The Microbiota-Gut-Brain Axis.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

Preventing adolescent stress-induced cognitive and microbiome changes by diet.

Psychological stress during adolescence may cause enduring cognitive deficits and anxiety in both humans and animals, accompanied by rearrangement of numerous brain structures and functions. A healthy diet is essential for proper brain development and maintenance of optimal cognitive functions during adulthood. Furthermore, nutritional components profoundly affect the intestinal community of microbes that may affect gut-brain communication. We adopted a relatively mild stress protocol, social instability stress, which when repeatedly administered to juvenile rats modifies cognitive behaviors and plasticity markers in the brain. We then tested the preventive effect of a prolonged diet enriched with the ω-3 polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid and vitamin A. Our findings highlight the beneficial effects of this enriched diet on cognitive memory impairment induced by social instability stress, as stressed rats fed the enriched diet exhibited performance undistinguishable from that of nonstressed rats on both emotional and reference memory tests. Furthermore, in stressed rats, the decline in brain-derived neurotrophic factor expression in the hippocampus and shifts in the microbiota composition were normalized by the enriched diet. The detrimental behavioral and neurochemical effects of adolescent stress, as well as the protective effect of the enriched diet, were maintained throughout adulthood, long after the exposure to the stressful environment was terminated. Taken together, our results strongly suggest a beneficial role of nutritional components in ameliorating stress-related behaviors and associated neurochemical and microbiota changes, opening possible new venues in the field of nutritional neuropsychopharmacology.

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner.

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc-/-) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc-/- and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.

Experience-dependent structural plasticity in the adult brain: How the learning brain grows.

Volumetric magnetic resonance imaging studies have shown that intense learning can be associated with grey matter volume increases in the adult brain. The underlying mechanisms are poorly understood. Here we used monocular deprivation in rats to analyze the mechanisms underlying use-dependent grey matter increases. Optometry for quantification of visual acuity was combined with volumetric magnetic resonance imaging and microscopic techniques in longitudinal and cross-sectional studies. We found an increased spatial vision of the open eye which was associated with a transient increase in the volumes of the contralateral visual and lateral entorhinal cortex. In these brain areas dendrites of neurons elongated, and there was a strong increase in the number of spines, the targets of synapses, which was followed by spine maturation and partial pruning. Astrocytes displayed a transient pronounced swelling and underwent a reorganization of their processes. The use-dependent increase in grey matter corresponded predominantly to the swelling of the astrocytes. Experience-dependent increase in brain grey matter volume indicates a gain of structure plasticity with both synaptic and astrocyte remodeling.

Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T+ Itpr3tf/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6Chi monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.

Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome.

Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.

Impact of host and environmental factors on ß-glucuronidase enzymatic activity: implications for gastrointestinal serotonin.

The gastrointestinal tract houses a reservoir of bacterial-derived enzymes that can directly catalyze the metabolism of drugs, dietary elements and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity. Intrinsic factors related to the host, including age, sex and genetic background, were also explored. Fecalase, a cell-free extract of feces, was prepared and used in a colorimetric-based assay to quantify enzymatic activity. To demonstrate the functional effects of fecal enzymatic activity, we examined ß-glucuronidase-mediated cleavage of serotonin ß-d-glucuronide (5-HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, ß-glucuronidase and ß-glucosidase activity were absent in germ-free mice. Enzymatic activity was significantly influenced by mouse strain and animal species. Sex and age significantly altered metabolic activity with implications for free 5-HT. ß-Glucuronidase and ß-glucosidase activity remained at reduced levels for nearly two weeks after cessation of antibiotic administration. This effect on fecalase corresponded to significantly lower 5-HT levels as compared with incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter ß-glucuronidase or ß-glucosidase activity. Our data demonstrate that multiple factors influence the activity of bacterial-derived enzymes which may have potential clinical implications for drug metabolism and the deconjugation of host-produced glucuronides in the gut.NEW & NOTEWORTHY This article explores a comprehensive range of host and environmental factors that introduce variability in the expression of bacterial-derived metabolic enzymes. Our results demonstrate that altered ß-glucuronidase activity has implications for the bioavailability of luminal serotonin. The experimental approach employed, fecalase, provides a mechanistic basis and translational platform to further delineate the functional outputs of altered metabolic activity, and the associated physiological effects of microbiota-targeted interventions on host response to drugs and host-produced glucuronides.

The role of the microbiota in acute stress-induced myeloid immune cell trafficking.

There has been a growing recognition of the involvement of the gastrointestinal microbiota in the development of stress-related disorders. Acute stress leads to activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells. Both these response systems are independently known to be primed by the microbiota, even though much is still unclear about the role of the gastrointestinal microbiota in acute stress-induced immune activation. In this study, we investigated whether the microbiota influences acute stress-induced changes in innate immunity using conventionally colonised mice, mice devoid of any microbiota (i.e. germ-free, GF), and colonised GF mice (CGF). We also explored the kinetics of stress-induced immune cell mobilisation in the blood, the spleen and mesenteric lymph nodes (MLNs). Mice were either euthanised prior to stress or underwent restraint stress and were then euthanised at various time points (i.e. 0, 45- and 240-minutes) post-stress. Plasma adrenaline and noradrenaline levels were analysed using ELISA and immune cell levels were quantified using flow cytometry. GF mice had increased baseline levels of adrenaline and noradrenaline, of which adrenaline was normalised in CGF mice. In tandem, GF mice had decreased circulating levels of LY6Chi and LY6Cmid, CCR2+ monocytes, and granulocytes, but not LY6C-, CX3CR1+ monocytes. These deficits were normalised in CGF mice. Acute stress decreased blood LY6Chi and LY6Cmid, CCR2+ monocytes while increasing granulocyte levels in all groups 45 min post-stress. However, only GF mice showed stress-induced changes in LY6Chi monocytes and granulocytes 240 min post-stress, indicating impairments in the recovery from acute stress-induced changes in levels of specific innate immune cell types. LY6C-, CX3CR1+ monocytes remained unaffected by stress, indicating that acute stress impacts systemic innate immunity in a cell-type-specific manner. Overall, these data reveal novel cell-type-specific changes in the innate immune system in response to acute stress, which in turn are impacted by the microbiota. In conclusion, the microbiota influences the priming and recovery of the innate immune system to an acute stressor and may inform future microbiota-targeted therapeutics aimed at modulating stress-induced immune activation in stress-related disorders.

Monocyte mobilisation, microbiota & mental illness.

The gastrointestinal microbiome has emerged as a key player in regulating brain and behaviour. This has led to the strategy of targeting the gut microbiota to ameliorate disorders of the central nervous system. Understanding the underlying signalling pathways in which the microbiota impacts these disorders is crucial for the development of future therapeutics for improving CNS functionality. One of the major pathways through which the microbiota influences the brain is the immune system, where there is an increasing appreciation for the role of monocyte trafficking in regulating brain homeostasis. In this review, we will shed light on the role of monocyte trafficking as a relay of microbiota signals in conditions where the central nervous system is in disorder, such as stress, peripheral inflammation, ageing, traumatic brain injury, stroke, multiple sclerosis, Alzheimer's disease and Parkinson's disease. We also cover how the gastrointestinal microbiota is implicated in these mental illnesses. In addition, we aim to discuss how the monocyte system can be modulated by the gut microbiota to mitigate disorders of the central nervous system, which will lead to novel microbiota-targeted strategies.

Resilience to chronic stress is associated with specific neurobiological, neuroendocrine and immune responses.

Research into the molecular basis of stress resilience is a novel strategy to identify potential therapeutic strategies to treat stress-induced psychopathologies such as anxiety and depression. Stress resilience is a phenomenon which is not solely driven by effects within the central nervous system (CNS) but involves multiple systems, central and peripheral, which interact with and influence each other. Accordingly, we used the chronic social defeat stress paradigm and investigated specific CNS, endocrine and immune responses to identify signatures of stress-resilience and stress susceptibility in mice. Our results showed that mice behaviourally susceptible to stress (indexed by a reduction in social interaction behaviour) had higher plasma corticosterone levels and adrenal hypertrophy. An increase in inflammatory circulating monocytes was another hallmark of stress susceptibility. Furthermore, prefrontal cortex mRNA expression of corticotrophin-releasing factor (Crf) was increased in susceptible mice relative to resilient mice. We also report differences in hippocampal synaptic plasticity between resilient and susceptible mice. Ongoing studies will interpret the functional relevance of these signatures which could potentially inform the development of novel psychotherapeutic strategies.

Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations.

KEY POINTS: Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders. ABSTRACT: There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.

The gut microbiota is an emerging target for improving brain health during ageing.

The gut microbiota plays crucial roles in maintaining the health and homeostasis of its host throughout lifespan, including through its ability to impact brain function and regulate behaviour during ageing. Studies have shown that there are disparate rates of biologic ageing despite equivalencies in chronologic age, including in the development of neurodegenerative diseases, which suggests that environmental factors may play an important role in determining health outcomes in ageing. Recent evidence demonstrates that the gut microbiota may be a potential novel target to ameliorate symptoms of brain ageing and promote healthy cognition. This review highlights the current knowledge around the relationships between the gut microbiota and host brain ageing, including potential contributions to age-related neurodegenerative diseases. Furthermore, we assess key areas for which gut microbiota-based strategies may present as opportunities for intervention.

Brain Macro-Structural Alterations in Aging Rats: A Longitudinal Lifetime Approach.

Aging is accompanied by macro-structural alterations in the brain that may relate to age-associated cognitive decline. Animal studies could allow us to study this relationship, but so far it remains unclear whether their structural aging patterns correspond to those in humans. Therefore, by applying magnetic resonance imaging (MRI) and deformation-based morphometry (DBM), we longitudinally screened the brains of male RccHan:WIST rats for structural changes across their average lifespan. By combining dedicated region of interest (ROI) and voxel-wise approaches, we observed an increase in their global brain volume that was superimposed by divergent local morphologic alterations, with the largest aging effects in early and middle life. We detected a modality-dependent vulnerability to shrinkage across the visual, auditory, and somato-sensory cortical areas, whereas the piriform cortex showed partial resistance. Furthermore, shrinkage emerged in the amygdala, subiculum, and flocculus as well as in frontal, parietal, and motor cortical areas. Strikingly, we noticed the preservation of ectorhinal, entorhinal, retrosplenial, and cingulate cortical regions, which all represent higher-order brain areas and extraordinarily grew with increasing age. We think that the findings of this study will further advance aging research and may contribute to the establishment of interventional approaches to preserve cognitive health in advanced age.

Bifidobacterium longum subsp. longum Reduces Perceived Psychological Stress in Healthy Adults: An Exploratory Clinical Trial.

Emerging science shows that probiotic intake may impact stress and mental health. We investigated the effect of a 6-week intervention with Bifidobacterium longum (BL) NCC3001 (1 × 1010 CFU/daily) on stress-related psychological and physiological parameters in 45 healthy adults with mild-to-moderate stress using a randomized, placebo-controlled, two-arm, parallel, double-blind design. The main results showed that supplementation with the probiotic significantly reduced the perceived stress and improved the subjective sleep quality score compared to placebo. Comparing the two groups, momentary subjective assessments concomitant to the Maastricht Acute Stress Test revealed a lower amount of pain experience in the probiotic group and a higher amount of relief at the end of the procedure in the placebo group, reflected by higher scores in the positive affect state. The awakening of the salivary cortisol response was not affected by the intervention, yet the reduction observed in the salivary cortisol stress response post-intervention was higher in the placebo group than the probiotic group. Multivariate analysis further indicated that a reduction in perceived stress correlated with a reduction in anxiety, in depression, and in the cortisol awakening response after the 6-week intervention. This exploratory trial provides promising insights into BL NCC3001 to reduce perceived stress in a healthy population and supports the potential of nutritional solutions including probiotics to improve mental health.

Microbiota from young mice counteracts selective age-associated behavioral deficits.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.

Distinct actions of the fermented beverage kefir on host behaviour, immunity and microbiome gut-brain modules in the mouse.

BACKGROUND: Mounting evidence suggests a role for the gut microbiota in modulating brain physiology and behaviour, through bi-directional communication, along the gut-brain axis. As such, the gut microbiota represents a potential therapeutic target for influencing centrally mediated events and host behaviour. It is thus notable that the fermented milk beverage kefir has recently been shown to modulate the composition of the gut microbiota in mice. It is unclear whether kefirs have differential effects on microbiota-gut-brain axis and whether they can modulate host behaviour per se. METHODS: To address this, two distinct kefirs (Fr1 and UK4), or unfermented milk control, were administered to mice that underwent a battery of tests to characterise their behavioural phenotype. In addition, shotgun metagenomic sequencing of ileal, caecal and faecal matter was performed, as was faecal metabolome analysis. Finally, systemic immunity measures and gut serotonin levels were assessed. Statistical analyses were performed by ANOVA followed by Dunnett's post hoc test or Kruskal-Wallis test followed by Mann-Whitney U test. RESULTS: Fr1 ameliorated the stress-induced decrease in serotonergic signalling in the colon and reward-seeking behaviour in the saccharin preference test. On the other hand, UK4 decreased repetitive behaviour and ameliorated stress-induced deficits in reward-seeking behaviour. Furthermore, UK4 increased fear-dependent contextual memory, yet decreased milk gavage-induced improvements in long-term spatial learning. In the peripheral immune system, UK4 increased the prevalence of Treg cells and interleukin 10 levels, whereas Fr1 ameliorated the milk gavage stress-induced elevation in neutrophil levels and CXCL1 levels. Analysis of the gut microbiota revealed that both kefirs significantly changed the composition and functional capacity of the host microbiota, where specific bacterial species were changed in a kefir-dependent manner. Furthermore, both kefirs increased the capacity of the gut microbiota to produce GABA, which was linked to an increased prevalence in Lactobacillus reuteri. CONCLUSIONS: Altogether, these data show that kefir can signal through the microbiota-gut-immune-brain axis and modulate host behaviour. In addition, different kefirs may direct the microbiota toward distinct immunological and behavioural modulatory effects. These results indicate that kefir can positively modulate specific aspects of the microbiota-gut-brain axis and support the broadening of the definition of psychobiotic to include kefir fermented foods. Video abstract.

Gut microbiome-mediated modulation of hepatic cytochrome P450 and P-glycoprotein: impact of butyrate and fructo-oligosaccharide-inulin.

OBJECTIVES: Our objective was to demonstrate microbial regulation of hepatic genes implicated in drug metabolism and transport using germ-free (GF) mice and to explore the impact of a microbial metabolite, butyrate, and a prebiotic dietary intervention on hepatic gene expression in mice. METHODS: Using reverse-transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug-resistance protein 1 (MDR1) expression in conventional, GF and colonised GF mice. To investigate the effects of butyrate, sodium butyrate (3 g/l) was administered for 21 days to conventional or GF mice. In the prebiotic study, young adult and middle-aged mice received diet enriched with 10% fructo-oligosaccharide (FOS)-inulin for 14 weeks. KEY FINDINGS: Colonisation of GF animals normalised expression of Cyp3a11 and Mdr1b to conventional levels. Butyrate upregulated Cyp2b10 in conventional mice (P < 0.05) but overall did not induce widespread changes in hepatic genes. FOS-inulin increased Cyp3a13 expression and had the opposite effect on Mdr1a expression in young adult mice (P < 0.05). Age, on the other hand, influenced the prebiotic effect on Cyp2a4 expression (P < 0.01). CONCLUSION: The expression of hepatic genes implicated in drug metabolism and transport displays sensitivity to the microbiome, microbiome-derived metabolites and a microbial-targeted intervention. Our study may provide the impetus to explore microbiota-targeted interventions in normalising host metabolic activity and reducing inter-individual variability in drug pharmacokinetics.

Impact of indomethacin on neuroinflammation and hippocampal neurogenesis in aged mice.

Age-induced neuroinflammation could be a contributing factor to the restricted neurogenesis in aged mice. Indomethacin, a common non-steroidal anti-inflammatory drug, has been demonstrated to partially restore neurogenesis under pathophysiological inflammation-associated conditions in adult C57BL/6 mice. This study investigated whether indomethacin is able to decrease age-related neuroinflammation in the hippocampus (24-month-old mice) and thereby stimulate neurogenesis. During hippocampal aging, the transcript expression of pro-inflammatory cytokines (Tnfα, Il-1α, Il-1ß), the chemokine Mip-1α, and markers for activated astrocytes (Gfap, Lcn2, but not Vim and Serpina3n) and microglia (Iba1, F4/80, Cd68, Cd86) significantly increased. Treatment with indomethacin significantly decreased COX-1 and COX-2 transcript expression. Of the age-related inflammatory mediators, only Gfap and Iba1 were affected by indomethacin treatment in the hippocampus, with a significantly reduced transcript expression being detected for both markers. Neurogenesis was unaffected by indomethacin. Thus, our data reveal that administration of indomethacin to aged mice is not able to effectively decrease neuroinflammation and promote neurogenesis.