Table 1. Summary of studies evaluating the effects of probiotics on mental disorders.

BAI, Beck Anxiety Inventory; BCAA, branched chain amino acids; BDI, Beck Depression Inventory score; BDNF, brain-derived neurotrophic factor; BUT, Body Uneasiness Test; CAN-BIND, Canadian Biomarker Integration Network in Depression; CANTAB Battery, Cambridge Neuropsychological Test Automated Battery; CES-D, Centre for Epidemiological Studies - Depression Scale; CFS, chronic fatigue syndrome; CRF, corticotropin-releasing factor; DASS, Depression Anxiety and Stress Scale; DSF, De Simone formulation; EWL, Eigenschaftswörterliste; FFQ, Food Frequency Questionnaire; FPG, fasting plasma glucose; GAD-7, Generalized Anxiety Disorder; GI, gastrointestinal; GOS, Galactooligosaccharide; HADS-A, Hospital Anxiety and Depression Scale-Anxiety; Gsh, glutathione; HADS-D, Hospital Anxiety and Depression Scale-Depression; HRQoL, Health-Related Quality of Life; HAM-A, Hamilton Anxiety Rating scale ; hs-CRP, high-sensitivity c-reactive protein; IBS, irritable bowel syndrome; iCGI, Improved Clinical Global Impression; IL, interleukin; KEGG, Kyoto Encylopedia of Genes and Genomes; LEIDS-r, Leiden Index of Depression Sensitivity – Revised; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; MCS-HRQol, Mental Component Score - Health-Related Quality of Life; MINI, Mini International Neuropsychiatric Interview; NFKB1, nuclear factor kappa B subunit 1; POMS, Profile of Mood States Scale; PSQI, Pittsburgh Sleep Quality Index; PSS, perceived stress scale; QIDS-SR16, Quick Inventory of Depressive Symptomatology – 16 items; SAMe, S-adenosylmethionine; SCL-90-R, Symptom Checklist-90-Revised; SECPT, Socially Evaluated Cold Pressor Test; SHAPS, Snaith-Hamilton Pleasure Scale; SSS, Symptom Severity Score; STAI, State Trait Anxiety Inventory; TAU, treatment as usual; TNF, tumor necrosis factor; VAS, visual analogue scale; VLMT, Verbal Learning Memory Test; Z-SDS, Zung Self-Rating Depression Scale

Author, Year	Aim	Participants	Intervention	Variables Measured in the Study	Results
Gruenwald et al. (2002) [31]	Evaluating effects of probiotic multivitamin on stress and immune function	42 adults experiencing moderate-to-intense burnout and stress	6-month intervention: multivitamin probiotic capsule: Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium longum	Stress/exhaustion reduction (EWL Questionnaire), GI disturbances, and number of infections	Reduction in infections and GI disturbances. Improved positive condition and reduced negative condition. Overall, general condition enhanced.
Marcos et al. (2004) [33]	Evaluating effect on the immune system and anxiety by milk containing probiotics in university students	155 college students facing examination stress	6-week intervention: 200 mL of fermented milk containing Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus subsp. salivarius thermophilus, and L. casei; or semi-skimmed milk of 200 mL	(State Trait Anxiety Inventory anxiety questionnaire) , blood hematology, lymphocyte production, cytokine production, serum cortisol, blood biochemistry	Rise in lymphocyte number and stable CD-56 immune cell count in the probiotic group. Anxiety levels increased in both groups between baseline and end results.
Diop et al. (2008) [34]	Assessing the effects of probiotics on psychological and GI symptoms caused by stress	75 volunteers with stress symptoms	3-week intervention: probiotics containing L. acidophilus and B. longum; or placebo	GI and psychological symptoms caused by stress	Psychological symptoms did not improve. Stress-induced symptoms such as abdominal pain and vomiting significantly reduced post-consumption of probiotics.
Berding et al. (2021) [35]	Determining the effect of probiotic supplement consumption on cognitive performance and acute stress	18 healthy female participants	12-week intervention: polydextrose or maltodextrin	CANTAB Battery, SECPT, Cohen’s PSS, BDI-II, HADS-A and HADS-D psychopathological symptoms (SCL-90-R); FFQ; GI symptom VAS	Improvement with polydextrose supplement in cognitive performance
Yang et al. (2016) [36]	Effects of probiotic supplementation in reducing pre- surgical anxiety in laryngeal cancer patients	30 laryngeal cancer patients with pre-surgery anxiety; 20 healthy volunteers	3-week intervention: probiotic containing Clostridium butyricum; or placebo	HAM-A scale, CRF levels, heartbeat check at morning and evening during waiting period for surgery	Anxiety scores significantly reduced in the probiotic group before surgery. There were steady heartbeat levels in the prebiotic group, whereas the placebo group showed risen heartbeat during surgery wait period. CRF levels were stable in the probiotic group, whereas they kept fluctuating in the placebo group.
Gualtieri et al. (2020) [40]	Determining the effect of psychobiotics in mainlining the allele A of IL-1β gene, which is the carrier of cytokines/psychological distress	97 subjects	12-week intervention: probiotic oral suspension group or placebo control group	HAM-A, BUT, and SCL-90-Revised, genotyping - DNA extracted from salivary samples	Probiotics mitigates anxiety symptoms.
Akkasheh et al. (2016) [42]	Assessing the effects of probiotics on metabolic status and depressive symptoms in MDD patients	40 patients with MDD	8-week intervention: Probiotics containing L. acidophilus, L. casei, and B. longum; or placebo	BDI for depressed mood, insulin metabolism, FPG, lipid concentrations, GSH levels, hs-CRP, antioxidant capacity	Significant reduction in BDI scores, oxidative damage, serum insulin levels, and hs-CRP levels. Gsh levels were increased and there was greater insulin resistance.
Romijn et al. (2017) [43]	Efficacy of probiotics as main treatment in individuals with low mood	79 adults with depression (mild to moderate)	8-week intervention: probiotics containing L. helveticus; or placebo	Depression and anxiety symptoms (DASS-42, iCGI, QIDS-SR, MADRS), severity (GAF), GI disturbance symptoms (IBS-SSS), hs-CRP, gene levels (IL-1β, IL-6) TNF-α, vitamin D, BDNF	Probiotic intervention increased vitamin D levels, improving mood. However, it did not affect other psychological symptoms and blood biomarkers. IBS symptoms were more severe in the probiotics group as compared with placebo.
Ghorbani et al. (2018) [45]	Effectiveness of synbiotic supplementation in treating moderate depression	40 outpatient adults with clinically diagnosed moderate depression	6-week intervention: synbiotic capsule and fluoxetine; and placebo capsule and fluoxetine	depression score (HAM-D)	Significant reduction in HAM- D scores of the synbiotic group.
Kazemi et al. (2019) [46]	Comparing the effects of prebiotics and probiotics supplementation on symptoms of depression and tryptophan metabolism	110 adults with depression (mild to moderate)	8-week intervention: Probiotics (L. helveticus and B. longum); or prebiotics includes GOS; or placebo	Depression intensity (BDI), tryptophan ratio, serum tryptophan/BCAAs ratio	Probiotics decreased BDI score and tryptophan ratio. Prebiotics significantly reduced tryptophan/branch chain amino acids ratio
Talbott et al. (2019) [47]	Evaluating effects of synbiotic supplementation in microbiome changes and mood states	32 individuals with "eustress"	1-month intervention: synbiotic supplement (L. helveticus R0052, B. longum R0175, L. rhamnosus R0011, GOS, and phytonutrients)	Psychological factors affecting mood state: POMS	Good bacteria (Lactobacillus and Bifidobacterium) increased in the microbiota; decrease in subscales of tension, depression, fatigue, and confusion; global mood score improved.
Wallace et al. (2021) [48]	Determining the efficacy, safety, and tolerability of probiotics on depression	10 participants	8 week intervention: L. helveticus R0052 and B. longum R0175	CAN-BIND, MADRS, QIDS-SR16, SHAPS, GAD-7, STAI, PSQI	Probiotics helped in alleviating the symptoms of depression in treatment-naïve and moderately depressed patients. Also, supported that probiotics are safe and well-tolerated in the population.
Saccarello et al. (2020) [49]	Assessing the effects of a combination of probiotics in mild-to-moderate symptoms of depression	90 patients with mild-to-moderate depression	6-week intervention: SAMe and Lactobacillus plantarum HEAL9 1 × 10⁹ CFU; or placebo	Z-SDS	Reduction in Z-SDS scores after 2 weeks of intervention; improved symptoms of anxiety, depression, and cognitive and somatic components.
Reininghaus et al. (2020) [50]	Evaluating the effect of supplementary probiotic treatment and vitamin B7 in depression	82 individuals with depression	28 days intervention: multistrain probiotic plus biotin treatment; or placebo plus biotin treatment	Microbiome samples, KEGG analysis	A 4-week probiotic plus biotin treatment inpatient individuals with MDD showed an improved overall effect in clinical treatment, whereas the placebo group only differed in microbial diversity profile.
Bourdel-Marchasson et al. (2020) [51]	Determining effect of combining healthy diet, probiotics, and argan oil in decreasing depressive symptoms	125 older subjects	8-week intervention: RISTOMED diet alone, or RISTOMED diet + DSF probiotic blend, or RISTOMED diet + AISA−5203-L orange peel extracted monoterpene d-limonene, or RISTOMED diet + Native® Argan oil	Inflammatory parameters, mental and physical components, HRQol, anxiety symptoms (STAI), and depressive symptoms (CES-D)	MCS-HRQoL improved in the first and third intervention groups. There was a decrease in depressive symptoms.
Reiter et al. (2020) [52]	Determining gene expression change in MDD patients after multispecies probiotic supplements	61 inpatients with MDD	4-week intervention: multispecies probiotic or placebo	Effects on gene expression of TNF, NFKB1, and IL-6	Intervention group showed decreasing IL-6 gene expression.
Heidarzadeh-Rad et al. (2020) [54]	Determining the effect of psychobiotic supplement on serum BDNF levels in depressive patients	110 patients with low-to-moderate depression	8-week intervention: B. longum and L. helveticus and excipients; or placebo containing only excipients	BDNF levels, BDI	Improvement in depressive symptoms with B. longum and L. helveticus possibly by increasing BDNF levels.
Schneider et al. (2023) [55]	Investigating the effects of probiotic supplementation on cognitive symptoms in depression	43 participants with MDD	4-week intervention: probiotic group (19 subjects) and placebo group (12 subjects)	VLMT, Corsi Block Tapping Test, Trail Making Test, and BDNF levels	Improved affective symptoms and verbal episodic memory. Balancing cognitive impairments and altered hippocampal activity.
Yamanbaeva et al. (2023) [57]	Assessing the effects of probiotics supplementation for four weeks on symptoms of depression by investigating fronto-limbic structure, function, and perfusion	32 inpatients with depressive episodes	4-week intervention: probiotic oral suspension consisting Streptococcus thermophilus, Bifidobacterium infantis, L. acidophilus, L. plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii; and placebo control group with TAU	Diffusion tensor imaging, resting state functional MRI, arterial spin labeling, HAM-D	Probiotics affected brain functions and structure in the fronto-limbic network, which are relatively reduced during depressive episodes.
Pinto-Sanchez et al. (2017) [60]	Assessing effects of supplementation of B. longum bacteria in IBS patients with anxiety and depression	44 IBS patients with depressive symptoms (mild to moderate)	6-week intervention: powdered probiotics (B. longum); or placebo	Anxiety and depression score (HAD), IBS symptoms, somatization, quality of life, brain activation changes, inflammatory biomarkers, neurotransmitter levels, and stool and urine microbiota population	Probiotics intake reduced HAD scores and depression levels significantly, quality-of-life scores improved, and there was no effect on anxiety and IBS symptoms. Probiotics lowered negative emotional stimuli responses; placebo and probiotic groups had similar levels of inflammatory biomarkers, stool microbiota, and neurotransmitters.
Ma et al. (2021) [63]	Determining probiotic supplements in alleviating stress and anxiety symptoms	79 subjects (follow-up study)	12-week intervention: L. plantarum P8 or placebo	Shannon diversity index	There was a positive association between probiotic-induced gut-microbiota modulation and stress/anxiety alleviation in stressed adults.
Lew et al. (2019) [64]	Assessing the effect of probiotic L. plantarum P8 in alleviating stress and anxiety and enhancing memory and cognition	103 adults with stress	12-weeks intervention: L. plantarum P8 or placebo	DASS-42 questionnaire, plasma cortisol levels	There was alleviation of selected stress, anxiety, and improved memory and cognitive symptoms such as social-emotional cognition and verbal learning.
Chahwan et al. (2019) [65]	Assessing probiotic supplementation on depressive symptoms	71 participants with depression (mild to severe)	8-week intervention: probiotics sachet (B. bifidum, B. lactis, L. acidophilus, L. brevis, L. casei, L. salivarius, and Lactococcus lactis) or placebo	Depression and anxiety scores (MINI; BDI; DASS-21; LEIDS-r, BAI) stool sample analysis, dietary assessments, client satisfaction questionnaire	Significant reduction in cognitive reactivity of the probiotic group compared with placebo. No appreciable difference in microbiota profiles and depression and anxiety scores.
Venkataraman et al. ( 2021) [67]	Determine effects of multi-strain probiotic supplements on students facing examination stress	80 students (18-24 years), but 74 completed	28-day intervention: Bacillus coagulans Unique IS2, Lactobacillus rhamnosus UBLR58, Bifidobacterium lactis UBBLa70, L. plantarum UBLP40 (each of 2 billion CFU); Bifidobacterium breve UBBr01, Bifidobacterium infantis UBBI01 (each of 1 billion CFU) capsule with glutamine (250 mg) twice a day	PSS, DASS, and STAI	The multi-strain probiotic is effective in reducing examination-associated stress.
Seigel et al. (2020) [68]	Determining reduction in stress, anxiety, and depressive symptoms with B. longum intake	84 students	1-week intervention: B. longum or placebo	PSS, CES-D, and STAI Y2 FORM	7 days of intervention did not reduce stress, depressive symptoms, or anxiety in generally healthy young adults.
Rao et al. (2009) [74]	Evaluating efficacy of probiotic administration in CFS patients with depression and anxiety symptoms.	35 patients with CFS	8-week intervention: probiotics (L. casei) or placebo	Depression and anxiety scores (BDI, BAI), profile of stool microbiota	Lactobacillus and Bifidobacterium fecal levels increased in the probiotic group with a significant improvement in anxiety symptoms, However, no change was seen in depression scores.