(Student Contributor: Prapam Nandi, UGIV-Biochemistry, Adamas University).
Despite various assumptions indicating deviations on the number of microbial cells in a healthy human body, it seems a fact that the number of bacteria easily outnumber the total number of human cells (Sender et al., 2016). Better known as the microbiome, trillions of microbes representing thousands of species including bacteria, viruses, fungi, and archaea inhabit the human body. If we consider the gene pool, its more than 20 million genes among them compared to a mere 20,000 genes that human genome harbors. The advent of high throughput and deep sequencing empowered metagenomic analysis enabled us to explore the compositions, organization, and multitudinous role of microbiome linked to health. Dysbiosis (loss of a specific member of normal microflora) has been associated with a cluster of chronic diseases (Wilkins et al., 2019). Gut microbiome, the major hub of microbes we host in our system, is regulating various response cascades including immune function, energy metabolism, and aging, to mention a few. Exploration of such regulation rendered us to perceive maneuvering microbiome as a therapeutic strategy. Microbiome grafting including fecal microbiota transplantation (FMT) has become a considerably successful bacterio-therapy for recurrent Clostridium difficile infection (Kachlíková et al., 2020). Revealing the factors influencing the composition of the microbiota and studying the dynamics are blossoming areas of microbiology research.
The gut microbiome, (~ 2 kilograms in mass, weighs more than most of the human organs) has been linked to several physiological responses. Whether it can affect behavior, cognition and mental health remained elusive until a decade ago, albeit various observations hinted toward such association for long. For example, persons with irritable bowel syndrome tend to be depressed, and on the flip side people on the autism and Parkinsons’s spectrum tend to have digestive problems. The gut-brain axis has been explored quite recently with Evans et al. reporting a direct correlation between the severity of the bipolar disorder and gut microbiome composition, particularly the lower abundance of Faecalibacterium in affected individuals (Evans et al., 2016). Earlier, a strong variance of gut microbiome composition between individuals with a major depressive disorder to those of healthy controls was reported with emulation of depression-like features by microbiome grafting in mice (Li et al., 2018). The same group linked the glucocorticoid receptor pathway and glycerophospholipid metabolism with behavior in nonhuman primate models (Luo et al., 2018). Lowry et al., reported that immunization with Mycobacterium vaccae reduced inflammatory response in the brain and curbed anxiety. In a similar study, they also observed that immunization after fear conditioning enhances fear extinction and ameliorate postoperative cognitive dysfunction (POCD, a common problem for older adults after surgery) (Hassel et al., 2019). With their consistent effort to characterize microbiome induced metabolic modulation, Cryan et al., have strengthened the relationship between gut microbes and brain. Murine models with fecal transplants from individuals with Parkinson’s, schizophrenia, autism, or depression recorded to develop rodent equivalents of such ailments (Golubeva et al., 2017). Microbe mediated tryptophan metabolism leads to the generation of serotonin (neurotransmitter) or kynurenine (pro-toxic product). The impact of dysbiosis on social brain function as evidenced by an association study that showed that autism-like condition had lower levels of Bifidobacterium and Blautia gut bacteria, their guts made less tryptophan and bile acid(needed for producing serotonin). Moreover in children with autism altered levels of Veillonellaceae, Coprococcus, and Prevotella gut bacteria were enumerated compared to individuals without such conditions (Golubeva et al., 2017).
Mechanistic understanding of the gut-brain axis remained obscure until very recently when Valles-Colomer et al. reported the outcome of a robust sequencing project comprising a fecal microbiome analysis of more than 1000 individuals (microbiome population cohort)which suggested the robust correlation with gut microbial activity and depression. Interestingly, with a higher quality of life, butyrate-producing bacteria Faecalibacterium and Coprococcuscould be associated while in depression condition, depletion of bacteria like Dialister, Coprococcus spp. were detected. Implementing a module-based framework for analysis, they assembled neuro-active potential of gut prokaryotes, which indicated microbial synthesis potential of the 3,4-dihydroxyphenylacetic acid (a metabolite for the neurotransmitter dopamine) with mental health and the potential role of microbial γ-aminobutyric acid production (GABA, an inhibitory neurotransmitter) in depression (Valles-Colomer et al., 2019).
In one of their recent works, Simpson et al. established the link between the presence of specific microbes with neurodevelopment and neurological disorders. Using α-syncluin overexpressing mice (mimicking synucleinopathies exemplified by Parkinson’s disease) they established the gut bacteria-neuro-degeneration link elegantly. The study indicated that alteration of the human microbiome represents an elevated risk of neurodegeneration (Sampson et al., 2020).
Based on such concepts, entrepreneurship endeavors are already underway. Phil Strandwitz, CEO of Holobiome, and his team are actively engaged in identifying microbes with psychobiont potential. Primarily they have identified Bacteroides, Parabacteroides, and Escherichia species as bacteria with GABA producing pathways through transcriptome analysis of human stool samples (Strandwitz et al., 2019). At Holobiome they have identified and ranked 30 promising GABA-producing bacteria and also discovered that the bacterially produce GABA in the gut increases its levels in the brain. The group is trying to develop a consortium of bacteria that would comprise a broader range of species and will be able to target various psychological conditions like depression (https://www.sciencemag.org/news/2020/05/meet-psychobiome-gut-bacteria-may-alter-how-you-think-feel-and-act#). Barring such consortia approach, prebiotic trials are also being attempted with the gross aim to enrich a good psychobiome. In one such trial Grimaldi et al. report Bimuno® galactooligosaccharide (B-GOS®) prebiotic intervention driving, enrichment of Lachnospiraceae family, and improvements in anti-social behavior (Grimaldi et al., 2018).
Despite its tremendous potential, optimizing microbiome therapy is not at all a smooth sail. Microbe-metal health interface research is still at a sprouting stage, primarily deciphering microbial metabolism linked to neurotransmitter generation/ stability. There are dimensions yet to be explored to have a systemic understanding. It would require a robust association study comprising substantial population and individual data. Individual microbiomes frequently expel the bacteria in standard probiotics, preventing the probiotic species from becoming established in gut microbiome (Suez et al., 2018). In this context, adopting parameters similar to precision medicine development while grafting microbiomes might accentuate the successful development of psychobiome therapy.
References:
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Golubeva AV, Joyce SA, Moloney G, et al. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism. EBioMedicine. 2017;24:166‐178. doi:10.1016/j.ebiom.2017.09.020
Grimaldi R, Gibson GR, Vulevic J, et al. A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome. 2018;6(1):133. Published 2018 Aug 2. doi:10.1186/s40168-018-0523-3
Hassell JE Jr, Fox JH, Arnold MR, et al. Treatment with a heat-killed preparation of Mycobacterium vaccae after fear conditioning enhances fear extinction in the fear-potentiated startle paradigm. Brain Behav Immun. 2019;81:151‐160. doi:10.1016/j.bbi.2019.06.008
Kachlíková M, Sabaka P, Koščálová A, Bendžala M, Dovalová Z, Stankovič I. Comorbid status and the faecal microbial transplantation failure in treatment of recurrent Clostridioides difficile infection – pilot prospective observational cohort study. BMC Infect Dis. 2020;20(1):52. Published 2020 Jan 16. doi:10.1186/s12879-020-4773-x
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Suez J, Zmora N, Zilberman-Schapira G, et al. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018;174(6):1406‐1423.e16. doi:10.1016/j.cell.2018.08.047
Valles-Colomer M, Falony G, Darzi Y, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4(4):623‐632. doi:10.1038/s41564-018-0337-x
Wilkins LJ, Monga M, Miller AW. Defining Dysbiosis for a Cluster of Chronic Diseases. Sci Rep. 2019;9(1):12918. Published 2019 Sep 9. doi:10.1038/s41598-019-49452-y
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