In vitro Characterization of Gut Microbiota-Derived Bacterial Strains With Neuroprotective Properties

Abstract

Neurodegenerative diseases are disabling, incurable, and progressive conditions characterized by neuronal loss and decreased cognitive function. Changes in gut microbiome composition have been linked to a number of neurodegenerative diseases, indicating a role for the gut-brain axis. Here, we show how specific gut-derived bacterial strains can modulate neuroinflammatory and neurodegenerative processes in vitro through the production of specific metabolites and discuss the potential therapeutic implications for neurodegenerative disorders. A panel of fifty gut bacterial strains was screened for their ability to reduce pro-inflammatory IL-6 secretion in U373 glioblastoma astrocytoma cells. Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029 had the strongest capacity to reduce IL-6 secretion in vitro. Oxidative stress plays a crucial role in neuroinflammation and neurodegeneration, and both bacterial strains displayed intrinsic antioxidant capacity. While MRx0005 showed a general antioxidant activity on different brain cell lines, MRx0029 only protected differentiated SH-SY5Y neuroblastoma cells from chemically induced oxidative stress. MRx0029 also induced a mature phenotype in undifferentiated neuroblastoma cells through upregulation of microtubule-associated protein 2. Interestingly, short-chain fatty acid analysis revealed that MRx0005 mainly produced C1-C3 fatty acids, while MRx0029 produced C4-C6 fatty acids, specifically butyric, valeric and hexanoic acid. None of the short-chain fatty acids tested protected neuroblastoma cells from chemically induced oxidative stress. However, butyrate was able to reduce neuroinflammation in vitro, and the combination of butyrate and valerate induced neuronal maturation, albeit not to the same degree as the complex cell-free supernatant of MRx0029. This observation was confirmed by solvent extraction of cell-free supernatants, where only MRx0029 methanolic fractions containing butyrate and valerate showed an anti-inflammatory activity in U373 cells and retained the ability to differentiate neuroblastoma cells. In summary, our results suggest that the pleiotropic nature of live biotherapeutics, as opposed to isolated metabolites, could be a promising novel drug class in drug discovery for neurodegenerative disorders.

In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice

“…This confirmed previous study performed in gnotobiotic mice colonized with P. distasonis showing an induction of Treg differentiation [ 84 ]. A strain of P. distasonis was shown to reduce neuroinflammation in vitro by exhibiting a strong capacity to reduce IL-6 secretion, but also antioxidant capacity on different brain cell lines [ 85 ]. All these results highlight the potential anti-inflammatory effect of this bacterium at multiple levels and its ability to promote intestinal barrier integrity, as we observed in our models.…”

Distinctive Microbial Signatures and Gut-Brain Crosstalk in Pediatric Patients with Coeliac Disease and Type 1 Diabetes Mellitus

“…Previous studies have reported reduction of the Parabacteroides in multiple sclerosis patients where its exerts a protective role by stimulating anti-inflammatory IL-10–expressing human CD4 + CD25 + T cells [ 81 ]. In a study assessing the neuroprotective ability of fifty gut bacterial strains, Parabacteroides distasonis had the strongest capacity to reduce IL-6, with a potential to be used as a live biotherapeutic in disorders characterized by neurodegeneration and neuroinflammation [ 82 ]. Oral administration of Parabacteroides components (mPd) is known to be effective in dampening the production of proinflammatory cytokines via innate and adaptive immunomodulatory mechanisms [ 83 ].…”

Cancer predictive studies

“…This, just to remain with the neuroblastoma example, are also of relevance in other cancer progression or even in neurophysiology. Accordingly, gut microbiota shows neuroprotective properties, reducing IL-6 secretion in different neural cell lines, including neuroblastoma [ 84 , 85 ]. Here, these investigators identified two specific strains, Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029, producing distinct C1-C3 or C4-C6 fatty acids [ 84 ] or, in another context, galacto-oligosaccharides [ 86 ] or short-chain fatty acid receptor 3 [ 87 ].…”

“…Accordingly, gut microbiota shows neuroprotective properties, reducing IL-6 secretion in different neural cell lines, including neuroblastoma [ 84 , 85 ]. Here, these investigators identified two specific strains, Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029, producing distinct C1-C3 or C4-C6 fatty acids [ 84 ] or, in another context, galacto-oligosaccharides [ 86 ] or short-chain fatty acid receptor 3 [ 87 ]. Similarly, Roseovarius albus increases brain derived neurotropic factor (BDNF) expression while reducing Bax/Bcl-2 ratio in neuroblastoma cell lines [ 88 ].…”