Table 2.

Translational approaches modulating gut microbiota in patients with BD.

Adjuvant approach	Therapeutic effect	Preliminary evidence in BD	Main findings on gut microbiota	References
Dietary interventions (Mediterranean diet)	Pleiotropic actions	Patients with BD frequently present lower Mediterranean Diet adherence and evidence of malnutrition (insulin resistance, higher levels of fasting triglycerides, glucose index and waist circumference) Diet modulates multiple biological mechanisms involved in BD, possibly influencing the clinical course and therapy success Mediterranean diet appears to decrease systemic inflammation Diet should be considered as an important coadjutant to pharmacotherapy	Increased SCFA and Faecalibacterium Increased gene bacterial gene richness Decreased Ruminococcus strains	[275, 279, 282–285, 288]
Omega-3 PUFA	Anti-inflammatory; antidepressant; pleiotropic actions	Improve depressive manifestations in BD, but not manic symptoms and seems to attenuate variability in mood, energy, irritability, and pain	Omega-3 PUFAs modify gut microbiota diversity by increasing the abundance of Bifidobacteria and Akkermansia as well as lowering Enterobacteria abundance Increase of Lactobacillus and Butyrivibrio, together with restoration of Firmicutes/Bacteroidetes ratio	[290–292]
Probiotics/psychobiotics and prebiotics	Health benefits; anti-inflammatory; decrease some risk factors for cardiovascular disease, enhance satiety and promote weight loss	Pro and prebiotics seem to have anxiolytic and antidepressant effect. Its usefulness in BD are promising, but still controversial	Probiotics are live microorganisms (generally Lactobacillus and Bifidobacterium strains) which can interact with gut microbiota, whereas prebiotics induce changes in the composition and/or activity in the gut microbiota, resulting in critical metabolites and products	[79, 295–298, 300, 301, 304, 306]
Postbiotics (SCFA)	Anti-inflammatory and immunomodulatory	SCFAs diminish inflammatory response and apoptosis In rats, sodium butyrate showed to have an antimanic effect SCFA seems to be associated with BD symptomatology	SCFA could have an epigenetic activity and they may modulate histone acetylation and NF-κB signaling	[205, 207, 311–313]
Antimicrobials (tetracyclines, i.e., minocycline and doxycycline)	Antibiotic and antidepressant effect	Anti-inflammatory and neuroprotective activity. Tetracycline antibiotics might have a lithium-like effect and an antidepressants activity Minocycline may be useful for patients with high GSH levels Aspirin and minocycline combination shown to be effective in BD depression	Minocycline modulates glutamate and monoaminergic pathways. It also Reduces gut microbiota diversity and reduces the Firmicutes/Bacteroidetes ratio Decreases Allobaculum, Bifidobacterium, Turicibacter and Clostridium genera. In humans, it lowers Lactobacillus salivarius, Bifidobacterium adolescentis and Bifidobacterium breve strains Increases Akkermansia, Lachnospiraceae and Ruminococcaceae incertae sedis Doxycycline drives to a short-term reduction of lactic acid bacteria like Bifidobacterium or Lactobacillus	[316–319, 323–325]
Fecal microbiota transplantation (FMT)	Gut microbiota restoration	A woman diagnosed with BD went through FMT from her healthy husband at least nine times. Afterward, she had neither manic nor depressive symptoms in the following sixth months, also presenting an important weight loss of nearly 33 kg	Possible beneficial changes of gut microbiota according to the healthy donor	[329, 331]
Immune-based approaches	Anti-inflammatory; antidepressant effects	Celecoxib reduces anxiety and accelerates treatment response in BD TNF-α inhibitors have also shown antidepressant properties NAC can be beneficial for alleviating depressive symptoms in patients with BD	Celecoxib does not seem to alter bacterial abundance, but relative changes in some bacterial populations have been described and it reduces butyrate production The administration of infliximab did not show significant differences in gut microbiota composition NAC alleviates gut dysbiosis and alterations in glucose metabolism in mice	[333, 334, 336–338, 340–342]
Physical activity	Pleiotropic effects	Patients with BD are less active and more sedentary than general population Physical activity can be a promising coadjutant to pharmacotherapy in BD patients	Physical activity widely increases bacterial diversity and beneficial bacteria	[344–347]
Light therapy and social rhythm therapy	Mood stabilizer; improves quality of life	Increases remission rates in BD. Clinical benefits have been reported, but the capacity of ameliorate mood symptoms and preventing episodes is yet uncertain	Beneficial changes in gut microbiota have been reported. Increases in Akkermansia muciniphila, Bifidobacterium sp., and Faecalibacterium sp Decreases in the Firmicutes:Bacteroides ratio	[350–352]