akkermansia ↑ Actinobacteria ↓ Deferribacteres ↓ Proteobacteria	NA	NA	(Mcgaughey et al. 2019)
	Male Wistar rats paradoxical sleep deprivation group, n = 10; control group, n = 10.	Paradoxical sleep deprivation group: ↓Akkermansia ↑ Oscillospira ↑Parabacteroides ↑Ruminococcus ↑Phascolarctobacterium ↑Aggregatibacter	After paradoxical sleep deprivation: Hyper-activated hypothalamic-pituitary-adrenal (HPA) axis.	NA	(Zhang et al. 2019a)
	Male Wistar rats ACTH-treated TRD model group, n = 10; Control group, n = 10.	ATCH-treated group: ↑ Ruminococcus ↑ Klebsiella ↓ Lactobacillus ↓Akkermansia	ATCH-treated group: ↓ Peripheral serotonin ↑ HPA axis activation.	NA	(Song et al. 2019)
	Male Sprague-Dawley rats (n = 43, 6 weeks old).	After feeding with olive oil-rich diet and induction of chronic mild stress: ↑Akkermansia ↑ Romboutsia	Chronic mild stress: ↓ weight gain during growing period ↑ Anxiety-like and anxiety-like behaviour ↑ Corticosterone Not relieved by olive oil.	NA	(Tung et al. 2019)
	Control group, n = 6; Chronic restraint stress (CRS) group, n = 6; CRS + AKK, group n = 6; AKK group, n = 6.	NA	NA	Treatment with AKK: Amelioration of depressive-like behaviour; Restoration of abnormal variations in corticosterone, dopamine, serotonin, and brain-derived neurotrophic factor.	(Ding et al. 2021)
Alzheimer’s Disease and cognitive deficit	Patients with mild cognitive impairment, n = 11; Mild cognitively normal participants, n = 6. With administration of a modified Mediterranean-ketogenic diet (MMKD).	After MMKD for 6 weeks: ↑Akkermansia ↑ Enterobacteriaceae ↑ Slackia ↑ Christensenellaceae ↑ Erysipelotriaceae ↓ Bifidobacterium ↓ Lachnobacterium (compared to microbiome before MMKD)	After MMKD for 6 weeks: Improved AD biomarker profile and brain vascular functions	NA	(Nagpal et al. 2019)
	Wild-type mice at 1, 2, 3, 6, and 9 months, n = 14,17, 17, 31, and 18, respectively; APP/PS mice at 1, 2, 3, 6, and 9 months, n = 21, 24, 24, 34, and 18, respectively.	Shifted with age alpha and beta diversity Ratio of Firmicutes/Bacteroidetes ↑ Enterobacteriaceae 1, 6 m ↑ Verrucomicrobiaceae 2, 6, 9 m ↑ Actinobacteria 2, 9 m ↑ Proteobacteria 2, 9 m ↑ Prevotellaceae 2 m ↑ Erysipelotrichaceae 2 m ↑ Bifidobacteriaceae 2 m ↓ Bacteroidaceae 6 m ↓ Rikenellaceae 6 m ↑ Desulfovibrionaceae 9 m ↑ Clostridiales 9 m	Detection by Aβ staining at 3 months; Detection of Aβ plaques at 6–9 months; Increased microglial activation at 6–9 months.	NA	(Chen et al. 2020)
	C57BL/6 male mice Ketogenic diet group (KD), n = 10; control regime group, n = 10.	After KD: ↑Akkermansia ↑ Lactobacillus ↓ Clostridiales ↓ Clostridium ↓ Dorea	After KD: Enhanced neurovascular functions, modulated blood ketone and glucose, ↓ Bodyweight	NA	(Ma et al. 2018)
	Juvenile C57BL/6J male mice fed a high-fat diet (HFD).	After HDF in early life: ↑ Firmicutes ↓ Bacteroidetes ↑↑ A. muciniphila	After HDF in early life: HFD impaired hippocampus-dependent contextual/spatial learning and memory.	A. muciniphila treatment: ↓ Hippocampal microgliosis ↑ Gut permeability ↓ Immune response ↑ Synapse plasticity ↑ Neuronal development ↓ Defects in learning and memory	(Yang et al. 2019)
	APP/PS1 mice: four groups (n = 10 per group) fed either a normal chow diet or HFD; Wild-type mice: two groups (n = 6 per group).	NA	NA	A. muciniphila treatment: ↑ Glucose homeostasis ↓ Damage to the intestinal barrier ↓ Hyperlipidemia ↓ Whitening of brown adipose tissue ↓ Deposits of Aβ plaque and increased Aβ levels in the brain Improved impaired cognitive, anxiety-related behaviours.	(Ou et al. 2020)
	Eight-week-old female C57BL/6 mice HFD-PBS, n = 10; HFD-AKK^sub, n = 10; NCD-PBS, n = 10; NCD-AKK^sub, n = 10.	NA	NA	A. muciniphila treatment of HFD-fed mice: ↓ Body weight and food consumption; ↑ Blood glucose control; ↑ Memory decay; ↓ Systemic inflammation; ↑ Tryptophan metabolism; ↑ Nissl bodies in neurons of the hippocampus; ↓ Liver steatosis	(Wu et al. 2020b)
	Normal chow (NC) NC + enriched environment (EE) High-fat, high cholesterol (HFHC) HFHC + EE, n = 8; NC HFHC + PBS HFHC + LGG (Lacticaseibacillus rhamnosus GG) HFHC + AKK (A. muciniphila).	HFHC vs NC ↓ Lactobacillaceae ↓ Ruminococ acceae ↑ Enterobacteriaceae ↑ Bacteroidaceae ↑ Peptostreptococ caceae Unique in NC + EE ↑ Micrococcaceae ↑ Christensenellaceae ↑ Ruminococcaceae Unique in HFHC + EE ↑ Firmicutes phyla ↑ Akkermansiaceae	EE restored HFHC-induced cognitive deficits, but further decreased brain metabolic activity	A. muciniphila restored HFHC-induced cognitive deficits and brain metabolic activity.	(Higarza et al. 2021)
Substance use disorders	Patients with AUD, n = 36; Controls, n = 36.	Patients with AUD: ↓Akkermansia ↑ Bacteroides	Patients with AUD showed increased serum levels of lipopolysaccharide (LPS), TNF-α, IL-1β, MCP-1, and IL-6.	NA	(Addolorato et al. 2020)
	Patients with alcoholic steatohepatitis (ASH), n = 21; Patients with severe ASH, n = 15; Healthy individuals without obesity, n = 16.	Patients with ASH compared with healthy individuals: ↓ A. muciniphila	NA	A. muciniphila treatment: ↓ Hepatic injury and established alcoholic liver disease	(Grander et al. 2018)
	Wild-type C57BL/6 6-to 8-week-old female mice	After alcohol induction: ↓Akkermansia ↓ Verrucomicrobiaceae ↓ Lachnospiraceae ↑ Eubacteriaceae	NA	NA	(Lowe et al. 2017)
	Male Sprague–Dawley rats: MA group, n = 17; Saline group, n = 5.	MA exposure: ↑ A. muciniphila ↑ Acetivibrio	NA	NA	(Yang et al. 2020)
Amyotrophic Lateral Sclerosis (ALS)	Antibiotic-treated mSod1G93A transgenic mice.	mSod1 ALS mice (before or after antibiotic treatment): ↓ A. muciniphila, Parabacteroides with diseases progression	NA	A. muciniphila treatment: ↓ ALS in mice by increasing NAM levels ↑ Survival of ALS mice (improved motor function)	(Blacher et al. 2019)
Multiple Sclerosis (MS)	MS mice, n = 60; healthy controls, n = 43.	Experimental autoimmune encephalomyelitis (EAE) mice: ↑ Methanobrevibacter ↑Akkermansia ↓ Butyricimonas	↑ Interferon, NF-κB, Toll-like receptor, and IL-6 signalling pathways; ↓ PPARα/RXRα.	NA	(Jangi et al. 2016)
	34 Monozygotic twin pairs discordant for MS	Untreated MS twins: ↑Akkermansia	NA	NA	(Berer et al. 2017)
	Germ-free mice with microbiome transplant twins with MS, n = 22–26, or healthy donors, n = 20–26.	Mice with microbiome transplant from twins with MS: ↓ Sutterella	Mice with microbiome transplant from twins with MS: ↑ Autoimmune ↓ IL-10
	MS patients not undergoing treatment, n = 71; healthy controls, n = 71.	MS patients: ↑ Acinetobacter ↑ A. muciniphila ↓ Parabacteroides	NA	NA	(Cekanaviciute et al. 2017)
	GF C57BL/6 mice Three MS and control donor pairs; n = 6–8 mice per group.	MS mice model: ↓ Sutterella ↑ Ruminococcus	↓ IL-10 + Treg induction in mesenteric lymph nodes from MS microbiome-colonized mice
	Patients with MS, n = 9; controls, n = 13 orally administered a probiotic.	Patients with MS: ↑Akkermansia ↑ Blautia ↑ Dorea	NA	NA	(Tankou et al. 2018)
	Female C57BL/6 mice Naive mice, n = 4; EAE-VEH, mice n = 5; EAE-(delta-9-tetrahydrocannabinol (THC)+ cannabidiol (CBD), n = 6.	MS mice model treated with THC + CBD: ↓ A. muciniphila ↓ Tenericutes ↑ Firmicutes	MS mice model treated with THC + CBD: ↑ Anti-inflammatory response ↑ Levels of LPS	NA	(Al-Ghezi et al. 2019)
	Relapsing remitting MS (RRMS), n = 135; Progressive MS mice, n = 31; Healthy controls, n = 38.	In both progressive and RRMS vs. healthy controls ↓ Blautia wexlerae ↓ Dorea formicigenerans ↑ Romboutsia timonensis ↑ Bacteroides Unique to RRMS ↓ Erysipelotrichaceae CCM ↓ Ruminococcaceae ↑ Bacteroides uniformis ↑ Pseudoflavonifractor Unique to progressive MS ↑Akkermansia ↑ Streptococcus ↓ Blautia ↓ Agathobaculum	Several Clostridium species in progressive MS (n = 27) and C. bolteae, C. leptum, and C. scindens in RRMS (n = 95) were associated with higher EDSS and fatigue scores. Akkermansia abundance was negatively correlated with EDSS and MRI measures of disease severity in patients with progressive disease.	MS-derived Akkermansia strains BWH-J5, BWH-H3, and BWH-I7 colonized C57/BL6 mice, lowered disease in the MOG/C57 model of EAE, with the strongest protective effect exerted by strain H3, which also reduced RORγT-positive γδ T cells and IL-17-producing γδ T cells.	(Cox et al. 2021)
Autism Spectrum Disorder (ASD)	Children with typically developed ASD, n = 23; Siblings of children from the ASD cohort, n = 22; Unrelated controls, n = 9.	Children with ASD: ↓ Bifidobacterium spp. ↓ A. muciniphila	NA	NA	(Wang et al. 2011)
	Healthy children, n = 10; Pervasive Developmental-Disorder Not Otherwise Specified, n = 10; autism, n = 10.	Children with ASD: ↓ Fusobacteria ↓ Verrucomicrobia	NA	NA	(De Angelis et al. 2013)
	Patients with autism with gastrointestinal symptoms, n = 33; Siblings not showing autistic symptoms, n = 7; Non-sibling control subjects, n = 8.	Patients with ASD: ↑ Desulfovibrio species ↑ Bacteroides vulgatus ↑ Verrucomicrobia	NA	NA	(Finegold 2008; Finegold et al. 2010)
	Infants with ASD, n = 6; Healthy infants, n = 6.	Patients with ASD: ↑ Faecalibacterium ↓ Blautia ↑Akkermansia	NA	NA	(Inoue et al. 2016)
	Individuals with ASD, n = 20; healthy subjects, n = 28.	Patients with ASD: ↑ Verrucomicrobia ↑ Firmicutes ↓ Proteobacteria ↓ Cyanobacteria	NA	NA	(Lee et al. 2017)
	Children with ASD, n = 20; neurotypical children, n = 20.	Children with ASD: ↑ Prevotella ↓Akkermansia	NA	NA	(Kang et al. 2013b)
	Individuals with autism, n = 40; Neurotypical controls, n = 40.	Patients with ASD: ↓Akkermansia ↓ Alistipes ↓ Bilophila, ↓ Dialister ↓ Parabacteroides ↑ Collinsella ↑ Corynebacterium ↑ Dorea ↑ Lactobacillus	NA	NA	(Strati et al. 2017)
	2-to-7-year-old children with ASD (n = 48).	↑Bacteroidetes/Firmicutes ratio ↓Akkermansia ↓ Dialister invisus	NA	NA	(Zou et al. 2020)
	C57BL/6 (B6) mice n = 21; BTBR^T + tf/j mice n = 25.	BTBR^- mice: ↓Akkermansia	↑ Abdominal pain; ↑ Inflammation; ↓ Gastric motility	NA	(Newell et al. 2016)
Epileptic Seizures	Healthy children, n = 20; Patients with cerebral palsy (CP) and epilepsy, n = 25.	Patients with CP: ↑ Bifidobacterium, ↑ Streptococcus, ↑Akkermansia, ↑ Enterococcus ↑ Prevotella ↑ Veillonella ↑ Rothia ↑ Clostridium IV ↓ Bacteroides, ↓Faecalibacterium, ↓Blautia ↓Ruminococcus, ↓Roseburia, ↓Anaerostipes ↓Parasutterella	NA	NA	(Huang et al. 2019)
	Kcna1^−/− SPF C3HeB/FeJ mice fed ketogenic diet (KD) or standard chow.	After KD: ↑Akkermansia ↑ Parabacteroides ↑ Sutterella ↑ Erysipelotrichaceae	After treatment with Akkermansia and Parabacteroides: ↓ Systemic gamma-aminobutyric acid (GABA) ↑ Hippocampal GABA ↑Hippocampal glutamate	Treatment with both Akkermansia and Parabacteroides: ↑ Acute electrically-induced seizure protection; Seizure protection was not observed with A. muciniphila alone	(Olson et al. 2018)
Parkinson’s Disease (PD)	Male patients with PD, i = 31; Male healthy controls, n = 28.	Patients with PD: ↑Akkermansia ↑ Firmicutes ↓ Prevotella copri ↓ Eubacterium biforme	NA	NA	(Bedarf et al. 2017)
	Patients with PD, n = 34; Healthy controls, n = 34.	Patients with PD: ↑Akkermansia ↑ Bifidobacterium ↑ Enterobacteriaceae ↓ Bacteroidetes ↓ Prevotellaceae ↓Lactobacillaceae	NA	NA	(Unger et al. 2016)
	Patients with PD, n = 72; Healthy control, n = 72.	Patients with PD: ↑ Lactobacillaceae ↑ Verrucomicrobiaceae ↑ Bradyrhizobiaceae ↑ Ruminococcaceae ↓ Prevotellaceae ↓ Clostridiales i.s. IV	NA	NA	(Scheperjans et al. 2015)
	Patients with PD, n = 38; Healthy controls, n = 34.	Patients with PD: ↑Akkermansia ↑ Ralstonia ↑Proteobacteria. ↑Bacteroidaceae, ↑Clostridiaceae, ↓ Blautia ↓ Coprococcus ↓ Roseburia ↓ Faecalibacterium ↓ Lachnospiraceae	NA	NA	(Keshavarzian et al. 2015)
	Patients with PD, n = 80; Healthy controls, n = 72.	Patients with PD: ↑Verrucomicrobiaceae ↑Lactobacillaceae ↑Enterobacteriaceae ↑Enterococcaceae ↓Lachnospiraceae	Patients with PD: ↑ Fatty acid and butanoate metabolism ↓Amino acid metabolism	NA	(Pietrucci et al. 2019)
	Patients with PD, n = 193; Patients with multiple system atrophy, n = 22; Patients with progressive supra-nuclear palsy, n = 22; Healthy controls, n = 113.	Patients with PD: ↑Akkermansia ↑ Proteobacteria ↑ Bifidobacteriaceae ↑ Christensenellaceae ↑ Coriobacteriaceae ↑ Lactobacillaceae ↑ Enterobacteriaceae ↑ Lactobacillaceae ↓ Lachnospiraceae ↓Prevotellaceae ↓Streptococcaceae	NA	NA	(Barichella et al. 2019)
	Dataset 1: Patients with PD, n = 212; Controls, n = 136; Dataset 2: Patients with PD, n = 323; Controls, n = 184.	Patients with PD: ↑Akkermansia ↑ Bifidobacterium ↑ Lactobacillus ↑ Prevotella ↓ Faecalibacterium ↓ Roseburia	NA	NA	(Wallen et al. 2020)
	Typical PD, n = 147 cases; controls, n = 162.	Patients with PD: ↑Akkermansia ↑Lactobacillus ↓Turicibacter	NA	NA	(Baldini et al. 2020)
	Patients with PD, n = 14; Healthy controls, n = 7.	Patients with PD: ↑Akkermansia ↑Gammaproteobacter	NA	NA	(Gorecki et al. 2019)
	Patients with PD, n = 51; Healthy controls, n = 48.	Patients with PD: ↑Akkermansia ↑Ruminococcaceae ↓Lactobacillus ↓Streptococcus ↑Prevotellaceae	NA	NA	(Li et al. 2019a)
	Patients with PD, n = 75; Healthy controls, n = 45.	Patients with PD: Slight changes ↑Akkermansia ↑Bifidobacteriaceae ↑Eubacteriaceae, ↓Lachnospiraceae ↓Firmicutes ↓Tenericutes, ↓Euryarchaeota. ↓Streptococcaceae,	NA	NA	(Lin et al. 2018)
	Cohort 1: Patients with PD, n = 80; Healthy controls, n = 77. Cohort 2: Patients with PD, n = 120; Healthy controls, n = 120.	Patients with PD: ↑Verrucomicrobia ↑Lactobacillus ↑Odoribacteraceae ↓Prevotellaceae	A correlation between Bacteroides abundance and plasma levels of TNF-α, and a correlation between Verrucomicrobia abundance and plasma levels of IFN-γ was observed	NA	(Lin et al. 2019)
	Patients with PD, n = 197; Healthy controls, n = 130.	Patients with PD: ↑Akkermansia ↑Lactobacillus ↑Bifidobacterium ↑Christensenellaceae ↑Ruminococcaceae ↑Tissierellaceae ↓Lachnospiraceae ↓Pasteurellaceae	Patients with PD: ↑Acetyl-CoA synthetase ↓Butyrate kinase	NA	(Hill-Burns et al. 2017)
	Patients with PD, n = 76; Patients with idiopathic rapid eye movement sleep behaviour disorder, n = 21; Healthy controls, n = 78.	Patients with PD: ↑Akkermansia ↑Actinomycetales, ↑Flavonifractor ↓Prevotella	NA	NA	(Heintz-Buschart et al. 2018)
	Twenty-eight 6–8-week-old male C57BL/6 mice were randomized into four groups evenly. Controls (10 mg/kg/day body weight, 4% carboxymethylcellulose and 1.25% chloroform), Rotenone (10 mg/kg/day body weight), Restraint stress (RS), RS + rotenone.	RS: ↓Lactobacillus RS + rotenone (compared to RS): ↑Verrucomicrobiaceae ↑ A. muciniphila ↓Coriobacteriaceae	Rotenone, RS, and RS + rotenone: increased immune cell infiltration in the lamina propria	NA	(Dodiya et al. 2020)
	Control group, n = 13; MPTP-injected group, n = 14; MPTP-injected plus KRG-treated group, n = 14; Vehicle-injected plus KRG-treated group, n = 14.	After MPTP injection: ↑Verrucomicrobia ↑Firmicutes ↑Tenericutes ↓Bacteroidetes ↓Proteobacteria ↓A. muciniphila	After MPTP injection: ↑Motor dysfunction ↑Iba-1 expression ↑aSyn expression in the SN ↑IL-1β and TNF-α ↓Number of TH-positive cells in the SN and optical density in the striatum ↓Occludin expression	NA	(Jeon et al. 2021)
Stroke	Healthy controls, n = 200; Patients with acute cerebral infarction, n = 198.	Patients with stroke: ↓Akkermansia ↓Mucispirillum ↑Aerococcaceae ↑Flavobacterium	NA	NA	(Chang et al. 2021)
	Healthy controls, n = 30; Patients with cerebral ischaemic stroke, n = 30.	Patients with stroke: ↑Odoribacter ↑Akkermansia ↑Ruminococcaceae_UCG_005 ↓Enterobacter	NA	NA	(Li et al. 2019b)
	Post-stroke animals; Sham-operated animals.	Post-stroke animals: ↑Akkermansia ↑Parabacteroides ↑Bacteroides	NA	NA	(Stanley et al. 2018)

Figure 1. The primary mechanism of action of Akkermansia muciniphila in the gut-brain axis. Besides the peripheral circulation system, the vagus nerve is an important structure involved in the bidirectional communication between the gut and the brain, as it is distributed in the major parts of the intestines, with 80% as afferent nerves and 20% as efferent nerves (Goswami et al. 2018). Mechanism of action in the (A): mucous membrane and (B): immune system. (C) and (D) show the relationship between A. muciniphila metabolites and brain functions: (C) mechanism of action of SCFAs: SCFAs produced by A. muciniphila and their transport pathway. a. Passive diffusion; b. MCT1pathway: through the MCT receptor coupled with H⁺ ions, one molecule of SCFA can be transported simultaneously by the delivery of one H⁺ ion into intestinal cells at a time; c. SMCT1 pathway: through the SMCT receptor coupled with Na⁺, two molecules of Na⁺ and one molecule of SCFA can be transported into intestinal cells simultaneously; d. Exchange with HCO₃^– through an unknown exchanger, followed by partial oxidation to carbon dioxide for additional cellular energy generation in the form of ATP. (D) Mechanism of action of amino acid derivatives. SCFA, short-chain fatty acid; HCO₃^–, bicarbonate; MCT1, monocarboxylate transporter 1; SMCT1, sodium-dependent monocarboxylate transporter 1; TER, transepithelial resistance; HPA, hypothalamic-pituitary-adrenal axis; HDAC, histone deacetylase; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; 5-HT, 5-hydroxytryptamine, GABA, gamma-aminobutyric acid.

Figure 2. Types of diseases associated with the abundance of Akkermansia muciniphila: This figure summarizes the diseases associated with the abundance of A. muciniphila and the gut-brain axis, as discussed in this review. (A. muc: A. muciniphila;↑: the relative abundance of A. muciniphila increased in patients with the disease compared to that in the control;↓: The relative abundance of A. muciniphila decreased in patients with the disease compared to that in the control;? : limited evidence is available.↑↓: inconsistent results from studies published to date.).

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