Table 1.

Clinical evidence for the role of Gut flora in neurophysiology.

S. No.	Investigators	Species used for Experimentation	Method(s)/Treatment(s) Employed	Effect on Neurofunction/ Behavioral Alterations	Conclusion
1.	Degroote et al., 2016 [19]	Wistar rats (male and female)	- Abx diet (Diet containing 1% succinyl sulfathiazole (SST) for parent female Wistar rats)	- Reduced social interactions, exploration, startle inhibition, and increased anxiety in infants born	- Maternal gut microbiota alterations affect infants’ behavioral patterns
2.	Heijtz et al., 2011 [20]	GF mice, SPF mice, Normal mice (NMRI Strain)	- Behavioral tests: Open field test, elevated plus maze, light dark box test - Neurochemical analysis of brain tissue: RP-HPLC, Western immunoblotting	- Increased motor activity and reduced anxiety-like behavior in GF mice compared to SPF mice - Increased NA, DA, 5-HT turnover in the striatum of GF mice compared to SPF mice - Altered expression in synaptic plasticity-related genes in GF mice - Reduced protein expression of synaptophysin and PSD-95 in the striatum of Gf mice due to gut microbiota colonization	- Altered expression profiles of canonical signalling pathways, neurotransmitter turnover, and synaptic related proteins may contribute to behavioral differences observed between GF and SPF mice.
3.	Addolorato et al., 2008 [21]	Humans (clinical study, outpatients with gastrointestinal disorders)	- State and trait anxiety, current depression were assessed by state and anxiety inventory and Zung self-rating depression scale, respectively.	- Varying percentages of anxiety and depression were observed in patients with gastrointestinal disorders such as IBS, Coeliac disease, ulcerative colitis, Helicobacter pylori infection, food allergies, etc.	The study supports that patients infected with gastrointestinal disorders also suffer from anxiety/ depression at varying levels, and they should be treated by a team of gastroenterologists and psychologists or alternatively by a gastroenterologist having expertise in treating psychological disorders.
4.	Desbonnet et al., 2008 [22]	20 adult male SD rats divided into treatment group (n=12) and control group (n=8)	- Bifidobacterium infantis in powdered form was dissolved in drinking water (dose = 1 x 1010 live bacterial cells in 100 ml water) and was given every morning for 14 days to the treatment group. The control group received normal drinking water. -Tests such as whole blood culture, cytokine analysis by flow cytometry, Plasma tryptophan pathway analysis by HPLC were performed after 14 days of treatment.	- Marked increase in tryptophan levels in the treatment group of rats compared to the control group. - Significant suppression of pro-inflammatory cytokine release (IL-6, INF-ү) following stimulation was observed in blood samples from rats that received B.infantis.	- Ingestion of B.infantis showed an elevation in levels of tryptophan, a precursor of 5-HT, a major neurotransmitter in the Gut-Brain Axis. This concludes that this strain of microbes plays some role in the regulation of ENS as well as in 5-HT synthesis.
5.	Cattaneo et al., 2017 [23]	Humans (241 patients with cognitive complaints and Alzheimer’s disease and 26 cognitively healthy volunteers)	- Treatment with antibiotics and anti-inflammatory drugs - Sample stool and blood collection and examination before and after the drug treatment - Amyloid imaging with Positron-Emission Tomography (PET) - Neuropsychological assessment, MRI and CSF analyses for Aβ and total phosphorylated tau assessment before and after drug treatment.	- High abundance of pro-inflammatory Escherichia/ Shigella and low abundance of anti-inflammatory E.rectale in stools of subjects with positive amyloidosis compared to amyloid negative subjects. - Increased levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1β) and reduced levels of anti-inflammatory cytokines (IL-10) in subjects with AD pathogenesis compared to control subjects.	- Genera Escherichia/ Shigella may significantly increase the formation of Aβ aggregates via activation of inflammatory processes and the release of several pro-inflammatory cytokines and chemokines. - A significant decrease in E.rectale species abundance may cause a reduction in levels of butyrate (produced by E.rectale itself), which is an anti-inflammatory compound and may cause a decline in the protective role against chronic inflammation leading to Aβ accumulation.
S. No.	Investigators	Species used for Experimentation	Method(s)/Treatment(s) Employed	Effect on Neurofunction/ Behavioral Alterations		Conclusion
6.	Keshavarzian et al., 2015 [24]	Humans (38 Parkinson’s patients and 34 healthy subjects)	- Sigmoid mucosal biopsy - Fecal sample collection - Predictive assessment of fecal microbial community by High through-put ribosomal RNA gene amplicon sequencing. - Data collected was correlated with clinical measures of PD to assess the functional potential of the microbial community.	- Marked difference in the fecal bacterial community between PD patients and control subjects. - Reduced levels of anti-inflammatory butyrate-producing genera of bacteria such as Blautia, Coprococcus, Roseburia and a significant increase in pro-inflammatory Proteobacteria of genus Ralstonia in PD patients compared to control subjects.		- This study reports evidence that increased pro-inflammatory dysbiosis and reduced protective anti-inflammatory action could trigger misfolding of α-synuclein and development of PD pathology.
7.	Tamtaji et al., 2017 [25]	- 40 human subjects suffering from multiple sclerosis (MS) were assigned in a randomized, double-blinded, placebo-controlled clinical trial	- 40 humans were divided into two groups (n=20) to receive a probiotic capsule or placebo for 12 weeks - Gene expression related to inflammation, insulin, and lipids was assessed in blood samples of MS patients via the RT-PCR method.	- Down-regulation of gene expression of IL-8 and TNF-α mRNA in peripheral blood mononuclear cells in MS patients who received probiotic supplementation compared to patients who received placebo.		- Probiotic supplementation may decrease the pro-inflammatory cytokine activation by reducing their gene expression, thus leading to amelioration of MS-related disorders such as mortality, morbidity, and insulin resistance.