Interactions between Mediterranean Diet Supplemented with Dairy Foods and the Gut Microbiota Influence Cardiovascular Health in an Australian Population.

The impact of a Mediterranean diet on the intestinal microbiome has been linked to its health benefits. We aim to evaluate the effects of a Mediterranean diet supplemented with dairy foods on the gut microbiome in Australians at risk of cardiovascular disease. In a randomised controlled cross-over study, 34 adults with a systolic blood pressure ≥120 mmHg and with risk factors for cardiovascular disease were randomly allocated to a Mediterranean diet with 3-4 daily serves of dairy foods (Australian recommended daily intake (RDI) of 1000-1300 mg per day (MedDairy)) or a low-fat (LFD) control diet. Between each 8-week diet, participants underwent an 8-week washout period. Microbiota characteristics of stool samples collected at the start and end of each diet period were determined by 16S rRNA amplicon sequencing. MedDairy-associated effects on bacterial relative abundance were correlated with clinical, anthropometric, and cognitive outcomes. No change in the overall faecal microbial structure or composition was observed with either diet (p > 0.05). The MedDairy diet was associated with changes in the relative abundance of several bacterial taxa, including an increase in Butyricicoccus and a decrease in Colinsella and Veillonella (p < 0.05). Increases in Butyricicoccus relative abundance over 8 weeks were inversely correlated with lower systolic blood pressure (r = -0.38, p = 0.026) and positively correlated with changes in fasting glucose levels (r = 0.39, p = 0.019), specifically for the MedDairy group. No significant associations were observed between the altered taxa and anthropometric or cognitive measures (p > 0.05). Compared to a low-fat control diet, the MedDairy diet resulted in changes in the abundance of specific gut bacteria, which were associated with clinical outcomes in adults at risk of CVD.

The Impact of Long-Term Macrolide Exposure on the Gut Microbiome and Its Implications for Metabolic Control.

Long-term low-dose macrolide therapy is now widely used in the treatment of chronic respiratory diseases for its immune-modulating effects, although the antimicrobial properties of macrolides can also have collateral impacts on the gut microbiome. We investigated whether such treatment altered intestinal commensal microbiology and whether any such changes affected systemic immune and metabolic regulation. In healthy adults exposed to 4 weeks of low-dose erythromycin or azithromycin, as used clinically, we observed consistent shifts in gut microbiome composition, with a reduction in microbial capacity related to carbohydrate metabolism and short-chain fatty acid biosynthesis. These changes were accompanied by alterations in systemic biomarkers relating to immune (interleukin 5 [IL-5], IL-10, monocyte chemoattractant protein 1 [MCP-1]) and metabolic (serotonin [5-HT], C-peptide) homeostasis. Transplantation of erythromycin-exposed murine microbiota into germ-free mice demonstrated that changes in metabolic homeostasis and gastrointestinal motility, but not systemic immune regulation, resulted from changes in intestinal microbiology caused by macrolide treatment. Our findings highlight the potential for long-term low-dose macrolide therapy to influence host physiology via alteration of the gut microbiome. IMPORTANCE Long-term macrolide therapy is widely used in chronic respiratory diseases although its antibacterial activity can also affect the gut microbiota, a key regulator of host physiology. Macrolide-associated studies on the gut microbiota have been limited to short antibiotic courses and have not examined its consequences for host immune and metabolic regulation. This study revealed that long-term macrolides depleted keystone bacteria and impacted host regulation, mediated directly by macrolide activity or indirectly by alterations to the gut microbiota. Understanding these macrolide-associated mechanisms will contribute to identifying the risk of long-term exposure and highlights the importance of targeted therapy for maintenance of the gut microbiota.

Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington's disease mice.

Huntington's disease is a neurodegenerative disorder involving psychiatric, cognitive and motor symptoms. Huntington's disease is caused by a tandem-repeat expansion in the huntingtin gene, which is widely expressed throughout the brain and body, including the gastrointestinal system. There are currently no effective disease-modifying treatments available for this fatal disorder. Despite recent evidence of gut microbiome disruption in preclinical and clinical Huntington's disease, its potential as a target for therapeutic interventions has not been explored. The microbiota-gut-brain axis provides a potential pathway through which changes in the gut could modulate brain function, including cognition. We now show that faecal microbiota transplant (FMT) from wild-type into Huntington's disease mice positively modulates cognitive outcomes, particularly in females. In Huntington's disease male mice, we revealed an inefficiency of FMT engraftment, which is potentially due to the more pronounced changes in the structure, composition and instability of the gut microbial community, and the imbalance in acetate and gut immune profiles found in these mice. This study demonstrates a role for gut microbiome modulation in ameliorating cognitive deficits modelling dementia in Huntington's disease. Our findings pave the way for the development of future therapeutic approaches, including FMT and other forms of gut microbiome modulation, as potential clinical interventions for Huntington's disease.

Contrasting temperature responses in seasonal timing of cercariae shedding by Rhipidocotyle trematodes.

Global warming is likely to lengthen the seasonal duration of larval release by parasites. We exposed freshwater mussel hosts, Anodonta anatina, from 2 high-latitude populations to high, intermediate and low temperatures throughout the annual cercarial shedding period of the sympatric trematodes Rhipidocotyle fennica and R. campanula, sharing the same transmission pathway. At the individual host level, under warmer conditions, the timing of the cercarial release in both parasite species shifted towards seasonally earlier period while its duration did not change. At the host population level, evidence for the lengthening of larvae shedding period with warming was found for R. fennica. R. campanula started the cercarial release seasonally clearly earlier, and at a lower temperature, than R. fennica. Furthermore, the proportion of mussels shedding cercariae increased, while day-degrees required to start the cercariae shedding decreased in high-temperature treatment in R. fennica. In R. campanula these effects were not found, suggesting that warming can benefit more R. fennica. These results do not completely support the view that climate warming would invariably increase the seasonal duration of larval shedding by parasites, but emphasizes species-specific differences in temperature-dependence and in seasonality of cercarial release.

The gut microbiome and mental health: advances in research and emerging priorities.

The gut microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in the development of psychiatric conditions and in the efficacy of many common therapies. With the growing acceptance of the role played by the gut microbiome in mental health outcomes, the focus of research is now beginning to shift from identifying relationships between intestinal microbiology and pathophysiology, and towards using this newfound insight to improve clinical outcomes. Here, we review recent advances in our understanding of gut microbiome-brain interactions, the mechanistic underpinnings of these relationships, and the ongoing challenge of distinguishing association and causation. We set out an overarching model of the evolution of microbiome-CNS interaction and examine how a growing knowledge of these complex systems can be used to determine disease susceptibility and reduce risk in a targeted manner.

Assessment of Long-Term Macrolide Exposure on the Oropharyngeal Microbiome and Macrolide Resistance in Healthy Adults and Consequences for Onward Transmission of Resistance.

While the use of long-term macrolide therapy to prevent exacerbations in chronic respiratory diseases is widespread, its impact on the oropharyngeal microbiota and macrolide resistance, and the potential for onward transmission of resistance to close contacts are poorly understood. We determined the effects of long-term exposure to azithromycin or erythromycin on phenotypic and genotypic macrolide resistance within the oropharyngeal microbiome of healthy adults and their close contacts in a randomized, single-blinded, parallel-group trial of 4 weeks of twice-daily oral 400 mg erythromycin ethylsuccinate or twice-daily oral 125 mg azithromycin. Using oropharyngeal swabs collected from 20 index healthy adults and 20 paired close contacts, the oropharyngeal microbial composition and macrolide resistance in streptococci were assessed by 16S rRNA sequencing and antibiotic susceptibility testing of oropharyngeal cultures, respectively, at baseline and weeks 4 and 8 (washout). Targeted quantitative PCR of antibiotic resistance genes was performed to evaluate paired changes in resistance gene levels in index patients and close contacts and to relate the potential transmission of antibiotic resistance. Neither azithromycin nor erythromycin altered oropharyngeal microbiota characteristics significantly. Proportional macrolide resistance in oropharyngeal streptococci increased with both erythromycin and azithromycin, remaining above baseline levels for the azithromycin group at washout. Levels of resistance genes increased significantly with azithromycin[erm(B) and mef] and erythromycin (mef), returning to baseline levels at washout only for the erythromycin group. We found no evidence of onward transmission of resistance to close contacts, as indicated by the lack of concomitant changes in resistance gene levels detected in close contacts. (This study has been registered with the Australian and New Zealand Clinical Trials Registry under identifier ACTRN12617000278336.).

Carriage and Transmission of Macrolide Resistance Genes in Patients With Chronic Respiratory Conditions and Their Close Contacts.

BACKGROUND: Long-term macrolide therapy has been shown to provide benefit to those with a range of chronic respiratory conditions. However, concerns remain about the impact of macrolide exposure on the carriage and abundance of antibiotic resistance genes within the oropharynx. The potential for onward transmission of resistance from macrolide recipients to their close contacts also is poorly understood. RESEARCH QUESTION: Does long-term macrolide use impact carriage of resistance within the oropharyngeal microbiota in people with chronic respiratory conditions and risk of onward transmission to their close contacts? STUDY DESIGN AND METHODS: Oropharyngeal swabs were collected from 93 individuals with chronic respiratory conditions, 53 of whom were receiving long-term macrolide therapy. An oropharyngeal swab also was collected from a close cohabiting contact of each patient. Detection and abundance of 10 macrolide-associated resistance genes with the potential to disseminate via horizontal gene transfer were assessed by quantitative polymerase chain reaction analysis. RESULTS: Detection of resistance genes in macrolide recipients was comparable with that in nonrecipients. However, the normalized gene abundance of erm(B) was significantly higher in the macrolide recipient group (P = .045). Among the close contacts, no between-group differences in resistance gene detection or abundance were identified. Within-group analysis showed that the detection of erm(F) and mef in macrolide recipients, but not nonrecipients, was associated significantly with detection in close contacts (P = .003 and P = .004, respectively). However, between-group analysis showed that treatment group did not predict cocarriage between patients and their close contacts (P > .05 for each gene). INTERPRETATION: Although levels of erm(B) were higher in those receiving long-term macrolide therapy and evidence of gene cocarriage with close contacts was found, no evidence was found that macrolide use increased the onward transmission risk to their close contacts. This study therefore addresses concerns that long-term macrolide therapy could promote the dissemination of transmissible macrolide resistance.

Ear microbiota and middle ear disease: a longitudinal pilot study of Aboriginal children in a remote south Australian setting.

BACKGROUND: Otitis media (OM) is a major disease burden in Australian Aboriginal children, contributing to serious long-term health outcomes. We report a pilot analysis of OM in children attending an outreach ear and hearing clinic in a remote south Australian community over a two-year period. Our study focuses on longitudinal relationships between ear canal microbiota characteristics with nasopharyngeal microbiota, and clinical and treatment variables. RESULTS: Middle ear health status were assessed in 19 children (aged 3 months to 8 years) presenting in remote western South Australia and medical interventions were recorded. Over the two-year study period, chronic suppurative OM was diagnosed at least once in 7 children (37%), acute OM with perforation in 4 children (21%), OM with effusion in 11 children (58%), while only 1 child had no ear disease. Microbiota analysis of 19 children (51 sets of left and right ear canal swabs and nasopharyngeal swabs) revealed a core group of bacterial taxa that included Corynebacterium, Alloiococcus, Staphylococcus, Haemophilus, Turicella, Streptococcus, and Pseudomonas. Within-subject microbiota similarity (between ears) was significantly greater than inter-subject similarity, regardless of differences in ear disease (p = 0.0006). Longitudinal analysis revealed changes in diagnosis to be associated with more pronounced changes in microbiota characteristics, irrespective of time interval. Ear microbiota characteristics differed significantly according to diagnosis (P (perm) = 0.0001). Diagnoses featuring inflammation with tympanic membrane perforation clustering separately to those in which the tympanic membrane was intact, and characterised by increased Proteobacteria, particularly Haemophilus influenzae, Moraxella catarrhalis, and Oligella. While nasopharyngeal microbiota differed significantly in composition to ear microbiota (P (perm) = 0.0001), inter-site similarity was significantly greater in subjects with perforated tympanic membranes, a relationship that was associated with the relative abundance of H. influenzae in ear samples (rs = - 0.71, p = 0.0003). Longitudinal changes in ear microbiology reflected changes in clinical signs and treatment. CONCLUSIONS: Children attending the ear and hearing clinic in a remote Aboriginal community present with a broad spectrum of OM conditions and severities, consistent with other remote Aboriginal communities. Ear microbiota characteristics align with OM diagnosis and change with disease course. Nasopharyngeal microbiota characteristics are consistent with the contribution of acute upper respiratory infection to OM aetiology.

Environmental dynamics of hospital microbiome upon transfer from a major hospital to a new facility.

BACKGROUND: Infection control is critical to safe hospital care. However, how bacteria within nosocomial environments relate to space utilisation and occupancy remains poorly understood. Our aim was to characterise the hospital microbiome in the context of the closure of a tertiary hospital and the opening of a new facility. METHODS: Environmental swabs were collected from common and inpatient areas in the old and new hospitals during a 12-month transition period. Microbiota characteristics were determined by 16S rRNA gene sequencing and quantitative (q)PCR. Targeted assays were used to detect Methicillin-resistant Staphylococcus aureus (MRSA) and vanB-positive Vancomycin-Resistant Enterococci (VRE). RESULTS: The transition to full occupancy in the new facility was associated with an increase in bacterial load (inpatient areas, 3 months p = 0.001; common areas, 6 months p = 0.039) and a change in microbiota composition (baseline-12 months, PERMANOVA p = 0.002). These changes were characterised by an increase in human microbiota-associated taxa, including Acinetobacter and Veillonella. Closure of the existing facility was associated with a decrease in bacterial load (p = 0.040). Detection of MRSA did not differ significantly between sites. CONCLUSIONS: Occupancy is a major determinant of bacterial dispersion within hospital environments. Steady-state bacterial levels and microbiota composition provide a basis for assessment of infection control measures.

The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life.

Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for more than 700 days in comparison with untreated control mice. We demonstrate the emergence of two different low-diversity community types, post-antibiotic microbiota (PAM) I and PAM II, following antibiotic exposure. PAM II but not PAM I mice have impaired immunity, increased insulin resistance, and evidence of increased inflammaging in later life as well as a reduced lifespan. Our data suggest that differences in the composition of the gut microbiota following antibiotic exposure differentially affect host health and longevity in later life.

Gut microbiota transplantation for colonization of germ-free mice.

The use of germ-free mice is integral to the understanding of host-gut microbiome relationships. Such models rely on faithful replication of the donor microbiome to establish causal effects of the gut microbiota on host pathophysiology. This protocol describes the preparation and transfer of donor microbiota, focusing on strict anaerobic processing methods and multiple instillations by gavage for optimal gut microbiota recovery. For complete details on the generation and use of this protocol, please refer to Choo and Rogers (2021).

Investigating potential transmission of antimicrobial resistance in an open-plan hospital ward: a cross-sectional metagenomic study of resistome dispersion in a lower middle-income setting.

BACKGROUND: Antimicrobial resistance (AMR) represents a profound global health threat. Reducing AMR spread requires the identification of transmission pathways. The extent to which hospital wards represent a venue for substantial AMR transmission in low- and middle-income countries settings is poorly understood. METHODS: Rectal swabs were obtained from adult male inpatients in a "Nightingale" model general medicine ward in Yangon, Myanmar. Resistome characteristics were characterised by metagenomic sequencing. AMR gene carriage was related to inter-patient distance (representing inter-patient interaction) using distance-based linear models. Clinical predictors of AMR patterns were identified through univariate and multivariate regression. RESULTS: Resistome similarity showed a weak but significant positive correlation with inter-patient distance (r = 0.12, p = 0.04). Nineteen AMR determinants contributed significantly to this relationship, including those encoding ß-lactamase activity (OXA-1, NDM-7; adjusted p < 0.003), trimethoprim resistance (dfrA14, adjusted p = 0.0495), and chloramphenicol resistance (catB3, adjusted p = 0.002). Clinical traits of co-located patients carrying specific AMR genes were not random. Specifically, AMR genes that contributed to distance-resistome relationships (OXA-1, catB3, dfrA14) mapped to tuberculosis patients, who were placed together according to ward policy. In contrast, patients with sepsis were not placed together, and carried AMR genes that were not spatially significant or consistent with shared antibiotic exposure. CONCLUSIONS: AMR dispersion patterns primarily reflect the placement of particular patients by their condition, rather than AMR transmission. The proportion of AMR determinants that varied with inter-patient distance was limited, suggesting that nosocomial transmission is a relatively minor contributor to population-level carriage.

Establishment of murine gut microbiota in gnotobiotic mice.

Determining whether associations between gut microbiota characteristics and host physiology represent causal relationships is a fundamental challenge for microbiome research. We report a detailed investigation of microbiome assembly in C57BL/6 germ-free mice across a period of 70 days and compare the effects of single and multiple rounds of gavage, using both native and antibiotic-disrupted murine donor material. Recipients of the native microbiota did not achieve compositional stability until day 28 and persistent differences to donor microbiota remained until day 70. Performing multiple rounds of gavage significantly increased the cumulative number of detected taxa (mean increase: 10.4%) and compositional similarity to donor, and significantly reduced within-group variance (p < 0.05). Multiple rounds of gavage with antibiotic-disrupted microbiota provided no substantial benefit in relation to compositional similarity to donor or within-group variance. The process of donor microbiota establishment in recipient animals is necessary before experimentation commences and is considerably influenced by donor microbiota characteristics.

Almond consumption affects fecal microbiota composition, stool pH, and stool moisture in overweight and obese adults with elevated fasting blood glucose: A randomized controlled trial.

Regular almond consumption has been shown to improve body weight management, lipid profile and blood glucose control. We hypothesized that almond consumption would alter fecal microbiota composition, including increased abundance and activity of potentially beneficial bacterial taxa in adults who are overweight and obese with elevated fasting blood glucose. A total of 69 adults who were overweight or obese with an elevated plasma glucose (age: 60.8 ± 7.4, BMI ≥27 kg/m2, fasting plasma glucose ≥5.6 to <7.0 mmol/L) were randomized to daily consumption of either 2 servings of almonds (AS:56 g/day) or an isocaloric, high carbohydrate biscuit snack for 8 weeks. AS but not biscuit snack experienced significant changes in microbiota composition (P= .011) and increases in bacterial richness, evenness, and diversity (P< .01). Increases in both the relative and absolute abundance of operational taxonomic units in the Ruminococcaceae family, including Ruminiclostridium (false discovery rate P = .002), Ruminococcaceae NK4A214 (P = .002) and Ruminococcaceae UCG-003 (P = .002) were the principal drivers of microbiota-level changes. No changes in fecal short chain fatty acid levels, or in the carriage of the gene encoding butyryl-CoA:acetate CoA-transferase (an enzyme involved in butyrate synthesis) occurred. Almond consumption was not associated with reduced gut permeability, but fecal pH (P= .0006) and moisture content (P = .027) decreased significantly in AS when compared to BS. Regular almond consumption increased the abundance of potentially beneficial ruminococci in the fecal microbiota in individuals with elevated blood glucose. However, fecal short-chain fatty acid levels remained unaltered and the capacity for such microbiological effects to precipitate host benefit is not known.

A High Amylose Wheat Diet Improves Gastrointestinal Health Parameters and Gut Microbiota in Male and Female Mice.

High amylose wheat (HAW) contains more resistant starch than standard amylose wheat (SAW) and may have beneficial effects on gastrointestinal health. However, it is currently unclear whether these effects differ according to the level of HAW included in the diet or between males and females. Male and female C57BL/6 mice (n = 8/group/sex) were fed SAW65 (65% SAW; control), HAW35 (35% HAW), HAW50 (50% HAW) or HAW65 (65% HAW) diet for eight weeks. Female but not male, mice consuming any amount of HAW exhibited accelerated gastric emptying compared to SAW65 group. In both sexes, relative colon weights were higher in the HAW65 group compared to SAW65 group and in females, relative weights of the small intestine and cecum were also higher in the HAW65 group. In females only, colonic expression of Pyy and Ocln mRNAs were higher in the HAW65 group compared to HAW35 and HAW50 groups. In both sexes, mice consuming higher amounts of HAW (HAW50 or HAW65) had increased fecal bacterial load and relative abundance of Bacteroidetes phylum and reduced relative abundance of Firmicutes compared to SAW65 group. These data are consistent with a beneficial impact of HAW on gastrointestinal health and indicate dose-dependent and sex-specific effects of HAW consumption.

Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks.

The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional route by which intestinal microbiology could mediate modifiable risk for neuropathology and neurodegeneration in particular. Autophagy, a ubiquitous cellular process involved in the prevention of cell damage and maintenance of effective cellular function, acts to clear and recycle cellular debris. In doing so, autophagy prevents the accumulation of toxic proteins and the development of neuroinflammation, both common features of dementia. Levels of autophagy are influenced by a range of extrinsic exposures, including nutrient deprivation, infection, and hypoxia. These relationships between exposures and rates of autophagy are likely to be mediated, as least in part, by the gut microbiome. For example, the suppression of histone acetylation by microbiome-derived short-chain fatty acids appears to be a major contributor to upregulation of autophagic function. We discuss the potential contribution of the microbiome-autophagy axis to neurological health and examine the potential of exploiting this link to predict and prevent neurodegenerative diseases.

Intestinal microbiology shapes population health impacts of diet and lifestyle risk exposures in Torres Strait Islander communities.

Poor diet and lifestyle exposures are implicated in substantial global increases in non-communicable disease burden in low-income, remote, and Indigenous communities. This observational study investigated the contribution of the fecal microbiome to influence host physiology in two Indigenous communities in the Torres Strait Islands: Mer, a remote island where a traditional diet predominates, and Waiben a more accessible island with greater access to takeaway food and alcohol. Counterintuitively, disease markers were more pronounced in Mer residents. However, island-specific differences in disease risk were explained, in part, by microbiome traits. The absence of Alistipes onderdonkii, for example, significantly (p=0.014) moderated island-specific patterns of systolic blood pressure in multivariate-adjusted models. We also report mediatory relationships between traits of the fecal metagenome, disease markers, and risk exposures. Understanding how intestinal microbiome traits influence response to disease risk exposures is critical for the development of strategies that mitigate the growing burden of cardiometabolic disease in these communities.

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. APPROACH AND RESULTS: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium-dependent BA transporter inhibitor (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSIONS: Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.

The gut microbiome regulates host glucose homeostasis via peripheral serotonin.

The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin.

Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition.

Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase (Casp1, Ifngr, Nos2)-/- present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, (Casp1, Ifngr, Nos2)-/- mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of (Casp1, Ifngr, Nos2)-/- mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.