Publications
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Kragsnaes MS, Miguens Blanco J, Mullish BH, et al., 2023, Small intestinal permeability and metabolomic profiles in feces and plasma associate with clinical response in patients with active psoriatic arthritis participating in a fecal microbiota transplantation trial: exploratory findings from the FLORA trial, ACR Open Rheumatology, ISSN: 2578-5745
Marchesi J, Alexander J, Balarajah S, et al., 2023, Identification of a sub-clinical Salmonella spp. infection in a dairy cow using a commercially available stool storage kit, Animals, Vol: 13, Pages: 1-11, ISSN: 2076-2615
Stool sampling is a useful tool for diagnosing gastrointestinal disease in veterinary medicine. The sub-clinical disease burden of Salmonella spp. in cattle can become significant for farmers. However, current methods of faecal sampling in a rural setting for diagnosis are not consistently sufficient for the preservation of Salmonella spp. in faeces. This study evaluated the use of a commercial stool storage kit for bacterial preservation in cow faecal samples compared to unpreserved stools placed into refrigeration at different time-points. A stool sample was collected per-rectum from one apparently healthy Holstein–Freisen cow. The sample was weighed and aliquoted into two sterile Falcon tubes and into two commercial kit tubes. The aliquots were then placed into refrigeration at 4 °C at 0, 24, and 96 h after processing. One commercial kit tube was not aliquoted and remained at ambient temperature. After 2 weeks, DNA was extracted from the samples and analysed using endpoint PCR, revealing a sub-clinical infection with Salmonella spp. The bacterium was best preserved when the stool was stored in the commercial kit at ambient temperature and re-homogenised immediately prior to DNA extraction. The unpreserved stool did not maintain obvious levels of Salmonella spp. after 24 h at ambient temperature. This commercial kit should be considered for use in the diagnosis of salmonellosis in cattle.
Yip AYG, King OG, Omelchenko O, et al., 2023, Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites, Nature Communications, Vol: 14, Pages: 1-20, ISSN: 2041-1723
The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Broad-spectrum antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. Here, we show that antibiotic-induced reduction of gut microbial populations leads to an enrichment of nutrients and depletion of inhibitory metabolites, which enhances CRE growth. Antibiotics decrease the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in ex vivo cultures of human faecal microbiota; this is accompanied by depletion of microbial metabolites and enrichment of nutrients. We measure the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several CRE strains. We find that CRE can use the nutrients (enriched after antibiotic treatment) as carbon and nitrogen sources for growth. These nutrients also increase in faeces from antibiotic-treated mice and decrease following intestinal colonisation with carbapenem-resistant Escherichia coli. Furthermore, certain microbial metabolites (depleted upon antibiotic treatment) inhibit CRE growth. Our results show that killing gut commensals with antibiotics facilitates CRE colonisation by enriching nutrients and depleting inhibitory microbial metabolites.
Lo J, Cozzetto D, Alexander J, et al., 2023, Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and dependent on IL23 and IFNg, Nature Communications, ISSN: 2041-1723
Gallacher DJ, Zhang L, Aboklaish AF, et al., 2023, Baseline azithromycin resistance in the gut microbiota of preterm born infants., Pediatr Res
BACKGROUND: Macrolides, including azithromycin, are increasingly used in preterm-born infants to treat Ureaplasma infections. The baseline carriage of macrolide resistance genes in the preterm stool microbiota is unknown. OBJECTIVES: Identify carriage of azithromycin resistant bacteria and the incidence of macrolide resistant genes. METHODS: Azithromycin resistant bacteria were isolated from serial stool samples obtained from preterm infants (≤32 weeks' gestation) by culturing aerobically/anaerobically, in the presence/absence of azithromycin. Using quantitative PCR, we targeted 6 common macrolide resistance genes (erm(A), erm(B), erm(C), erm(F), mef(A/E), msr(A)) in DNA extracted from selected bacteria resistant to azithromycin. RESULTS: From 89 stool samples from 37 preterm-born infants, 93.3% showed bacterial growth in aerobic or anaerobic conditions. From the 280 azithromycin resistant isolates that were identified, Staphylococcus (75%) and Enterococcus (15%) species dominated. Macrolide resistance genes were identified in 91% of resistant isolates: commonest were erm(C) (46% of isolates) and msr(A) (40%). Multiple macrolide resistance genes were identified in 18% of isolates. CONCLUSION: Macrolide resistance is common in the gut microbiota of preterm-born infants early in life, most likely acquired from exposure to the maternal microbiota. It will be important to assess modulation of macrolide resistance, if macrolide treatment becomes routine in the management of preterm infants. IMPACT STATEMENT: Azithromycin resistance is present in the stool microbiota in the first month of life in preterm infants 91% of azithromycin resistant bacteria carried at least one of 6 common macrolide resistant genes Increasing use of macrolides in the preterm population makes this an important area of study.
Routy B, Lenehan JG, Miller WH, et al., 2023, Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial, Nature Medicine, ISSN: 1546-170X
Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899.
Garaiova I, Paduchová Z, Nagyová Z, et al., 2023, Probiotics with low dose vitamin C reduce antibiotic prescriptions in children: A secondary analysis of a multicentre randomised double-blind placebo-controlled trial, Journal of Functional Foods, Vol: 106, ISSN: 1756-4646
As part of a randomised, double-blind, placebo-controlled study in children looking at the impact of a combination of a multistrain probiotic and vitamin C on upper respiratory tract infection symptoms, we have explored antibiotic prescription during the study. Antibiotic usage in children for acute respiratory tract infections is quite widespread. In this study the incidence rates for oral antibiotic prescriptions were significantly reduced in the Lab4 probiotic/vitamin C group compared to the placebo; children had a lower risk of being prescribed antibiotics (Risk Ratio: 0.60, 95 % CI: 0.39, 0.94, P = 0.0239, per protocol; Risk Ratio: 0.72, 95 % CI: 0.49, 1.05, P = 0.0890, intention to treat, respectively). These data suggest that supplementation with the probiotic/vitamin C may help to reduce antibiotic prescriptions in children.
Dos Santos Correia G, Marchesi J, MacIntyre D, 2023, Moving beyond DNA: towards functional analysis of the vaginal microbiome by non-sequencing-based methods, Current Opinion in Microbiology, Vol: 73, Pages: 1-11, ISSN: 1369-5274
Over the last two decades, sequencing-based methods have revolutionised our understanding of niche-specific microbial complexity. In the lower female reproductive tract, these approaches have enabled identification of bacterial compositional structures associated with health and disease. Application of metagenomics and metatranscriptomics strategies have provided insight into the putative function of these communities but it is increasingly clear that direct measures of microbial and host cell function are required to understand the contribution of microbe–host interactions to pathophysiology. Here we explore and discuss current methods and approaches, many of which rely upon mass-spectrometry, being used to capture functional insight into the vaginal mucosal interface. In addition to improving mechanistic understanding, these methods offer innovative solutions for the development of diagnostic and therapeutic strategies designed to improve women’s health.
Churchward MA, Michaud ER, Mullish BH, et al., 2023, Short-chain fatty and carboxylic acid changes associated with fecal microbiota transplant communally influence microglial inflammation, Heliyon, Vol: 9, Pages: 1-16, ISSN: 2405-8440
The intestinal microbiota has been proposed to influence human mental health and cognition through the gut-brain axis. Individuals experiencing recurrent Clostridioides difficile infection (rCDI) frequently report depressive symptoms, which are improved after fecal microbiota transplantation (FMT); however, mechanisms underlying this association are poorly understood. Short-chain fatty acids and carboxylic acids (SCCA) produced by the intestinal microbiota cross the blood brain barrier and have been proposed to contribute to gut-brain communication. We hypothesized that changes in serum SCCA measured before and after successful FMT for rCDI influences the inflammatory response of microglia, the resident immune cells of the central nervous system. Serum SCCA were quantified using gas chromatography-mass spectroscopy from 38 patients who participated in a randomized trial comparing oral capsule- vs colonoscopy delivered FMT for rCDI, and quality of life was assessed by SF-36 at baseline, 4, and 12 weeks after FMT treatment. Successful FMT was associated with improvements in mental and physical health, as well as significant changes in a number of circulating SCCA, including increased butyrate, 2-methylbutyrate, valerate, and isovalerate, and decreased 2-hydroxybutyrate. Primary cultured microglia were treated with SCCA and the response to a pro-inflammatory stimulus was measured. Treatment with a combination of SCCA based on the post-FMT serum profile, but not single SCCA species, resulted in significantly reduced inflammatory response including reduced cytokine release, reduced nitric oxide release, and accumulation of intracellular lipid droplets. This suggests that both levels and diversity of SCCA may be an important contributor to gut-brain communication.
Skov Kragsnaes M, Miguens Blanco J, Mullish B, et al., 2023, POS0423 PLASMA METABOLOMIC PROFILES OF PATIENTS WITH ACTIVE PERIPHERAL PSORIATIC ARTHRITIS CAN DIFFERENTIATE TREATMENT RESPONDERS FROM FAILURES: EXPLORATORY FINDINGS FROM THE FLORA TRIAL, Publisher: BMJ, Pages: 467.1-468, ISSN: 0003-4967
<jats:sec><jats:title>Background</jats:title><jats:p>Metabolite profiling of biofluids has an emergent role in exploring the contribution of host-microbiome interactions to the treatment response of immune-mediated arthritis.[1]</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>As part of the FLORA trial (exploring the impact of gut microbiome manipulation upon response to methotrexate [MTX]),[2] we investigated plasma metabolomic profiles of adults with psoriatic arthritis (PsA) and whether they correlated with the primary trial outcome, which was clinical response to MTX (responder vs failure) following one faecal microbiota transplant (FMT) or sham transplant.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Thirty-one PsA patients with active peripheral disease, despite at least 3 months of steady-state dose MTX, were included in the 26-week, double-blind, parallel-group, 1:1 randomised, sham-controlled, superiority trial (FLORA trial;<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03058900">NCT03058900</jats:ext-link>).[2] Patients were randomly allocated to receive either one gastroscopic-guided FMT (n = 15) or sham transplant (n = 16). Each FMT product encompassed 50 g of processed faeces obtained from one of four healthy, thoroughly screened donors. Patients continued MTX throughout the trial. The primary trial endpoint was the proportion of treatment failures through 26 weeks, defined as need for treatment escalation (in most cases instigation of TNF inhibitors) due to insufficient improvement of disease activity or disease worsening.[2] Li-Hep plasma samples were collected at baseline, week 4, 12, and 26. The metabolic profiles were measured using<jats:sup>1</jats:sup>H Nuclear Magnetic Resonance (NMR). We u
Payne T, Appleby M, Buckley E, et al., 2023, A double-blind, randomized, placebo-controlled trial of ursodeoxycholic Acid (UDCA) in Parkinson's disease, Movement Disorders, Vol: 38, Pages: 1493-1502, ISSN: 0885-3185
Background:Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.Objectives:To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.Methods:The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.Results:UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.Conclusions:High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD.
Verhasselt HL, Ramakrishnan E, Schlag M, et al., 2023, Fungal gut microbiome in myasthenia gravis: a sub-analysis of the MYBIOM study, Journal of Fungi, Vol: 9, Pages: 1-8, ISSN: 2309-608X
An altered gut microbiota is a possible contributing pathogenic factor in myasthenia gravis (MG), an autoimmune neuromuscular disease. However, the significance of the fungal microbiome is an understudied and neglected part of the intestinal microbiome in MG. We performed a sub-analysis of the MYBIOM study including faecal samples from patients with MG (n = 41), non-inflammatory neurological disorder (NIND, n = 18), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 6) and healthy volunteers (n = 12) by sequencing the internal transcribed spacer 2 (ITS2). Fungal reads were obtained in 51 out of 77 samples. No differences were found in alpha-diversity indices computed between the MG, NIND, CIDP and HV groups, indicating an unaltered fungal diversity and structure. Overall, four mould species (Penicillium aurantiogriseum, Mycosphaerella tassiana, Cladosporium ramonetellum and Alternaria betae-kenyensis) and five yeast species (Candida. albicans, Candida. sake, Candida. dubliniensis, Pichia deserticola and Kregervanrija delftensis) were identified. Besides one MG patient with abundant Ca. albicans, no prominent dysbiosis in the MG group of the mycobiome was found. Not all fungal sequences within all groups were successfully assigned, so further sub-analysis was withdrawn, limiting robust conclusions.
Short C-E, 2023, Comparative analysis of vaginal microbiota sampling using menstrual cups and high vaginal swabs in pregnant women living with HIV-1 infection, Frontiers in Cellular and Infection Microbiology, Vol: 13, ISSN: 2235-2988
Background: Menstrual cups (MCs) are increasingly used to collect cervicovaginal secretions to characterise vaginal mucosal immunology, in conjunction with high vaginal swabs (HVS) for metataxonomics, particularly in HIV transmission studies. We hypothesised that both methods of collecting bacterial biomass are equivalent for 16S rRNA gene sequencing.Material and Methods: Cervicovaginal fluid (CVF) samples from 16 pregnant women with HIV-1 (PWWH) were included to represent the major vaginal bacterial community state types (CST I-V). Women underwent sampling during the second trimester by liquid amies HVS followed by a MC (Soft disc™) and samples were stored at -80°C. Bacterial cell pellets obtained from swab elution and MC (500 µL, 1 in 10 dilution) were resuspended in 120 µL PBS for DNA extraction. Bacterial 16S rRNA gene sequencing was performed using V1-V2 primers and were analysed using MOTHUR. Paired total DNA, bacterial load, amplicon read counts, diversity matrices and bacterial taxa were compared by sampling method using MicrobiomeAnalyst, SPSS and R.Results: The total DNA eluted from one aliquot of diluted CVF from an MC was similar to that of a HVS (993ng and 609ng, p=0.18); the mean bacterial loads were also comparable for both methods (MC: 8.0 log10 16S rRNA gene copies versus HVS: 7.9 log10 16S rRNA gene copies, p=0.27). The mean number of sequence reads generated from MC samples was lower than from HVS (MC: 12730; HVS:14830, p=0.05). The α-diversity metrices were similar for both techniques; MC Species Observed: 41 (range 12-96) versus HVS: 47 (range 16-96), p=0.15; MC Inverse Simpson Index: 1.98 (range 1.0-4.0) versus HVS: 0.48 (range 1.0-4.4), p=0.22). The three most abundant species observed were: Lactobacillus iners, Lactobacillus crispatus and Gardnerella vaginalis. Hierarchical clustering of relative abundance data showed that samples obtained using different techniques in an individual clustered in the same CST group.
Alexander J, Posma J, Scott A, et al., 2023, Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer, Microbiome, Vol: 11, Pages: 1-14, ISSN: 2049-2618
Background and aimsThe gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes.MethodsA multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months.ResultsThirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10−11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR&
Michael DR, Kerry-Smith J, Webberley TS, et al., 2023, Does flow culture impact upon gut-probiotic interactions: A comparison with static culture, Journal of Functional Foods, Vol: 104, ISSN: 1756-4646
Conventional tissue culture models often lack physiological relevance. In this exploratory study, dynamic flow conditions were applied to 21-day cultured Caco-2 intestinal epithelial cells and their response compared with statically cultured counterparts. Host:microbiome interactions were also explored through co-incubation with Gram positive bacteria (Lab4 probiotics) or the Gram positive cell wall component, lipoteichoic acid (LTA). Under flow, Caco-2 cells displayed increased viability, mucin production and pH tolerance compared to cells under static conditions. Measurement of secretion rates of the pro-inflammatory cytokine, interleukin-8, showed that cells under flow were unresponsive towards stimulation with Lab4 or LTA that was in complete contrast to inductions observed under static conditions. Given that Gram positive bacteria are well tolerated within the healthy gastrointestinal tract, these data suggest that flow conditions may improve the physiological relevance of Caco-2 cells. This preliminary study encourages further work exploring the impact of flow on cell-based in vitro models.
Cherta-Murillo A, Danckert NP, Valdivia-Garcia M, et al., 2023, Gut microbiota fermentation profiles of pre-digested mycoprotein (Quorn) using faecal batch cultures in vitro: a preliminary study., Int J Food Sci Nutr, Vol: 74, Pages: 327-337
High-fibre diets are beneficial for many health outcomes via a wide range of mechanisms including gut microbiota fermentation-derived short-chain fatty acid (SCFAs) production. Mycoprotein (marketed as Quorn) is a food high in fibre (>6 g/100 g wet weight (ww)) and protein (13 g/100 g ww) which has been shown to have positive effects on glycemic control and appetite in humans. Nevertheless, the mechanisms underpinning this are poorly understood. Here, we investigate the changes in gut microbiota α- and β-diversity, pH and SCFAs production in faecal batch cultures supplemented with pre-digested mycoprotein (Quorn), soy, chicken and control (unsupplemented) using eight fresh stools from healthy donors. The results showed that pre-digested mycoprotein did not alter pH (p = .896), α- or β-diversity of the gut microbiota when compared to the control, soy, and chicken. Nevertheless, chicken led to a significant increase in total SCFAs post-24 h vs. control (+57.07 mmol/L, p = .01). In particular, propionate increased when compared to soy (+19.59 mmol/L, p = .03) and the control (+23.19 mmol/L, p < .01). No other differences in SCFAs were detected. In conclusion, pre-digested mycoprotein was not fermented in vitro by healthy gut microbiota in the settings of this experiment.
Semertzidou A, Grout-Smith H, Kalliala I, et al., 2023, Diabetes and anti-diabetic interventions and the risk of gynaecological and obstetric morbidity: an umbrella review of the literature, BMC Medicine, Vol: 21, Pages: 1-15, ISSN: 1741-7015
BackgroundDiabetes has reached epidemic proportions in recent years with serious health ramifications. The aim of this study was to evaluate the strength and validity of associations between diabetes and anti-diabetic interventions and the risk of any type of gynaecological or obstetric conditions.MethodsDesign: Umbrella review of systematic reviews and meta-analyses.Data sources: PubMed, Medline, Embase, Cochrane Database of Systematic Reviews, manual screening of references.Eligibility criteria: Systematic reviews and meta-analyses of observational and interventional studies investigating the relationship between diabetes and anti-diabetic interventions with gynaecological or obstetric outcomes. Meta-analyses that did not include complete data from individual studies, such as relative risk, 95% confidence intervals, number of cases/controls, or total population were excluded.Data analysis: The evidence from meta-analyses of observational studies was graded as strong, highly suggestive, suggestive or weak according to criteria comprising the random effects estimate of meta-analyses and their largest study, the number of cases, 95% prediction intervals, I2 heterogeneity index between studies, excess significance bias, small study effect and sensitivity analysis using credibility ceilings. Interventional meta-analyses of randomised controlled trials were assessed separately based on the statistical significance of reported associations, the risk of bias and quality of evidence (GRADE) of included meta-analyses.ResultsA total of 117 meta-analyses of observational cohort studies and 200 meta-analyses of randomised clinical trials that evaluated 317 outcomes were included. Strong or highly suggestive evidence only supported a positive association between gestational diabetes and caesarean section, large for gestational age babies, major congenital malformations and heart defects and an inverse relationship between metformin use and ovarian cancer incidence. Only a fifth
Mullish BH, Michael DR, Webberley TS, et al., 2023, The gastrointestinal status of healthy adults: a post hoc assessment of the impact of three distinct probiotics, Beneficial Microbes, Pages: 1-14, ISSN: 1876-2883
There is a growing awareness that supplementation with probiotic bacteria can impart beneficial effects during gastrointestinal disease, but less is known about the impact of probiotics on healthy subjects. Here, we report the outcomes of a post hoc analysis of recorded daily gastrointestinal events and bowel habits completed by healthy adults participating in a placebo-controlled, single-centre, randomised, double-blind, quadruple-arm probiotic tolerability study. Extensive screening ensured the healthy status of subjects entering the study and during a 2-week pre-intervention run-in period, a burden of gastrointestinal events (stomach pains, indigestion, acid reflux, stomach tightening, nausea and vomiting, stomach rumbling, bloating, belching and flatulence) was identified suggesting GI discomfort within the population. In the subsequent 12-week intervention period with 3 distinct probiotic formulations and a matched-placebo, reductions in the incidence rates of bloating, borborygmus, stomach pains, slow faecal transit and incomplete defecations were observed in the probiotic groups compared to the placebo. These results highlighted differing responses among the probiotic formulations tested and indicated potential anti-constipation effects. Product specific modulations in circulating interleukin-6 levels and in the composition of the gut microbiota were also detected. Together, these data suggest a role for probiotic supplementation to exert beneficial effects on the gastrointestinal functioning of healthy subjects and highlight the need for further longer-term studies in healthy populations to gain a greater understanding of the impact of probiotics.
Preda VG, Roberts LA, Quinlan RA, et al., 2023, Antiretroviral therapy (ART) inhibits the growth of cervicovaginal microbiome species in vitro: potential role in preterm birth (PTB), British HIV Association, Publisher: Wiley, Pages: 11-11, ISSN: 1464-2662
Webberley TS, Bevan RJ, Kerry-Smith J, et al., 2023, Assessment of Lab4P Probiotic Effects on Cognition in 3xTg-AD Alzheimer's Disease Model Mice and the SH-SY5Y Neuronal Cell Line, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24
Alexander J, Powell N, Marchesi J, et al., 2023, Considerations for peripheral blood transport and storage during large-scale multicentre metabolome research, Gut, Pages: 1-4, ISSN: 0017-5749
Alexander JL, Mullish BH, Danckert NP, et al., 2023, The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients, EBioMedicine, Vol: 88, ISSN: 2352-3964
Background:Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients.Methods:Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination.Findings:Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithoc
Chrysostomou D, Roberts LA, Marchesi JR, et al., 2023, Gut Microbiota Modulation of Efficacy and Toxicity of Cancer Chemotherapy and Immunotherapy, GASTROENTEROLOGY, Vol: 164, Pages: 198-213, ISSN: 0016-5085
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Biscarini F, Masetti G, Muller I, et al., 2023, Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, ISSN: 0021-972X
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Radhakrishnan ST, Gallagher KI, Mullish BH, et al., 2023, Rectal swabs as a viable alternative to faecal sampling for the analysis of gut microbiota functionality and composition, Scientific Reports, Vol: 13, Pages: 1-9, ISSN: 2045-2322
Faecal or biopsy samples are frequently used to analyse the gut microbiota, but issues remain with the provision and collection of such samples. Rectal swabs are widely-utilised in clinical practice and previous data demonstrate their potential role in microbiota analyses; however, studies to date have been heterogenous, and there are a particular lack of data concerning the utility of swabs for the analysis of the microbiota’s functionality and metabolome. We compared paired stool and rectal swab samples from healthy individuals to investigate whether rectal swabs are a reliable proxy for faecal sampling. There were no significant differences in key alpha and beta diversity measures between swab and faecal samples, and inter-subject variability was preserved. Additionally, no significant differences were demonstrated in abundance of major annotated phyla. Inferred gut functionality using Tax4Fun2 showed excellent correlation between the two sampling techniques (Pearson’s coefficient r = 0.9217, P < 0.0001). Proton nuclear magnetic resonance (1H NMR) spectroscopy enabled the detection of 20 metabolites, with overall excellent correlation identified between rectal swab and faecal samples for levels all metabolites collectively, although more variable degrees of association between swab and stool for levels of individual metabolites. These data support the utility of rectal swabs in both compositional and functional analyses of the gut microbiota.
Martinez Gili L, Pechlivanis A, McDonald J, et al., 2023, Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis, Gut Microbes, Vol: 15, Pages: 1-19, ISSN: 1949-0976
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.
Koutoukidis DA, Jebb SA, Zimmerman M, et al., 2022, The association of weight loss with changes in the gut microbiota diversity, composition, and intestinal permeability: a systematic review and meta-analysis, GUT MICROBES, Vol: 14, ISSN: 1949-0976
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- Citations: 12
Bustamante J-M, Dawson T, Loeffler C, et al., 2022, Impact of fecal microbiota transplantation on gut bacterial bile acid metabolism in humans, Nutrients, Vol: 14, ISSN: 2072-6643
Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included Desulfovibrio fairfieldensis and Clostridium hylemonae. To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. Bacteroides ovatus and Phocaeicola dorei were positively correlated with unconjugated bile acids. Bifidobacterium adolescentis, Collinsella aerofaciens, and Faecalibacterium prausnitzii were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.
Misra R, Sarafian M, Pechlivanis A, et al., 2022, Ethnicity associated microbial and metabonomic profiling in newly diagnosed ulcerative colitis, Clinical and Experimental Gastroenterology, Vol: 15, Pages: 199-212, ISSN: 1178-7023
Introduction:Ulcerative colitis (UC) differs across geography and ethnic groups. Gut microbial diversity plays a pivotal role in disease pathogenesis and differs across ethnic groups. The functional diversity in microbial-driven metabolites may have a pathophysiologic role and offer new therapeutic avenues.Methods:Demographics and clinical data were recorded from newly diagnosed UC patients. Blood, urine and faecal samples were collected at three time points over one year. Bacterial content was analysed by 16S rRNA sequencing. Bile acid profiles and polar molecules in three biofluids were measured using liquid-chromatography mass spectrometry (HILIC) and nuclear magnetic resonance spectroscopy.Results:We studied 42 patients with a new diagnosis of UC (27 South Asians; 15 Caucasians) with 261 biosamples. There were significant differences in relative abundance of bacteria at the phylum, genus and species level. Relative concentrations of urinary metabolites in South Asians were significantly lower for hippurate (positive correlation for Ruminococcus) and 4-cresol sulfate (Clostridia) (p<0.001) with higher concentrations of lactate (negative correlation for Bifidobacteriaceae). Faecal conjugated and primary conjugated bile acids concentrations were significantly higher in South Asians (p=0.02 and p=0.03 respectively). Results were unaffected by diet, phenotype, disease severity and ongoing therapy. Comparison of time points at diagnosis and at 1 year did not reveal changes in microbial and metabolic profile.Conclusion:Ethnic-related microbial metabolite associations were observed in South Asians with UC. This suggests a predisposition to UC may be influenced by environmental factors reflected in a distinct gene-environment interaction. The variations may serve as markers to identify risk factors for UC and modified to enhance therapeutic response.
Creedon AC, Dimidi E, Hung ES, et al., 2022, The impact of almonds and almond processing on gastrointestinal physiology, luminal mand gastrointestinal symptoms: a randomized controlled trial and mastication study., American Journal of Clinical Nutrition, Vol: 116, Pages: 1790-1804, ISSN: 0002-9165
BACKGROUND: Almonds contain lipid, fiber and polyphenols and possess physicochemical properties that impact nutrient bioaccessibility, which are hypothesized to impact gut physiology and microbiota. OBJECTIVES: Investigate the impact of whole almonds and ground almonds (almond flour) on fecal bifidobacteria (primary outcome), gut microbiota composition and transit time. DESIGN: Healthy adults (n = 87) participated in a parallel, 3-arm randomized controlled trial. Participants received whole almonds (56 g/d), ground almonds (56 g/d) or an isocaloric control muffin in place of habitual snacks for 4 weeks. Gut microbiota composition and diversity (16S rRNA gene sequencing), short-chain fatty acids (gas-chromatography), volatile organic compounds (gas-chromatography mass-spectrometry), gut transit time (wireless motility capsule), stool output and gut symptoms (7-day diary) were measured at baseline and endpoint. The impact of almond form on particle size distribution (PSD) and predicted lipid release was measured in a subgroup (n = 31). RESULTS: Modified intention-to-treat analysis was performed on 79 participants. There were no significant differences in abundance of fecal bifidobacteria following consumption of whole almonds (8.7%, SD 7.7%), ground almonds (7.8%, SD 6.9%) or control (13.0%, SD 10.2%; q = 0.613). Consumption of almonds (whole and ground pooled) resulted in higher butyrate (24.1 μmol/g, SD 15.0 μmol/g) in comparison to control (18.2 μmol/g, SD 9.1 μmol/g; p = 0.046). There was no effect of almonds on gut microbiota at the phylum level or diversity, gut transit time, stool consistency or gut symptoms. Almond form (whole versus ground) had no effect on study outcomes. Ground almonds resulted in significantly smaller PSD and higher predicted lipid release (10.4%, SD 1.8%) in comparison to whole almonds (9.3%, SD 2.0%; p = 0.017). CONCLUSIONS: Almond consumption has limited impact on g
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