The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

Intestinal persistence of Bifidobacterium infantis is determined by interaction of host genetics and antibiotic exposure.

Probiotics have gained significant attention as a potential strategy to improve health by modulating host-microbe interactions, particularly in situations where the normal microbiota has been disrupted. However, evidence regarding their efficacy has been inconsistent, with considerable interindividual variability in response. We aimed to explore whether a common genetic variant that affects the production of mucosal α(1,2)-fucosylated glycans, present in around 20% of the population, could explain the observed interpersonal differences in the persistence of commonly used probiotics. Using a mouse model with varying α(1,2)-fucosylated glycans secretion (Fut2WT or Fut2KO), we examined the abundance and persistence of Bifidobacterium strains (infantis, breve, and bifidum). We observed significant differences in baseline gut microbiota characteristics between Fut2WT and Fut2KO littermates, with Fut2WT mice exhibiting enrichment of species able to utilize α(1,2)-fucosylated glycans. Following antibiotic exposure, only Fut2WT animals showed persistent engraftment of Bifidobacterium infantis, a strain able to internalize α(1,2)-fucosylated glycans, whereas B. breve and B. bifidum, which cannot internalize α(1,2)-fucosylated glycans, did not exhibit this difference. In mice with an intact commensal microbiota, the relationship between secretor status and B. infantis persistence was reversed, with Fut2KO animals showing greater persistence compared to Fut2WT. Our findings suggest that the interplay between a common genetic variation and antibiotic exposure plays a crucial role in determining the dynamics of B. infantis in the recipient gut, which could potentially contribute to the observed variation in response to this commonly used probiotic species.

Experience-dependent grooming microstructure alterations and gastrointestinal dysfunction in the SAPAP3 knockout mouse model of compulsive behaviour.

BACKGROUND: Compulsive- and anxiety-like behaviour can be efficiently modelled in SAPAP3 knockout (KO) mice, a preclinical model of relevance to obsessive-compulsive disorder (OCD). Although there is emerging evidence in the clinical literature of gastrointestinal dysfunction in OCD, no previous studies have investigated gut function in preclinical models of relevance to OCD. Similarly, the effects of voluntary exercise (EX) or environmental enrichment (EE) have not yet been explored in this context. METHOD: We comprehensively phenotyped the SAPAP3 KO mouse model, including the assessment of grooming microstructure, anxiety- and depressive-like behaviour, and gastrointestinal function. Mice were exposed to either standard housing (SH), exercise (EX, provided by giving mice access to running wheels), or environmental enrichment (EE) for 4 weeks to investigate the effects of enriched housing conditions in this animal model relevant to OCD. FINDINGS: Our study is the first to assess grooming microstructure, perseverative locomotor activity, and gastrointestinal function in SAPAP3 KO mice. We are also the first to report a sexually dimorphic effect of grooming in young-adult SAPAP3 KO mice; along with changes to grooming patterning and indicators of gut dysfunction, which occurred in the absence of gut dysbiosis in this model. Overall, we found no beneficial effects of voluntary exercise or environmental enrichment interventions in this mouse model; and unexpectedly, we revealed a deleterious effect of wheel-running exercise on grooming behaviour. We suspect that the detrimental effects of experimental housing in our study may be indicative of off-target effects of stress-a conclusion that warrants further investigation into the effects of chronic stress in this preclinical model of compulsive behaviour.

Intestinal microbiology and urinary tract infection associated risk in long-term aged care residents.

BACKGROUND: Urinary tract infections (UTI) are the most frequently diagnosed infection in residents of long-term care and are a major risk factor for urosepsis, hospitalisation, and death. Translocation of gut pathobionts into the urinary tract is the presumed cause of most UTIs. While specific gut microbiota characteristics have been linked to UTI risk in younger adults, their relevance in aged care residents remains uncertain. METHODS: The faecal microbiome was assessed in 54 long-term aged care residents with a history of UTIs and 69 residents without a UTI history. Further comparisons were made to microbiome characteristics in 20 younger adults without UTIs. Microbiome characteristics were examined in relation to prior and subsequent UTIs, as well as antibiotic therapy. RESULTS: In long-term aged care residents, prior UTI history and exposure to UTI-exclusive antibiotics do not significantly affect microbiome composition or functional capacity. However, exposure to antibiotics unrelated to UTI treatment is associated with distinct microbiota compositional traits. Adjustment for dementia, incontinence, diabetes, and prior antibiotic use finds no microbiota characteristic linked to UTI development. However, prior UTI is identified as a predictor of future UTIs. Comparison with younger adults identifies greater within-participant dispersion in aged care residents, as well as lower microbiota diversity and altered microbiome functional potential. CONCLUSIONS: No association between the gut microbiome and UTI incidence, as has been reported in younger individuals, is evident in long-term aged care residents. Considerable variability in gut microbiome characteristics, relating to high antibiotic exposure and age-related physiological and immunological factors, could mask such a relationship. However, it cannot be discounted that increased UTI risk in the elderly is independent of microbiome-mediated mechanisms.

Urinary tract infections (UTIs) are common in residents of long-term aged care facilities, posing serious health risks. Harmful bacteria moving from the gut to the urinary tract is thought to cause most UTIs. It is still unclear, however, how differences in gut bacteria contribute to UTI risk in older adults. Here, we investigate the gut bacteria of aged care residents, both with and without a history of UTIs, and compare them to younger adults. While prior UTIs did not alter gut bacteria, antibiotic use did. We observed greater variability in gut bacteria among aged care residents compared to younger adults. These observations suggest that both high antibiotic exposure and age-related factors may mask any potential relationship between gut bacteria and UTI risk in this population. Understanding these factors could lead to improved UTI prevention and treatment strategies for elderly individuals.

Effects of weight loss through dietary intervention on pain characteristics, functional mobility, and inflammation in adults with elevated adiposity.

Background: The relationship between adiposity and pain is complex. Excess weight increases the risk for chronic musculoskeletal pain (CMP), driven by increased biomechanical load and low-grade systemic inflammation. Pain limits physical function, impacting energy balance contributing to weight gain. The primary aims of this study were to profile pain characteristics in participants with overweight or obesity and determine if weight loss through dietary-induced energy restriction, and presence of CMP, or magnitude of weight loss, was associated with changes in adiposity, pain, functional mobility, and inflammation. Methods: This was a secondary analysis of data from adults (25-65 years) with overweight or obesity (BMI 27.5-34.9 kg/m2) enrolled in a 3-month, 30% energy-restricted dietary intervention to induce weight loss (January 2019-March 2021). Anthropometric measures (weight, waist circumference and fat mass), pain prevalence, pain severity (McGill Pain Questionnaire, MPQ), pain intensity (Visual Analog Scale, VAS), functional mobility (timed up and go, TUG) and inflammation (high sensitivity C-Reactive Protein, hsCRP) were assessed at baseline and 3-months. Results: One hundred and ten participants completed the intervention and had weight and pain assessed at both baseline and 3-months. Participants lost 7.0 ± 0.3 kg, representing 7.9% ± 3.7% of body mass. At 3-months, functional mobility improved (TUG -0.2 ± 0.1 s, 95% CI -0.3, -0.1), but there was no change in hsCRP. Compared to baseline, fewer participants reported CMP at 3-months (n = 56, 51% to n = 27, 25%, p < 0.001) and presence of multisite pain decreased from 22.7% to 10.9% (p < 0.001). Improvements in anthropometric measures and functional mobility did not differ between those presenting with or without CMP at baseline. Improvements in pain were not related to the magnitude of weight loss. Conclusion: Weight loss was effective in reducing pain prevalence and improving functional mobility, emphasizing the importance of considering weight-loss as a key component of pain management. Clinical trial registration: identifier, ACTRN12618001861246.

The genomic epidemiology of Neisseria meningitidis carriage from a randomised controlled trial of 4CMenB vaccination in an asymptomatic adolescent population.

Background: Oropharyngeal carriage of Neisseria meningitidis is frequent during adolescence, representing a major source of invasive meningococcal disease. This study examined the impact of a serogroup B vaccination (Bexsero, GSK 4CMenB) programme on adolescent N. meningitidis carriage using genomic data. Methods: A total 34,489 oropharyngeal samples were collected as part of a state-wide cluster randomised-controlled trial in South Australia during 2017 and 2018 (NCT03089086). Samples were screened for the presence of N. meningitidis DNA by porA PCR prior to culture. Whole genome sequencing was performed on all 1772 N. meningitidis culture isolates and their genomes were analysed. Findings: Unencapsulated meningococci were predominant at baseline (36.3% of isolates), followed by MenB (31.0%), and MenY (20.5%). Most MenB were ST-6058 from hyperinvasive cc41/44, or ST-32 and ST-2870 from cc32. For MenY, ST-23 and ST-1655 from cc23 were prevalent. Meningococcal carriage was mostly unchanged due to the vaccination programme; however, a significant reduction in ST-53 capsule-null meningococci prevalence was observed in 2018 compared to 2017 (OR = 0.52; 95% CI: 0.30-0.87, p = 0.0106). This effect was larger in the vaccinated compared to the control group (OR = 0.37; 95% CI: 0.12-0.98, p = 0.0368). Interpretation: While deployment of the 4CMenB vaccination did not alter the carriage of hyperinvasive MenB in the vaccinated population, it altered the carriage of other N. meningitidis sequence types following the vaccination program. Our findings suggest 4CMenB vaccination is unlikely to reduce transmission of hyperinvasive N. meningitidis strains and therefore ongoing targeted vaccination is likely a more effective public health intervention. Funding: This work was funded by GlaxoSmithKline Biologicals SA.

Exposure to doxycycline increases risk of carrying a broad range of enteric antimicrobial resistance determinants in an elderly cohort.

OBJECTIVES: High rates of antibiotic prescription in residential aged care are likely to promote enteric carriage of antibiotic-resistant pathogens and increase the risk of antibiotic treatment failure. Despite their importance, relationships between antibiotic exposures and patterns of enteric resistance carriage in this population remain poorly understood. METHODS: We conducted a cross-sectional metagenomic cohort analysis of stool samples from residents of five long-term aged-care facilities in South Australia. Taxonomic composition was determined, and enteric carriage of antibiotic resistance genes (ARGs) was identified and quantified against the Comprehensive Antibiotic Resistance Database. Both the detection and abundance of stool taxa and ARGs were related to antibiotic exposures up to 12 months prior. Factors associated with the abundance of ARGs of high clinical concern were identified. RESULTS: Stool samples were provided by 164 participants (median age: 88 years, IQR 81-93; 72% female). Sixty-one percent (n = 100) of participants were prescribed antibiotics at least once in the prior 12 months (median prescriptions: 4, range: 1-52), most commonly a penicillin (n = 55, 33.5%), cephalosporin (n = 53, 32.3%), diaminopyrimidine (trimethoprim) (n = 36, 22%), or tetracycline (doxycycline) (n = 21, 12.8%). More than 1100 unique ARGs, conferring resistance to 38 antibiotic classes, were identified, including 20 ARGs of high clinical concern. Multivariate logistic regression showed doxycycline exposure to be the greatest risk factor for high ARG abundance (adjusted odds ratio [aOR]=14.8, q<0.001) and a significant contributor to inter-class selection, particularly for ARGs relating to penicillins (aOR=3.1, q=0.0004) and cephalosporins (aOR=3.4, q=0.003). High enteric ARG abundance was associated with the number of separate antibiotic exposures (aOR: 6.4, q<0.001), exposures within the prior 30 days (aOR: 4.6, q=0.008) and prior 30-100 days (aOR: 2.6, q=0.008), high duration of antibiotic exposure (aOR: 7.9, q<0.001), and exposure to 3 or more antibiotic classes (aOR: 7.4, q<0.001). Carriage of one or more ARGs of high clinical concern was identified in 99% of participants (n = 162, median: 3, IQR: 2-4), involving 11 ARGs conferring resistance to aminoglycosides, four to beta-lactams, one to glycopeptides, three to fluoroquinolones, and one to oxazolidinones. Carriage of ARGs of high clinical concern was positively associated with exposure to doxycycline (aminoglycoside, fluoroquinolone, and oxazolidinone ARGs) and trimethoprim (fluoroquinolone and beta-lactam ARGs). Analysis of doxycycline impact on microbiota composition suggested that observed resistome changes arose principally through direct ARG selection, rather than through the antibiotic depletion of sensitive bacterial populations. CONCLUSIONS: The gut microbiome of aged care residents is a major reservoir of antibiotic resistance. As a critical antibiotic in medical practice, a comprehensive understanding of the impact of doxycycline exposure on the gut resistome is paramount for informed antibiotic use, particularly in an evolving landscape of prophylactic applications. Near-universal asymptomatic carriage of clinically critical resistance determinants is highly concerning and reinforces the urgent need for improved management of antibiotic use in long-term aged care.