TABLE 1.

Main findings from studies describing the role of microbiota in the pathogenesis of neurodegenerative/psychiatric diseases.

Disorders	Main findings	References
Neurodegenerative
Parkinson’s disease (PD)	(i) Gut microbiota influence the activity of enteric neurons, affecting cellular α-synuclein (α-syn) secretion, characterized by the accumulation and aggregation of α-syn in the substantia nigra (SN).	Braak et al., 2003
	(ii) Gastrointestinal dysfunction is present in ∼80% of PD patients.	Mulak and Bonaz, 2015
	(iii) α-Synucleinopathy is suggested to be an early indicator of PD pathology.	Nair et al., 2018
	(iv) The vagal nerve, which serves as channel for α-syn from the ENS to the CNS, is crucial for the communication between gut microbiota and the brain.	Ulusoy et al., 2013; Scheperjans et al., 2015; Fitzgerald et al., 2019
	(v) Pathological hallmarks of PD are a loss of dopaminergic neurons in the SN and the presence of cytoplasmic eosinophilic inclusions termed Lewy bodies (LBs).	Lebouvier et al., 2009
	(vi) Immunolabeling with α-syn antibodies have become the reference standard in the assessment of LBs and Lewy neurites in both the CNS and peripheral nervous system. Hence, α-synucleinopathy affects all levels of the BGA.	Lebouvier et al., 2009
Alzheimer’s disease (AD)	(i) AD is characterized by a deposition of amyloid beta (Aβ) followed by the formation of plaques, characterized by a progressive decline in cognitive function.	Wang et al., 2014; Jouanne et al., 2017
	(ii) Gut microbiota produce amyloids which aid bacterial cell binding, and form part of the biofilm protecting these from destruction by host immune factors.	Friedland and Chapman, 2017
	(iii) Bacterial amyloid proteins exposure to the host, from the gut, may be detrimental since they prime of the host’s immune system against endogenous production of neuronal amyloids in the brain.	Kowalski and Mulak, 2019
	(iv) Bacterial lipopolysaccharides are increased in the neocortex and the hippocampus in AD.	Zhao et al., 2017
	(v) Calprotectin is indicative of inflammation and has be detected in elevated amounts in the CSF, brain and fecal matter of AD patients.	Kowalski and Mulak, 2019
Multiple sclerosis (MS)	(i) MS is a demyelinating disease, clinically associated with autoimmune disease. Progressive degradation of the integrity of the epithelia that comprise cellular barriers essential to maintaining the integrity of both intestine and CNS, have been associated in MS patients suffering from autoimmunity, resulting in paralysis and other related symptoms of MS.	Ochoa-Repáraz and Kasper, 2014; Dendrou et al., 2015; Ochoa-Repáraz et al., 2018
	(ii) Clinical signs of MS are relapse of sensory, motor and cerebellar complications; while an acute disease stage is a characteristic feature of the relapsing-remitting MS (the latter of which are often diagnosed with neuronal dysfunction).	Johnston and Joy, 2001; D’Amico et al., 2016; Connick et al., 2018
	(iii) Secondary-progressive MS develops and transcends into progressive neurological impairment.	D’Amico et al., 2016
	(iv) Dysbiosis affects the immunological responses of the host to the microbiota, as described in an experiment where germ-free mice with an immune dysfunction, were characterized by an imbalance between pro- and anti-inflammatory immune cells in the gut, where after colonization of the gut with commensal microbes restored immune function.	Mazmanian et al., 2005; Kirby and Ochoa-Repáraz, 2018; Ochoa-Repáraz et al., 2018
Neuropsychiatric
Autism spectrum disorders (ASD)	(i) Dysbiosis in children with ASD has been show to contribute to both gastrointestinal and CNS abnormalities.	Wang et al., 2011; Santocchi et al., 2016
	(ii) Short-chain fatty acid producing bacteria, and their metabolites, especially propionic acid, has been indicated to adversely affect the CNS and contribute to autism behavior by modulating the BGA.	De Angelis et al., 2015
	(iii) Behavioral abnormalities are accompanied by imaging abnormalities in the sensory and emotion regulation regions of the brain.	Green et al., 2013
	(iv) Abnormally elevated levels of lipopolysaccharides have also been associated with the pathogenesis of autism.	Fattorusso et al., 2019
	(v) 40% of ASD patients complain of GI symptoms; abnormalities such as chronic diarrhea, constipation, vomiting, feeding problems, reflux and abdominal pain, as well as anxiety.	Mayer et al., 2014; Fattorusso et al., 2019
	(vi) Patients with ASD also have high fecal and urinary levels of bacterially derived p-cresol, and further exposure to p-cresol has been shown to contribute to the severity of behavioral symptoms and cognitive impairment in ASD.	Altieri et al., 2011; Persico and Napolioni, 2013; Gabriele et al., 2014
	(vii) Optimized remedies that are practiced include rehabilitation, educational therapy and psycho-pharmacological approaches.	Fattorusso et al., 2019
Depression, anxiety, and major depressive disorder (MDD)	(i) Pre-clinical studies of depression, anxiety and MDD indicate that the altered brain function associated with these, can partly be attributed to disturbances in the gut microbiota composition.	Bercik et al., 2011; Park et al., 2013; Jiang et al., 2015; Kelly et al., 2016
	(ii) Studies have shown that the microbiome has the capacity to influence on emotional behavior, and is associated with various parameters relating to depression pathogenesis and severity.	Bercik et al., 2011; Clemente et al., 2012; Cryan and Dinan, 2012
	(iii) Hippurate, dimethylamine and dimethylglycine, all by-products of gut microbiota, have been detected in abnormal concentrations in MDD patients which further substantiates the aforementioned observations.	Zheng et al., 2013, 2016
	(iv) Increased severity in depression and anxiety have been noted following bacterial infection in patients.	Naseribafrouei et al., 2014