Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication

Abstract

Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.

Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat

“…However, we do find some similarities between our antibioticinduced microbiota depletion model and GF rats with GF rats displaying increased As expected, chronic antibiotic exposure during adulthood significantly reduced the diversity and richness of the gut microbiota with significant decreases in both firmicutes and bacteriodetes which were the most abundant phylum present in vehicle treated animals, which is consistent with previous studies examining the effects of antibiotic exposure (Verdú et al, 2006;Cho et al, 2012;Zhang et al, 2014;Fröhlich et al, 2016). Additionally, changes in these specific phyla have been associated with neurodevelopmental disorders such as autism and many gastrointestinal disorders (Clemente et al, 2012;Hsiao et al, 2013).…”

“…However, we did not see a change in noradrenaline which has been hypothesized to be Previous studies have highlighted the decline in cognition in relation to microbiota deficient models when tested in in the NOR (Gareau et al, 2010;Fröhlich et al, 2016) but a decline in spatial memory has not been observed in other studies. This highlights again that timing of depletion can have varying effects on behavioral outcome as we see a subtle profile of cognitive impairment following microbiota-depletion during adulthood which is apparent in the MWM but not the NOR.…”

“…One recent study highlighted the impact of short 7 day exposure to antibiotics in adulthood (Fröhlich et al, 2016) however, few have looked at the impact of chronic long term treatment in adulthood (Möhle et al, 2016). Subsequently the use of antibiotics in order to deplete intestinal microbiota is a more controlled animal model as these animals are not hindered by any additional physiological differences as in the GF animals which have underdeveloped immune systems as well as major differences in metabolic processing.…”

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…Preclinical studies utilising various strategies including GF and GI infection models (Gareau, 2014;Gareau et al, 2011), antibiotic treatment (Desbonnet et al, 2015;Fröhlich et al, 2016) dietary manipulation (Li et al, 2009;Ohland et al, 2013) and probiotic treatment (Davari et al, 2013;Ohland et al, 2013), have found that cognitive function is influenced by the composition of the gut microbiota. Preliminary findings in healthy populations have shown that a prebiotic can modulate emotional attention performance , and a probiotic can alter functional brain activity when performing a similar emotional attention task (Tillisch et al, 2013).…”

How to Determine the Role of the Microbiome in Drug Disposition

“…Compared to conventional mice, germ-free and antibiotic treated mice exhibit increased permeability of the BBB and decreased expression of occludin and claudin-5 tight junction proteins (Fröhlich et al, 2016), which is reversible upon introduction of sodium butyrate or by mono-colonization of butyrate producing bacteria (Braniste et al, 2014). An important point to keep in mind when conducting distribution assays in rodents is the interspecies variation in PXR ligands; typical rodent models do not accurately recapitulate the range of ligand activation possible for human PXR.…”