The contribution of age-related changes in the gut-brain axis to neurological disorders

Figures & data

Figure 1. The bidirectional communication between the gut and central nervous system is regulated by multiple pathways(BBB = blood brain barrier, CRH = corticotropin-releasing hormone, ACTH = adrenocorticotropic hormone, HPA = hypothalamic-pituitary-adrenal, GABA = gamma-aminobutyric acid, SCFA = short chain fatty acid, 5-HT = 5-hydroxytryptamine). Created in Biorender.com.

Figure 2. Vagus nerve interactions with the gut epithelium and the ENS. Created in Biorender.com.

Table 1. Neuroactive metabolites and their effects.

Metabolite	Brain effects	Gut effects	Immune system effects	References
SCFAs Propionate, Acetate, Butyrate	Inflammation – Neuronal activation + Axonal damage – Treg differentiation + GABA/Glutamate in hypothalamus + Occludin + (in frontal cortex and hippocampus)	Colonic inflammation – (through GPCR binding on APCs)	Inflammation – (activation of GPRCs) Oxidative stress - (Cd41 expression on HCMEC/D3 cells downregulated)	^Citation85–87
Tryptophan metabolites Indoles, Kynurenine	Vagal stimulation +	Intestinal barrier function + Mucus production +	Generation of regulatory T-cells + (through Ahr receptor)	^Citation21,Citation85,Citation88
GABA	Vagal nerve firing +	Modulate intestinal motility and inflammation	Inflammation – (through decrease of T-cell activity)	^Citation21
Bile Acids	Elevated levels cause inhibition of hepatic glucocorticoid clearance, leading to HPA-Axis disruption	Intestinal absorption of lipids and vitamins +	T-reg cell differentiation + Th1/17 differentiation -	^Citation90,Citation91
Serotonin	Receptors in hippocampus and neocortex support cognition and afferent signaling	Intestinal motility + 5-HT1A receptor degranulates enteric mast cells, histamine + Enterochromaffin cells +	Induces pro-inflammatory cytokines + T-cell activation	^Citation92,Citation93

Table 2. Gut microbiota alterations in aging.

Microbiota Alterations	Analysis Method	Key Results	Potential Mechanism	Subjects	Reference
Clinical
Decreases in Faecalibacterium, Odoribacter, and Dorea Increases in Clostridium species and Ruminococcus	Analysis study using shotgun and 16S rRNA gene amplicon-based sequencing profiles	Specific gut bacterial taxa are better markers of unhealthy aging than summary or diversity indices; healthy aging markers occupy core positions in the gut microbiome	No specific mechanisms proposed	Analysis of 21,041 gut microbiome profiles from ages 18 to 100+ years	^Citation6
Increases in Clostridiaceae and Megamonas	V3-V4 16s rRNA sequencing	The gut microbiota in subjects younger than 20 years changed with age as it matured, and that of subjects older than 70 years changed into an aged composition	No specific mechanisms proposed	367 total subjects; ages 0–104 years	^Citation103
Decreases in Lactobacillus and Oxalobacter (in extremely aged subjects)	16s rRNA sequencing	Age-related decline of the beneficial functions of gut microbiota, as well as increase of inflammation and disease, especially for people older than 90s.	No specific mechanisms proposed	371 total subjects, ages newborn to centenarian	^Citation105
Experimental
Increases in Odoribacter, Clostridium, Porphyromonadaceae and Butyricimonas	V3-V4 16s rRNA sequencing	The cecal microbiota of mice is significantly altered with aging; perturbations of the MGBA, resultant of normal aging, may contribute to peripheral inflammation, altered anxiety behaviors and cognitive impairment	No specific mechanisms proposed	12 young (2 month old) and 10 aged (18 month old) male WT mice	^Citation106
Decreases in Akkermansia, Parabactreoides Increases in Helicobacter, Turicibacter, and Prevotella	16S ribosomal RNA and metagenomic sequencing	Age-associated changes are present in the compositional structure of the gut microbiome and its function Rejuvenation models (i.e. through parabiotic pairing of an aged mouse with a young mouse) restore age-dependent alterations of intestinal function	Akkermansia administration restored intestinal integrity by activating epithelial cells, supporting the growth of other beneficial commensals	3 models of aging: co-housing (4 and 18 month old mice), serum injection (5 month and 20 month old mice treated with aged serum), and parabiosis (aged mice paired with young mice or age controls)	^Citation101

Figure 3. Environmental factors causing detrimental alterations in the maternal exposome. Toxin and pollutant exposure, infection during pregnancy, diet and metabolic status, smoking, psychosocial stressors such as low socioeconomic status, major life events, and pregnancy-related stressors, can determine broad changes in the maternal environment, thereby jeopardizing pregnancy outcomes and fetal developmental programming. Created in Biorender.com.

Figure 4. Proposed mechanism for AMA-related fetal programming and increased risk for brain disorders in offspring. AMA-associated gut dysbiosis and increased inflammation may drive abnormal immune activation in both the placenta and the fetal brain, specifically in microglial cells. Therefore, increased brain inflammation could alter neurodevelopment through multiple mechanisms, including epigenetic modifications in neuronal and glial cells. At birth, vertical transmission of a dysbiotic gut microbiome sustains this systemic neuroinflammation in the neonate, jeopardizing postnatal neurodevelopment and adult health. Created in Biorender.com.

Table 3. Gut microbiota alterations in Parkinson’s disease (PD).

Microbiota Alterations	Analysis Method	Key Results	Potential Mechanism	Subjects	Reference
Clinical
Decreases in Prevotellaceae, Faecalibacterium, and Lachnospiraceae Increases in Ruminococcaceae, Verrucomicrobiaceae, and Bifidobacteriaceae	Meta-analysis; inclusion criteria list fecal samples	Shared alterations of certain gut microbiota are present in PD patients across different geographical regions	Alterations in specific microbiota levels contribute to the pathogenesis of PD; abnormalities in gut microbiota and its metabolic products may be triggers for the formation of Lewy bodies in PD	959 patients with PD, 744 healthy controls; ages 62 to 76.5 years	^Citation134
Decreases in Lachnospiraceae and Faecalibacterium Increases in Akkermansia, and Collinsella	16S rDNA V4 amplicon sequencing and qPCR of fecal samples; serum metabolomics	Alterations in PD are most pronounced at the level of coabundant bacterial clusters; PD patients had significantly lower SCFA-producing bacteria levels; taxonomic differences in the gut composition of PD patients	Decrease in butyrate production contribute to disrupted colonic motility. Alterations found in the enrichment of fucose degradation pathways, which may cause breakdown of the intestinal mucosal layer in PD and hinder the process of proteolytic metabolite generation	197 PD and 103 control subjects; ages 40 to 85 years	^Citation135
Decrease in Lachnospiraceae, and Butyricoccus Increase in Akkermansia	16s sequencing of fecal samples	Gut microbiome alterations are already present in PD patients prior to treatment with dopaminergic medication	No specific mechanism proposed; In pre-treatment PD subjects: overall dopaminergic input may influence gut microbiome composition via cerebral signaling or modulation of stool transit times	56 PD and 87 control patients; ages 64 to 67 years	^Citation136
Experimental
Decrease in Lachnospiraceae, Proteobacteria Increases in Prevotellaceae and Akkermansia	V3–V4 regions of bacterial 16S rRNA gene were amplified using PCR	MPTP affects the composition of gut microbiota and damages the intestinal barrier in mice	No specific mechanism proposed	20 MPTP PD-model mice, 20 control mice	^Citation137
Decreases in Lachnospiraceae and Butyricicoccus	V4 16s rRNA sequencing	PD causes gut dysbiosis in mice colonized with Pd-microbiota and PD-derived gut microbiota promote motor dysfunction	aSyn aggregation by the inflammatory environment found I the gut of PD patients may be related to activation of microglia which enhances inflammatory PD pathology; may implicate potential PD therapies based on targeting inflammation via the gut	ASO mice and WT control mice	^Citation138

Table 4. Gut microbiota alterations in Alzheimer’s disease (AD).

Microbiota Alterations	Analysis Method	Key Results	Potential Mechanism	Subjects	Reference
Clinical
Decreases in Actinobacteria (Bifidobacterium) Increase in Bacteroides	16s rRNA sequencing of fecal samples and PICRUSt metagenomics analysis	AD patients have reduced microbiome richness compared to healthy controls	Increased abundance of gram-negative bacteria (Bacteroides) in AD patients causes increased translocation of LPS from the gut to systemic circulation, which exacerbates AD pathology through inflammatory pathways	50 subjects, ages 69–71 years; 25 AD and 25 control	^Citation145
Decreases in Bacteroides, Dorea, and Faecalibacterium	16s rRNA sequencing of fecal samples	A significant negative correlation is observed between the severity of gut barrier dysfunction and cognitive function in AD and MCI patients	Increased production of SCFA’s by the microbiota enriched in control patients compared to AD patients elucidates a mechanism through which decreases in butyrate-producing bacteria, correlated with AD progression, limits anti-inflammatory effects in the gut exacerbating AD symptoms	97 subjects, ages 50–85 years; AD, MCI, and control groups	^Citation146
Decrease in Ruminococcus, Butyricimonas, and Oxalobacter Increase in Flavonifractor	16S rRNA sequencing of fecal samples	Gut microbiome alterations precede onset of clinical AD symptoms, independently of the influence of cognitive impairment	Specific mechanism not proposed	31 MCI patients; 65 healthy controls, ages 65+	^Citation149
Experimental
Decreases in Bifidobacterium, Lactobacillus, Firmicutes	16s rRNA qPCR analysis of colonic flushings	Significant microbiota alterations and gut barrier dysfunction in AD mice compared to non-Tg controls	Gut microbiota modulate peripheral inflammatory pathways through inflammasome (NLRP3) signaling that contribute to CNS neuroinflammation and subsequent neurodegeneration	5×FAD mice, ages 5 and 15 months Non-Tg WT controls	^Citation150
Specific bacterial taxon alterations not reported	454 pyrosequencing of 16S rRNA gene amplicons, on fecal metagenomic DNA	Significant community-level microbiota alterations and altered colonic gene expression in AD mice; FMT-induced modifications toward the microbiota pattern of WT mice ameliorated amyloidosis, tau pathology, reactive gliosis and cognitive impairment in ADLP^APT mice	The downregulation of genes related to mitochondrial and ribosomal activities in ADLP^APT mice may lead to aberrations in ATP synthesis and protein synthesis, key features of NDs	ADLP^APT mice, age 8 months	^Citation151
Decreases in Actinobacteriota, Verrucomicrobiota Increases in Proteobacteria	16S rRNA sequencing of fecal samples	Microbial diversity is reduced in patients with advanced AD	Increased abundances of pro-inflammatory bacteria in AD patients exacerbate and trigger AD symptoms prior to onset of apparent cognitive impairment	3×Tg-AD mice; 3-, 6- and 9-month-old aged-matched WT control mice	^Citation152

Table 5. Gut microbiota alterations in stroke.

Microbiota Alterations	Analysis Method	Key Results	Potential Mechanism	Subjects	Reference
Clinical
Decreases in Lachnospiraceae and Ruminococcaceae Increases in Enterobacteriaceae, Veillonellaceae (opportunistic pathogens), Bifidobacterium, and Lactobacillus (lactate-producers)	16S rRNA gene amplicon next-generation-sequencing and gas chromatography (SCFAs) on fecal samples	Participants at higher risk of stroke were characterized by the enrichment of opportunistic pathogens, low abundance of butyrate-producing bacteria, and reduced concentrations of fecal butyrate	No specific mechanism proposed	141 subjects ages 60+ years; low-, medium- and high-risk groups for stroke	^Citation172
Decrease in Bacteroides Increases in Akkermansiaceae, Fusobacteriota, Desulfobacterota, Ruminococcaceae, and Oscillospirales	16S rRNA sequencing and gas chromatography (SCFAs) on fecal samples	Poststroke subjects harbor an altered gut microbiota composition. SCFAs may play a significant role as key mediators in the modulation of pain in poststroke patients	No specific mechanism proposed;	20 stroke patients and 20 healthy controls, ages 18–80 years	^Citation173
Decrease in Ruminococcaceae Increases in Proteobacteria and Gordonibacter	Two-sample Mendelian randomization analysis to test the causal relationship between gut microbiome and stroke subtypes	There is a causal effect of the abundance of specific bacterial features on the risk of certain stroke subtypes (large artery, small vessel, and cardioembolic)	No specific mechanism proposed	Genetics from 18,430 subjects, stroke gene data on 40,858 cases from 3 subtypes of stroke	^Citation174
Experimental
Bifidobacterium, Bacteroides, Prevotella, Clostridia, and Faecalibacterium are significantly altered post-stroke	16s rRNA V1-V3 amplicon sequencing on mouse fecal samples	Stroke induces intestinal microbiota dysbiosis and reduces species diversity in the gut microbiome composition Fecal microbiota transplant from control mice is neuroprotective after stroke	Post-stroke dysbiosis favors predominant expansion of proinflammatory T-cell subpopulations, T cell priming in stroke and the role of gut-resident T cells	WT and GF mice	^Citation166
Increase in Enterobacteriaceae	16s RNA sequencing	Stroke mice receiving FMT from stroke patients present higher Enterobacteriaceae abundance and lower fecal butyrate levels than control mice	Enterobacteriaceae, or other butyrate-producing bacteria may be involved in rhANP-mediated changes in the gut microbiota which contribute to post-stroke pathology	WT mice with MCAO; 83 human fecal samples	^Citation175

Figure 5. Major symptoms and features of NDs are accompanied by multiple alterations in specific microbial species, changes which can be consistent or contradictory between the human microbiome and mouse models. Created in Biorender.com.

Table 6. Gut microbiota alterations in traumatic brain injury (TBI).

Microbiota Alterations	Analysis Method	Key Results	Potential Mechanism	Subjects	Reference
Clinical
Decreases in Prevotella and Bacterioidies Increases in Ruminococcaceae, Actinobacteria, and Verrucomicrobia	16s V4 rRNA sequencing on fecal samples	Fecal microbiome composition was altered in the chronic TBI cohort compared to controls	Intestinal microenvironment alterations associated with TBI may be linked to alterations of amino acid metabolism in TBI patients	22 chronic, moderate-to-severe TBI patients and 18 healthy controls	^Citation179
Decrease in Lachnospiraceae Increase in Ruminococcaeae	16s rRNA sequencing	The overall alpha diversity of the microbiome composition did not differ between the time point groups; in concussed TBI patients, some bacterial taxon were significantly altered compared to non-concussed athletes	Processes related to the synthesis and degradation of sugars and aromatic compounds were among those showing the most significant fold changes in TBI; specific mechanisms yet to be proposed	33 male football players, ages 18–23 years; grouped as mid-, post-, and off-season	^Citation178
Experimental
Decreases in Ruminococcaceae Increase in Verrucomicrobiaceae and Bacteriodaceae	Fecal bacterial 16S rRNA gene analysis	Alerted microbiome composition is observed in TBI mice, and the local and peripheral immune infiltration in GF mice post-FMT is altered	Gut microbiota control post-TBI hippocampal neurogenesis and its association with microglial morphology and T cell infiltration changes after injury; specific mechanistic link yet to be reported	GF and WT mice; cortical controlled impact (CCI) model of TBI	^Citation180
Decreases in Bacteroidetes, Faecalibacterium, and Agathobacter Increases in Prevotella and Helicobacter	V3-V4 16s rRNA sequencing	Microbiome composition and metabolic functions were altered in rats receiving TBI, the most pronounced of these alterations was a decrease in Agathobacter (butyrate-producer)	No specific mechanism proposed	25 3–4 month-old rats; focal open severe brain trauma model of TBI	^Citation177

Table 7. Microbiome-targeted treatments for NDs.

Treatment Design	Key Results	Reference
Clinical
Probiotic treatment; 169 middle-aged and older adults with MCI randomized to either probiotic (Lactobacillus rhamnosus) or placebo treatments for 3 months	Probiotic supplementation led to a decrease in the levels of Prevotella (which is enriched in MCI subjects prior to treatment) and this decrease was associated with an improved cognitive score	^Citation182
FMT; 36-week clinical trial including 34 PSP-RS patients (receiving healthy donor FMT) and 34 placebo controls (receiving saline)	The group receiving FMT had significantly improved symptoms of depression and anxiety, in addition to increases in levels of butyrate-producing bacteria (Faecalibacterium) post-FMT	^Citation183
Dietary intervention; NU-AGE diet randomized trial, 1279 older adults were included and divided into control or intervention groups, adhering to the diet for 1-year	Participants with higher adherence to the NU-AGE diet (Mediterranean-like diet) showed significant improvements in cognition and episodic memory compared to those with lower diet adherence	^Citation184
Experimental
Dietary intervention; 2-month administration of either soluble fiber diet or control diet in a mouse model of AD	AD mice receiving the soluble fiber diet displayed lower memory impairments and anxiety than WT mice receiving the control diet. Additionally, intestinal morphological alterations were reduced in AD mice receiving the fiber diet, an effect accompanied by restoration of butyrate and propionate production in the gut content	^Citation185
FMT; 4-weeks of FMT administration from WT control mice to an aged mouse model of AD	FMT from age-matched WT control mice alleviated cognitive deficits and reduced the deposition of amyloid-beta in AD mice; FMT also reversed the alterations in specific microbiota changes seen in the AD mouse model prior to FMT	^Citation155
FMT; 2-weeks of FMT from control donor mice to a rotenone-induced model of PD mice	PD mice receiving FMT from control donors displayed alleviated motor symptoms and better gastrointestinal function, and restores blood-brain-barrier impairment	^Citation187
Probiotic treatment; oral administration of Bifidobacterium breve MCC1274 in WT mice	Thea administration of the B. breve MCC1274 probiotic decreased Ad-like pathologies in WT mice; soluble hippocampal amyloid-beta levels and neuroinflammation were decreased in mice receiving the treatment	^Citation186

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