TABLE 1.

Summary of the studies included in our review.

Studies included	Type of study	Study participant characteristics	Gut–brain axis changes in BD	BD symptom changes after gut microbiota alterations	Effectiveness of gut microbiota balancing methods for BD	Summary of findings
Interventional studies
Eslami Shahrbabaki et al. (2020)	Randomized, Double‐Blind, Placebo‐controlled trial	Type 1 patients with BD‐38 Probiotic: 25 ‐ Mean age: 38.9 y Placebo: 25 ‐ Mean age: 35 y Lost to follow‐up: 12 (6 in each group) *Patients in both groups were allowed to receive lithium oxide, with a maximum dose of 900 mg per day, sodium valproate, with a maximum dose of 1200 mg per day, and, if necessary, risperidone	–	No significant reductions in Young Mania Rating Scale (YMRS) and Hamilton's Depression Rating Scale (HDRS) scores over time between placebo and probiotic groups, but probiotic consumption significantly reduced the severity of depression and mania over time.		There is a decrease in the severity of depression and mania in the group using probiotics, despite no significant changes in depression or mania between the control and placebo groups.
Dickerson et al. (2018)	Randomized controlled trial	Recently hospitalized manic patients: 66 Probiotic group: 33 Placebo group: 33 Mean age probiotic group: 37.9 years Mean age placebo group: 33.3 years Probiotic group females average: 24 years Placebo group females average: 18 years Cigarette smoking probiotic group: 14 Cigarette smoking placebo group: 13 BMI probiotic group: 29.2 BMI placebo group: 31.6 In the Probiotic group: ‐YMRS score: 11.9 ‐Bipolar I, manic:17 ‐Bipolar I, mixed: 8 ‐Schizoaffective disorder bipolar type: 8 ‐Antipsychotics: 43 ‐Mood stabilizers: 20 ‐Lithium: 13 ‐Antidepressants: 8	‐		Variants of Bifidobacterium and Lactobacillus in probiotic patients led to reductions in hospitalizations. Significant reductions in psychiatric rehospitalization frequency and duration (a total of 182 fewer days rehospitalized during the trial)	There are lower rehospitalization rates in manic patients with supplementation of probiotics as compared to the control group.
Observational Studies
Aizawa et al. (2019)	Case‐control study	Patients with BD‐39 Females: 22 Males: 17 Mean age: 40.3 y Mean HAM‐D 17: 10.3 Mean YMRS: 2.1 Probiotic use: 9 pts Medication: ‐ Antipsychotic: 13 ‐ Antidepressant: 12 ‐ Sodium Valproate: 8 ‐ Lamotrigine: 13 ‐ Carbamazepine: 4 Healthy controls‐58 Age: 43.1 y Females: 36 Males: 22	No significant difference was found in either bacterial count between patients with BD and HCs. Low Bifidobacterium levels were found in correlation to low cortisol levels, but no significant difference in cortisol levels was found in BD or controls.	–	–	No significant bacterial differences were found between BD and controls. Lactobacillus was negatively correlated to sleep. Bifidobacterium was negatively correlated to cortisol levels.
Painold et al. (2019)	Cross‐sectional study	Patients with BD (medicated): 32 Males: 18 Females: 14 Mean age: 41.3 years Mean BMI: 24.6 BDI‐II score: 18 Atypical antipsychotics: 24 Lithium: 8 Anticonvulsants: 11 Antidepressants: 23 Healthy controls‐10 Females: 6 Mean age: 31.4 Mean BMI: 24.26	‐higher IL6 levels had higher levels of Lactobacillus, Streptococcaceae, and Bacilli. Faecalibacterium found to be higher in HCs versus patients with BD.	–		Gut microbiota can affect inflammatory markers like IL‐6 through its direct correlation with increased Lactobacillus, Streptococcaceae, and Bacilli levels.
Coello et al. (2019)	Cross‐sectional study	Patients with BD‐113 ‐ Mean age: 31 years ‐ Females: 70 ‐ Males: 43 ‐ BMI: 24.8 kg/m2 ‐ Waist circumference: 85.5 cm ‐ Mean Physical activity: 1980 MET‐minutes per week ‐ Smokers: 40 ‐ HDRS‐17: 10 ‐ YMRS: 2 ‐ BD I: 44 ‐ BD II: 65 ‐ Illness duration: 11 y ‐ No psychotropic medication: 14 ‐ Lithium treatment: 44 ‐ Antidepressant treatment: 30 ‐ Antipsychotic treatment: 43 Unaffected first‐degree relatives‐ 39 ‐ Mean age: 28 ‐ Females: 21 ‐ Males: 18 ‐ BMI: 24.4 kg/m2 ‐ Waist circumference: 80 cm ‐ Physical activity: 2400 MET‐minutes per week ‐ Smokers: 10 ‐ HDRS‐17: 2 ‐ YMRS: 0 Healthy controls‐ 77 ‐ Mean age: 29 ‐ Females: 47 ‐ Males: 30 ‐ Number of smokers: 8 ‐ BMI: 24.2 kg/m2 ‐ Waist circumference: 85.5 cm ‐ Physical activity: 2160 MET‐minutes per week ‐ HDRS‐17: 0 ‐ YMRS: 1	Flavinofactor was significantly more prevalent in patients with BD compared to healthy individuals. 90% of all serotonin is produced in GI tract affecting vagus nerve and permeability of BBB barrier.	–	–	Microbiota genus Flavonifractor is prevalent in patients with BD and may induce host inflammation.
Hu et al. (2019)	Case‐control study	Patients with BD‐52 Mean age: 24.15 Females: 25 Males: 27 Mean MADRS score: 28.15 Mean HDRS‐17: 30.15 Mean YMRS: 1.87 BD I: 12 BD II: 38 NOS: 2 Family History: ‐ Yes: 14 ‐ No: 38 Healthy controls‐ 45 Mean age: 36.29 Females: 22 Males: 23	Gut microbiota compositions in untreated patients with BD were dominantly characterized by Bacteroidetes. In healthy controls, gut microbiota compositions were dominantly characterized by Firmicutes. Microbiotas producing butyrate were abundant in controls and absent in untreated BD patients. Patients with BD had lower levels of bacteria who use SCFA's to reduce inflammation	–	–	Gut microbiota compositions were significantly different in patients with BD. The amounts of specific genera could be correlated with depressive severity. Patients with BD and healthy controls could be distinguished by gut microbiota meaning that microbial markers could be used in treatment.
Evans et al. (2017)	Case‐control study	Patients with BD‐115 and healthy controls (HC)‐64 Mean age HC: 48.6 Mean age BD: 50.2 Females HC: 40 Females BD: 83 Mean BMI HC: 26.0 Mean BMI BD: 29.3 BD 1: 76 BD NOS: 10 BD II: 29	Decreased levels of Faecalibacteriu, a gut bacterium associated with a balanced microbiota, in bipolar patients compared to healthy controls	Faecalibacterium was associated with improved depression scores (PHQ9), sleep quality scores, and improved physical health. Changes were specifically seen in sleep quality, latency, and changes to daytime lethargy rating via Pittsburg Sleep Quality Index (PSQI). No significant difference in the fractional representation of Faecalibacterium and sleep duration. Percent sleep duration and awakening events were found.	–	Increasing levels of Faecalibacterium in Bipolar patients can have positive psychiatric outcomes.
Lu et al. (2019)	Case‐control study	Patients with BD: 36 BD I: 10 BD II: 26 Mean age: 32.64 years Education more than 12 years: 44.44% Mean BMI: 22.16 BMI > 25 = 25% Lost to follow‐up: 19 Males: 21 Females: 15 Drug Naive: 17 Medication free for 3 months.: 19 Healthy controls‐27 Mean age: 28.89 years Education more than 12 years: 81.48% Mean BMI: 21.84 BMI > 25: 18.52% Males: 15 Females: 12	Counts of Faeclibacterium prausnitzii, Bacteroides‐Prevotella, Eneterobactor spp., and Clostridium Cluster IV were significantly increased in bipolar patients. microbial colonization resistance was significantly decreased in bipolar patients	–	–	Gut microbiota composition in patients with BD differed from that in HCs and was associated with illness severity and immune alterations. Expansion of the Bacteroides–Prevotella group and Enterobacter spp. indicated disturbance of gut microbiota. Decrease of Bifidobacteria to Enterobacteriaceae ratio was related to weakened microbial colonization resistance.
Lai et al. (2021)	Cross‐sectional study	Patients with BD‐25 and healthy controls (HC)‐28 Mean age of patients with BD: 36.9 Mean age of HC: 39.2 Females BD: 11 Males BD: 14 Females HC:15 Males HC:13 HAMD: 20.12 MDQ: 8.60 HAMA: 14.72 HCL‐32: 19.88 BPD‐I: 18 BPD‐II: 7 Atypical antipsychotics: 3 Anticonvulsants: 2 Lithium: 1 Antidepressants: 1 Combinations of the above medications: 15 Atypical antipsychotics + lithium: 2 Atypical antipsychotics + anticonvulsants: 1 Lithium +antidepressants: 1 Anticonvulsants + antidepressants: 6 Atypical antipsychotics + anticonvulsants + antidepressants: 2 Atypical antipsychotics + anticonvulsants + antidepressants lithium: 1	Decreased plasma Trp levels in BD	–	–	Gut microbiota changes can be used as biomarkers for BD identification; there are increased amounts of Bacteroidetes, Firmicutes, and Actinobacteria in patients with BD. There are impairments to the gut MiTBamp gene in patients with BD
Bengesser et al. (2019)	Cross‐sectional study	Patients with BD‐32 Mean age: 41.67 years Females with BD: 7 Males with BD: 25 BD depression: 13 Euthymia: 19 HAMD mean: 13 BDI mean: 14.73 YMRS mean: 0.81 BMI mean: 27.99	Methylation status (in %) of the ARNTL CpG position cg05733463 correlated significantly with gut bacterial diversity.	‐	–	There is a correlation between CpG methylation status of the clock gene ARNTL, gut microbiome diversity, and evenness in BD. Methylation status at cg05733463 of the clock gene ARNTL showed a negative correlation with bacterial diversity and evenness. Low microbiome diversity may lead to increased ARNTL and MAOA gene expression, leading to decreased breakdown and a promanic effect.
Reininghaus et al. (2020)	Cohort Study	Euthymic patients with BD ‐ 38 Mean age: 51.5 Females, %: 55 Males, %: 45 BMI: 30.1 YMRS:1.85 HAMD:1.75 Number of lifetime manic episodes: 9.28 Number of lifetime depressive episodes: 18.17 Duration of euthymia before testing, months: 6.89 Lithium, %: 40 Atypical antipsychotics, % : 40 Anticonvulsants, %: 20 SSRIs, %: 20 SNRI, %: 25 Tricyclics, %: 10	–	Improved cognition in euthymic patients with BD	Lactobacillus, Bifidobacterium, and Lactococcus supplementation improved cognitive function in patients with BD.	After 1 and 3 months of probiotic treatment, there was a significant improvement in attention, psychomotor processing speed, and executive function in bipolar patients.
Reininghaus et al. (2020)	Cohort Study	Euthymic patients with BD‐ 27 Mean age: 50.7 years Gender count: Females (%) 40.7 BMI mean‐29.0 Probiotic history (%)‐31.3 Nicotine dependence mean: 1.2 Psychiatric illness duration: 19.3 years Manic episodes: 9 Depressive episodes: 17.6 Current symptomatology: HAMD: 2.2 BDI: 25.0 YMRS: 2.4 MSS: 5.62 Lithium intake, % 40.7 SSRI (%)‐14.8 SNRI (%)‐33.3 Atypical antipsychotics, % 44.4 Anticonvulsants, % 25.9	–	Lowered manic symptoms, less ruminative thoughts.	Lactobacillus and Bifidobacterium variants in probiotic supplements improved manic symptoms	1 and 3 months of “OMNi‐BiOTiC” probiotic use showed a reduction in ruminative thoughts related to sad moods (possibly reducing the transition to depressive symptoms) as well as a significant reduction in manic symptoms.

Note. BDI‐II, Beck Depression Inventory; BMI, Body Mass Index; HAMD, Hamilton Depression Scale; HCL‐32, Hypomania; MADRS, Montgomery‐Åsberg Depression Rating Scale; MET‐minutes, metabolic equivalent minutes; MSS, Mania Symptom Scale; NOS, not otherwise specified; SNRIs, serotonin and noradrenaline reuptake inhibitor; SSRIs, Selective serotonin reuptake inhibitors; YMRS, Young Mania Rating Scale.