Linking microbiome species, their metabolites and brain changes in bipolar depression 
This is one of those studies in China that we can only assume that human participants are ethnically similar, getting about the same amount of exercise, and eating the same general foods. This study could not have been conducted before rapid geneome sequencing was available, identification of small molecules in the plasma, neuro imaging, and the compute power to connect the three in very large data sets. Images from this publication will not be presented because the publication is not public access.
A cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterize the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy.
- Serum metabolites, 12,000 characterized a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids.
- Fecal meta genome Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundii and Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederiksenii and Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacae and Enterobacter kobei) and Flavobacterium spp.
- neuroimaging studies, resting state fMRI
Fig. 1 Altered metabolites in serum of BD patients compared to healthy controls.
- a The effect size of phenotype indices contributed significantly to the variance (R2) of the serum metabolome (all subjects, BD: 80, HC: 38). The test scores and T cell subsets contributed significantly to the discrepancy between serum metabolites between normal controls and bipolar patients. Sex and years of education contributed significantly. (p<0.01).
- b A clear discrepancy of serum metabolomes between BD patients and healthy controls, revealed by the dbRDA. The metabolites (squares), which were identified as the main contributors to the discrepancy are specified.
- c This panel examined changes in genes in bacteria involved in vitamin synthesis. The premise is that the right microbiome is making nutrients for the normal control.
- d Genes involved in coritisol and derivatives were incresed in the microbiome of the healthy controls. Tryptophan metaboism gene transcripts were also increased in the feces of this group. Malic and succinic acids synthesis related genes were increased in the feces of bipolar patients. And polyamine synthesis pathway transcripts were increased in the bipolar patient feces.
Fig. 2 Global changes in the microflora in normal control vs bipolar
- a Per microbial family, the number of increased or decreased species wereshown including 135 species in BD belonging to 33 families and 465 species in HC belonging to 59 families.
Akkermansiaceae six species were enriched in the controls vs the bipolar feces. Desulfovibrionaceae
had one increase in the control and one increase in the bipolar feces. Overall, the trend was for the microbiome of bipolar patients to be less diverse.
- b boxplots show the prominent species (including Yersiniaceae spp., Akkermansiaceae spp., Streptococcaceae spp., Ruminococcaceae spp. and Enterobacteriaceaespp.) that differed significantly in abundances between BD patients and HC. While there were differences, these species were far less than 0.1% of the entire microbiome.
Fig. 3 Relationships between specific gut microbial functions and concentrations of bipolar depression serum metabolites.
The heatmap displays the Spearman correlation coefficients between functional modules and serum metabolite clusters. Pyridoxal biosynthesis, erythrose-4P => pyridoxal-5P exhibited a strong, positive correlation between multiple plasma metabolic groups. Pyridoxal phosphate, vitamin B6, is involved in the metabolism and synthesis of histamine, serotonin, γ-aminobutyric acid (GABA), and dopamine. 
Fig. 4-5 Connecting changes in bacteria to changes in neuroactive small molecules…. and within brain connectivity…
Figures 4 and 5 went on to convince the reader that the gut microbiome controls neurotransmitter levels and brain connectivity. No figures in this publication are shown because it is not public access. The general take home seem to be that fecal microbial transplantation is the only option to restore order, without saying so in so many words. Were those subjects with bipolar depression more or less likely to be eating Western fast food, walking or taking autos or public transportation to their destinations, getting regular sleep, or not? Smoking and drinking alcohol, or not if we are to bring in brain connectivity.
The role of gut derived B vitamins ?
The massive Li 2022 study  seems to point in the direction of a fecal microbial transplantation. According to a recent review  B-vitamins are involved in many physiological processes such as
- glucose metabolism
- , fatty acids and amino acids metabollsim
- tryptophan in the kynurenine pathway
- homocysteine metabolism
- and of course synthesis and metabolism of various neurotransmitters: serotonin, dopamine, adrenaline, acetylcholine, GABA, glutamate, D-serine, glycine, histamine and melatonin. 
The authors also claim involvement of B vitamins in maintenance of the blood-brain and lumen barrier of the GI tract.  “The majority of gut-resident microbes and the broad range of bacteria available in fermented food, express genetic machinery enabling the synthesis and metabolism of B-vitamins and, consequently, intestinal microbiota and fermented food rich in probiotic bacteria are essential sources of B-vitamins for humans. “ 
A fecal microbial transplant that did some good 
This single case report out of Australia involves a 28 year old male that had much more than bipolar II depression. This male had manic episodes as well as ADHD and obsessive/compulsive behaviors interspersed with depression. This male had benefited from probiotics before undergoing an FMT
The last few days of Figure 1 of the Parker 2022 case report have been expanded to illustrate stretches of several days in which the patient experienced no mood swings at all. The days he did experience and up or down could be explained by the ups and downs of everyday life. The Parker report describes medication before and after the FMT and other incidentals in the patient’s own words. This information is all public access and a good read.
A review voice of reason 
A 2022 with Chinese and Australian authors documents what seems like every study linking the microbiome and bipolar disorder ever published. The review also suggests four basic treatments to cover the course of the disease.
- pro- and prebiotics Bifidobacterium and Lactobacillus were mentioned in this review as being beneficial for bipolar disorder.  Perhaps the bipolar patient might want to consider a probiotic that produces vitamin B6 and other B vitamins.
- diet The Mediterranean diet with emphasis on fruits, vegetables, polyunsaturated fatty acids,and legumes and small amounts of meat was mentioned. The point was made that red meats and saturated fats can lead to the growth of bacteria associated iwth anxiety. 
- exercise The authors cited the role of exercise in increasing the β diversity of gut microbiota and the production of short chain fatty acids. 
- FMT This review was published the same year as the Parker case report.  Zhang 2022  referenced a “no abstract available” case report of a bipolar woman being free of syptoms after an FMT from her husband.
The massive Li study did highlight a connection between brain connections in bipolar depression, the microbiome, and its products.  This study hinted that pyridoxal phosphate and it’s role in neurotransmitter sylnthesis and degradation may be a factor. The study was bewildering and left the impression that not just one species of bacteria whold the answer.  On the other hand,the gut is a recognized source of B vitamins and fermented foods may be a source of such bacteria.  Switching back to bipolar disorder, there has been a single case of a man who hand symptoms that far exceeded just bipolar depression. His manic symptoms were also helped by a FMT.  Perhaps, bipolar symptoms warrant a four tiered approach suggested by the Zhang review.
- Li Z, Lai J, Zhang P, Ding J, Jiang J, Liu C, Huang H, Zhen H, Xi C, Sun Y, Wu L, Wang L, Gao X, Li Y, Fu Y, Jie Z, Li S, Zhang D, Chen Y, Zhu Y, Lu S, Lu J, Wang D, Zhou H, Yuan X, Li X, Pang L, Huang M, Yang H, Zhang W, Brix S, Kristiansen K, Song X, Nie C, Hu S. Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression. Mol Psychiatry. 2022 Apr 20.
- Rudzki L, Stone TW, Maes M, Misiak B, Samochowiec J, Szulc A. Gut macrobiotic-derived vitamins – underrated powers of a multipotent ally in psychiatric health and disease. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Apr 20;107:110240.
- Parker G, Spoelma MJ, Rhodes N. Faecal microbiota transplantation for bipolar disorder: A detailed case study. Bipolar Disord. 2022 Aug;24(5):559-563. PMC free paper
- Zhang P, Kong L, Huang H, Pan Y, Zhang D, Jiang J, Shen Y, Xi C, Lai J, Ng CH, Hu S. Gut Microbiota – A Potential Contributor in the Pathogenesis of Bipolar Disorder. Front Neurosci. 2022 Mar 23;16:830748. PMC free article