Alterations In Gut Microbiome Research Articles

The use of an in vitro fecal fermentation model to uncover the beneficial role of omega-3 and punicic acid in gut microbiota alterations induced by a Western diet.

The influence of gut microbiota in the onset and development of several metabolic diseases has gained attention over the last few years. Diet plays an essential role in gut microbiota modulation. Western diet (WD), characterized by high-sugar and high-fat consumption, alters gut microbiome composition, diversity index, microbial relative levels, and functional pathways. Despite the promising health effects demonstrated by polyunsaturated fatty acids, their impact on gut microbiota is still overlooked. The effect of Fish oil (omega-3 source) and Pomegranate oil (punicic acid source), and a mixture of both oils in gut microbiota modulation were determined by subjecting the oil samples to in vitro fecal fermentations. Cecal samples from rats from two different dietary groups: a control diet (CD) and a high-fat high-sugar diet (WD), were used as fecal inoculum. 16S amplicon metagenomics sequencing showed that Fish oil + Pomegranate oil from the WD group increased α-diversity. This sample can also increase the relative abundance of the Firmicutes and Bacteroidetes phylum as well as Akkermansia and Blautia, which were affected by the WD consumption. All samples were able to increase butyrate and acetate concentration in the WD group. Moreover, tyrosine concentrations, a precursor for dopamine and norepinephrine, increase in the Fish oil + Pomegranate oil WD sample. GABA, an important neurotransmitter, was also increased in WD samples. These results suggest a potential positive impact of these oils' mixture on gut-brain axis modulation. It was demonstrated, for the first time, the great potential of using a mixture of both Fish and Pomegranate oil to restore the gut microbiota changes associated with WD consumption.

Study of gut microbiome alterations in plaque psoriasis patients compared to healthy individuals.

Many studies have shown significant alterations in the gut microbiome of patients with psoriasis compared to healthy controls. The primary objective of the current research was to explore the impact of gut microbiome composition on the progression and severity of plaque psoriasis. A total of 20 patients with moderate-to-severe psoriasis and 20 healthy individuals were recruited and provided a stool sample to assess the gut microbiome. After the samples were prepared according to the NGS library preparation workflow, they were sequenced using the Illumina platform and the report was generated that underwent statistical analysis. The microbiome profiles of psoriasis patients exhibited significant differences compared to healthy controls as evidenced by the statistical analysis of various bacterial genera, with the median abundance significantly lower in psoriasis patients compared to healthy controls (p = 0.033). The analysis of the Firmicutes-to-Bacteroidetes ratio, a commonly evaluated marker of dysbiosis, did not reach statistical significance (p = 0.239). However, there was a noticeable trend towards a higher median ratio in psoriasis patients compared to healthy controls. The ratio did not show significant associations with PASI or BSA but trends towards significance with DLQI (B = -12.11, p = 0.095). Overall, the above findings underscore the importance of the gut microbiome in psoriasis and suggest that modulation of specific bacterial genera, especially that with significant differences, could be a potential strategy for therapeutic intervention. Targeting these depleted genera through microbiome-based interventions, such as probiotic supplementation or faecal microbiota transplantation, could potentially help to restore gut homeostasis and alleviate the inflammatory burden in psoriasis.

Nové perspektivy v bariatricko-metabolické léčbě

Summary: Obesity is a chronic disease that affects millions of people worldwide and is associated with many health complications. The main goal of obesity treatment is to improve health by achieving and maintaining weight loss or through imposing metabolic changes. For treatment, there are several interventions available, such as diet and exercise, drug therapy, surgical procedures. If used as MONO therapy, they often show insufficiency to achieve/maintain adequate weight loss and/or metabolic improvement in long term. Patients seeking low invasive, however still efficient treatment or those with insufficient treatment results or side effects may, under view of new developments both in pharma and surgery, benefit from combined approach of both, anti-obesity medications and very low invasive bariatric-metabolic surgery, such as gastric plication (namely endoscopic plication), partial jejuno-ileal diversion and left gastric artery embolization. There are several new anti-obesity drugs that have been developed or are in development. These drugs target different pathways in the body, such as hormones, neurotransmitters, receptors, enzymes, i.e. to reduce food intake, increase energy expenditure, alter nutrient absorption. In bariatric-metabolic surgery new understanding of the mechanisms of action, which involve not only mechanical restriction or malabsorption, but also neurohormonal modulation, gut microbiome alteration, immune system regulation, and epigenetic changes is being applied to the treatment pathways. For optimal success, heterogeneity of treatment response needs to be incorporated into management plans. Low invasive bariatric-metabolic surgery combined with pharmacotherapy can lead to additive weight-loss benefits and less side effects and it usually works in synergy with medications. Thus, combined approach to obesity treatment that involves anti-obesity medications and BMS are complementary to each other. Laparoscopic PJID seems to be one of the promising non-drug interventions, especially for type 2 diabetic patients with poorly controlled diabetes. Pilot results at two, five and seven years are presented in the article. In 5 years after PJID mean BMI decreased by –12.4%. Mean HbA1c decreased in 2 years after the operation by mean of –2.48 (–32.3%), after 5 years by –3,51 (–45.8%) and in 7 years still decrease of –2.39 (–31.2%) was noted. Glycaemia decreased by mean of –2.5 mmol/l in 2 years, in 5 years postoperatively mean decrease was –4.8 (–44.0%) a in 7 years the mean decrease was – 5.5 mmol/l (–50.4%) in comparison with the pre-op values. Partial jejunal diversion provides an anatomy sparing, low risk, potentially reversible, metabolic procedure, especially in a view of potential use of magnetic approach. The operation does not neccessitate significant alterations in lifestyle, mineral and/or vitamin supplementation and offers rapid recovery. Anti-obesity medications may help prepare patients for bariatric surgery by inducing preoperative weight loss and reducing surgical risk and/or through leveraging treatment outcomes if used in the immediate postoperative period. May also help to prevent or treat weight regain after bariatric surgery by enhancing satiety and reducing hunger. In non-responders to medication before they get surgery may trigger respond to the medication after surgery. New obesity treatment model that utilizes combination of new drugs and low invasive treatment (such as surgical, endoscopic and other new technologies, e.i.magnetic surgery), can enhance and leverage treatment outcomes without increasing risks. Key words: obesity – bariatric-metabolic surgery – pharmacotherapy – combined treatment

Current Understating of Gut Microbiome Alterations and Therapeutic Approaches for Improving Human Health

Millions of microorganisms, including bacteria, fungi, and viruses compose the human gut microbiome. There is variation in the composition of species from the moment of birth throughout the whole human lifecycle. Gut microbiome play a central role in maintaining body equilibrium, influencing a range of physiological processes including metabolism, the maintenance of barriers, inflammation, and hematopoiesis, both within and outside the intestines. An imbalanced microbial environment within the gastrointestinal tract is at the core of numerous diseases, such as inflammatory bowel disorder, obesity, diabetes, and Clostridioides difficile infection, and plays a pivotal role in their development. In this review, we discuss the therapeutic approaches of gut microbiome-related therapies including fecal microbiota transplantation, anti-microbial therapies, prebiotics, probiotics and Dietary interventions to repair the altered gut microbiome composition. The pursuit of new therapies and their subsequent improvement is propelled by an ongoing requirement for evaluation, experimentation, laboratory procedures, and the ethical and technological limitations associated with clinical translation.

Gut microbiome and plasma metabolome alterations in myopic mice.

Myopia is one of the most common eye diseases leading to blurred distance vision. Inflammatory diseases could trigger or exacerbate myopic changes. Although gut microbiota bacteria are associated with various inflammatory diseases, little is known about its role in myopia. The mice were randomly divided into control and model groups, with the model group being attached-30D lens onto the eyes for 3 weeks. Then, mouse cecal contents and plasma were collected to analyze their intestinal microbiota and plasma metabolome. We identified that the microbial composition differed considerably between the myopic and non-myopic mice, with the relative abundance of Firmicutes phylum decreased obviously while that of Actinobacteria phylum was increased in myopia. Furthermore, Actinobacteria and Bifidobacterium were positively correlated with axial lengths (ALs) of eyeballs while negatively correlated with refractive diopters. Untargeted metabolomic analysis identified 141 differentially expressed metabolites, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed considerable enrichment mainly in amino acid metabolism pathways. Notably, pathways involved glutamate metabolism including "Glutamine and D-glutamate metabolism" and "Alanine, aspartate and glutamate metabolism" was changed dramatically, which presented as the concentrations of L-Glutamate and L-Glutamine decreased obviously in myopia. Interestingly, microbiome dysbiosis and metabolites alternations in myopia have a disrupting gut barrier feature. We further demonstrated that the gut barrier function was impaired in myopic mice manifesting in decreased expression of Occludin, ZO-1 and increased permeation of FITC-dextran. Myopic mice had obviously altered gut microbiome and metabolites profiles compared to non-myopic mice. The dysbiosis and plasma metabolomics shift in myopia had an interrupting gut barrier feature. Our study provides new insights into the possible role of the gut microbiota in myopia and reinforces the potential feasibility of microbiome-based therapies in myopia.

Dynamical alterations of brain function and gut microbiome in weight loss.

Intermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis. In this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples. Our results showed that IER longitudinally reduced the activity of obese-related brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes. There was dynamical alteration of BGM axis (the communication of E. coli with specific brain regions) during the weight loss under the IER.

Neuroblastoma is associated with alterations in gut microbiome composition subsequent to maternal microbial seeding

Neuroblastoma is the most frequent extracranial solid tumour in children, accounting for ∼15% of deaths due to cancer in childhood. The most common clinical presentation are abdominal tumours. An altered gut microbiome composition has been linked to multiple cancer types, and reported in murine models of neuroblastoma. Whether children with neuroblastoma display alterations in gut microbiome composition remains unexplored. We assessed gut microbiome composition by shotgun metagenomic profiling in an observational cross-sectional study on 288 individuals, consisting of patients with a diagnosis of neuroblastoma at disease onset (N=63), healthy controls matching the patients on the main covariates of microbiome composition (N=94), healthy siblings of the patients (N=13), mothers of patients (N=59), and mothers of the controls (N=59). We examined taxonomic and functional microbiome composition and mother-infant strain transmission patterns. Patients with neuroblastoma displayed alterations in gut microbiome composition characterised by reduced microbiome richness, decreased relative abundances of 18 species (including Phocaeicola dorei and Bifidobacterium bifidum), enriched protein fermentation and reduced carbohydrate fermentation potential. Using machine learning, we could successfully discriminate patients from controls (AUC=82%). Healthy siblings did not display such alterations but resembled the healthy control group. No significant differences in maternal microbiome composition nor mother-to-offspring transmission were detected. Patients with neuroblastoma display alterations in taxonomic and functional gut microbiome composition, which cannot be traced to differential maternal seeding. Follow-up research should include investigating potential causal links. Italian Ministry of Health Ricerca Corrente and Ricerca Finalizzata 5 per mille (to MPonzoni); Fondazione Italiana Neuroblastoma (to MPonzoni); European Research Council (ERC-StG project MetaPG-716575 and ERC-CoG microTOUCH-101045015 to NS); the European H2020 program ONCOBIOME-825410 project (to NS); the National Cancer Institute of the National Institutes of Health 1U01CA230551 (to NS); the Premio Internazionale Lombardia e Ricerca 2019 (to NS); the MIUR Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN) Bando 2017 Grant 2017J3E2W2 (to NS); EMBO ALTF 593-2020 and Knowledge Generation Project from the Spanish Ministry of Science and Innovation (PID2022-139328OA-I00) (to MV-C).

Midgut neuroendocrine tumor patients have a depleted gut microbiome with a discriminative signature

RationaleWhen compared to other types of cancer, the prevalence of midgut neuroendocrine tumors (NET) has disproportionally increased over the past decades. To date, there has been very little progress in discovering (epi)genetic drivers and treatment options for these tumors. Recent microbiome research has revealed that enteroendocrine cells communicate with the intestinal microbiome and has provided novel treatment targets for various other cancer types. Hence, our aim was to analyze the role of the gut microbiome in midgut NET patients. MethodsFecal samples, prospectively collected from patients and control subjects, were analyzed with next generation 16S sequencing. Patients with neuroendocrine carcinomas and recent antibiotics use were excluded. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between groups within the patient cohort. Results87 midgut NET patients and 95 controls were included. Midgut NET patients had a less rich and diverse gut microbiome than controls (p < 0.001). Moreover, we identified 31 differentially abundant species and a gut microbial signature consisting of 17 species that was predictive of midgut NET presence with an area under the receiver operating characteristic curve of 0.863. Gut microbial composition was not directly associated with the presence of the carcinoid syndrome, tumor grade or multifocality. Nonetheless, we did observe a potential link between microbial diversity and the presence of carcinoid syndrome symptoms within the subset of patients with elevated 5-hydroxyindolacetic acid levels. ConclusionMidgut NET patients have an altered gut microbiome which suggests a role in NET development and could provide novel targets for microbiome-based diagnostics and therapeutics.

Chronic jet lag alters gut microbiome and mycobiome and promotes the progression of MAFLD in HFHFD-fed mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide. Circadian disruptors, such as chronic jet lag (CJ), may be new risk factors for MAFLD development. However, the roles of CJ on MAFLD are insufficiently understood, with mechanisms remaining elusive. Studies suggest a link between gut microbiome dysbiosis and MAFLD, but most of the studies are mainly focused on gut bacteria, ignoring other components of gut microbes, such as gut fungi (mycobiome), and few studies have addressed the rhythm of the gut fungi. This study explored the effects of CJ on MAFLD and its related microbiotic and mycobiotic mechanisms in mice fed a high fat and high fructose diet (HFHFD). Forty-eight C57BL6J male mice were divided into four groups: mice on a normal diet exposed to a normal circadian cycle (ND-NC), mice on a normal diet subjected to CJ (ND-CJ), mice on a HFHFD exposed to a normal circadian cycle (HFHFD-NC), and mice on a HFHFD subjected to CJ (HFHFD-CJ). After 16 weeks, the composition and rhythm of microbiota and mycobiome in colon contents were compared among groups. The results showed that CJ exacerbated hepatic steatohepatitis in the HFHFD-fed mice. Compared with HFHFD-NC mice, HFHFD-CJ mice had increases in Aspergillus, Blumeria and lower abundances of Akkermansia, Lactococcus, Prevotella, Clostridium, Bifidobacterium, Wickerhamomyces, and Saccharomycopsis genera. The fungi-bacterial interaction network became more complex after HFHFD and/or CJ interventions. The study revealed that CJ altered the composition and structure of the gut bacteria and fungi, disrupted the rhythmic oscillation of the gut microbiota and mycobiome, affected interactions among the gut microbiome, and promoted the progression of MAFLD in HFHFD mice.

The gut microbiome and metabolites are altered and interrelated in patients with functional constipation.

Gut microbiota and metabolites have been identified to contribute to the pathogenesis of functional constipation (FC); however, the underlying mechanism(s) have not been elucidated, and the relationship between the gut microbiota and metabolites in FC has received limited attention in the literature. 16S rDNA sequencing and non-targeted metabolomic detection based on liquid chromatography-mass spectrometry (LC-MS/MS) technologies were combined to analyze the altered gut microbiome and metabolic profile of fecal samples from FC patients and healthy individuals (healthy control; HC). The richness and diversity of gut microbiota significantly (p < 0.01) increased in FC patients. Compared to the HC group, 18 genera, including Intestinibacter, Klebsiella, and Akkermansia, exhibited statistically significant changes (p < 0.05). Metabolic analysis showed that metabolic profiles were also markedly altered with 79 metabolites, such as (-)-caryophyllene oxide, chenodeoxycholic acid, and biliverdin, indicating significant inter-group differences (p < 0.05). Besides, the primary bile acid biosynthesis, as well as the metabolic profile of porphyrin and chlorophyll, were the most dominant enriched pathways (FDR < 0.01), in which chenodeoxycholic acid and biliverdin were significantly enriched, respectively. Correlation analysis demonstrated a strong relationship between 10 genera and 19 metabolites (r > 0.6, FDR < 0.05), and notably, Intestinibacter showed a negative correlation with biliverdin (FDR < 0.001), which highlighted the interplay of the gut microbiota and metabolites in the pathogenesis of FC. Our research describes the characteristics of the gut microbiota and metabolic profiles and the correlation between the gut microbiota and metabolites in FC patients. This may contribute to the understanding of the underlying mechanisms involved in FC pathogenesis and may provide novel insights into therapeutic interventions.

Correlation between gut microbiome and cognitive impairment in patients undergoing peritoneal dialysis

BackgroundGrowing evidence has demonstrated that patients undergoing peritoneal dialysis (PD) are more likely to experience cognitive impairment than patients with non-dialysis end-stage renal disease (ESRD); however, the underlying mechanisms remain unclear. This study aimed to identify the role and predictive significance of gut microbiome alterations in PD-associated cognitive impairment.MethodsA total of 29 non-dialysis ESRD patients and 28 PD patients were enrolled in this study and divided into subgroups according to the Montreal Cognitive Assessment (MoCA). Faecal samples were analyzed using 16 S rRNA. Mini-Mental State Examination (MMSE) and MoCA scores were used to assess the degree of cognitive impairment in patients.ResultsThe 16 S rRNA analysis demonstrated differences in gut microbiome abundance and structure between PD and non-dialysis ESRD patients and between PD patients with cognitive impairment (PCI) and PD patients with normal cognition (PNCI). At family and genus levels, Prevotellaceae exhibited the greatest structure difference, while Lactobacillus exhibited the greatest abundance difference between PCI and PNCI. Altered microbiota abundance significantly correlated with cognitive function and serum indicators in PD. In addition, different modules related to fatty acid, lipid, pantothenate, and coenzyme A biosynthesis, and tyrosine and tryptophan metabolism were inferred from 16 S rRNA data between PCI and PNCI. Both groups could be distinguished using models based on the abundance of Lactobacillaceae (Area under curve [AUC] = 0.83), Actinomycetaceae (AUC = 0.798), and Prevotellaceae (AUC = 0.778) families and Lactobacillus (AUC = 0.848) and Actinomyces (AUC = 0.798) genera.ConclusionGut microbiome evaluation could aid early cognitive impairment diagnosis in patients undergoing PD.

Gut microbiome alterations are differentially associated with handgrip strength and physical fitness

Gut microbiome alterations are differentially associated with handgrip strength and physical fitness

Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid β-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.

Mediterranean versus Western diet and the gut‐brain axis: Diet‐induced links between gut Oscillospira abundance, plasma branched‐chain amino acid concentrations and insulin resistance, and change in white matter volumes in nonhuman primates

AbstractBackgroundWestern vs. Mediterranean patterned diets have been associated with divergent effects on neurodegenerative diseases including Alzheimer’s Disease (AD). Such effects may be mediated through the gut microbiome, although the exact mechanisms linking diet, microbiome, and brain outcomes remain unclear. Oscillospira, a genus of gut‐dwelling bacteria, appears to be a good candidate which may help explain the mechanistic underpinnings of this relationship. Previous studies have shown associations between Oscillospira abundance, blood biomarkers, and brain physiology in rodents, and patients with neurodegenerative diseases including AD exhibit decreased gut Oscillospira abundances. Notably, Oscillospira may alter myelination by modifying branched‐chain amino acid (BCAA) concentrations in blood and preventing or minimizing insulin resistance.MethodIn the present study, we test a mechanistic role for Oscillospira on white matter volumes in cynomolgus monkeys (Macaca fascicularis) experimentally fed either a Mediterranean or Western‐type diet. We analyzed associations between gut Oscillospira abundances, plasma BCAA concentrations (i.e., leucine, isoleucine, and valine), plasma insulin, beta‐amyloid (Aβ) 42 to 40 ratio in cerebrospinal fluid (CSF), and magnetic resonance imaging‐derived white matter volumes.ResultWe found that Oscillospira abundance was significantly higher in the Mediterranean diet cohort than in the Western cohort (β = 0.258, SE = 0.084, p = 0.004). Oscillospira abundance was significantly negatively associated with plasma leucine (β = ‐0.169, SE = 0.059, p = 0.007) and valine concentrations (β = ‐0.206, SE = 0.069, p = 0.005); a similar, non‐significant (p = 0.066) trend was observed for isoleucine. Similarly, Oscillospira abundance was negatively associated with insulin area under the curve (AUC) at 26 months (β = ‐0.282, SE = 0.125, p = 0.031) and change in insulin AUC from baseline to 26 months (β = ‐14.6, SE = 6.97, p = 0.044), suggesting better insulin sensitivity in individuals with higher Oscillospira abundance. Oscillospira abundance was also positively associated with CSF Aβ42:40 ratio (β = 0.013, SE = 0.004, p = 0.007). Furthermore, the percent change in white matter volume over the study period was positively associated with Oscillospira abundance (β = 2.45, SE = 0.915, p = 0.012) and negatively associated with leucine (β = ‐2.39, SE = 0.920, p = 0.014), isoleucine (β = ‐2.67, SE = 0.895, p = 0.005), and valine concentrations (β = ‐2.28, SE = 0.929, p = 0.020) as well as change in insulin AUC (β = ‐2.04, SE = 0.947, p = 0.039).ConclusionThese results suggest that diet impacts the central nervous system by altering gut microbiome composition and highlight the complexity of relationships between BCAAs and brain health.

Altered intestinal microbiota enhances adenoid hypertrophy by disrupting the immune balance.

Adenoid hypertrophy (AH) is a common upper respiratory disorder in children. Disturbances of gut microbiota have been implicated in AH. However, the interplay of alteration of gut microbiome and enlarged adenoids remains elusive. 119 AH children and 100 healthy controls were recruited, and microbiome profiling of fecal samples in participants was performed using 16S rRNA gene sequencing. Fecal microbiome transplantation (FMT) was conducted to verify the effects of gut microbiota on immune response in mice. In AH individuals, only a slight decrease of diversity in bacterial community was found, while significant changes of microbial composition were observed between these two groups. Compared with HCs, decreased abundances of Akkermansia, Oscillospiraceae and Eubacterium coprostanoligenes genera and increased abundances of Bacteroides, Faecalibacterium, Ruminococcus gnavus genera were revealed in AH patients. The abundance of Bacteroides remained stable with age in AH children. Notably, a microbial marker panel of 8 OTUs were identified, which discriminated AH from HC individuals with an area under the curve (AUC) of 0.9851 in the discovery set, and verified in the geographically different validation set, achieving an AUC of 0.9782. Furthermore, transfer of mice with fecal microbiota from AH patients dramatically reduced the proportion of Treg subsets within peripheral blood and nasal-associated lymphoid tissue (NALT) and promoted the expansion of Th2 cells in NALT. These findings highlight the effect of the altered gut microbiota in the AH pathogenesis.

696. Effectiveness of Oral Vancomycin as Prophylaxis against Clostridioides difficile Infection in Hematopoietic Stem Cell Transplant Patients

Abstract Background Patients receiving hematopoietic stem cell transplants (HSCT) are at increased risk for Clostridioides difficile infection (CDI) due to decreased immune function, frequent exposure to broad-spectrum antibiotics and chemotherapy, prolonged hospitalizations, and alteration in gut microbiome. The purpose of this study was to assess the effectiveness of oral vancomycin prophylaxis (OVP) for CDI in all patients admitted for HSCT. Methods This was a single-center, retrospective, cohort study conducted at a tertiary care academic medical center in New Jersey. Medical records of patients admitted between June 2019 to August 2022 to undergo an allogeneic or autologous HSCT were reviewed. Universal OVP from admission to discharge for HSCT patients began December 2019. Patients ≥ 18 years at the time of admission for the HSCT were included. Patients who were admitted less than 72 hours or who were being treated for an active CDI prior to HSCT were excluded. The primary endpoint was the incidence of in-hospital CDI. Secondary endpoints included incidence of vancomycin-resistant enterococci (VRE) bloodstream infections, VRE isolated from any clinical culture, gram-negative bloodstream infections, hospital survival, and hospital length of stay. Exploratory endpoints including one-year survival, relapse, and incidence of graft-versus-host disease were also collected. Confounding by relevant covariates were assessed and controlled for in a multivariable regression model. Results A total of 132 HSCT patients were included. There was one case (1/68, 1.47%) of CDI in the prophylaxis group compared to six CDI cases (6/64, 9.38%) in the no prophylaxis group (P=0.057). There were no significant (P&amp;gt;0.05) between-group differences of incidence of gram-negative bloodstream infections, hospital survival, and length of stay. There were zero clinical cultures positive for VRE in either group. Conclusion In-hospital incidence of CDI in HSCT patients was decreased with the use of OVP but did not meet statistical significance. Randomized controlled trials are needed in this high-risk patient population to assess the efficacy and long-term risks of OVP for CDI. Disclosures Pinki Bhatt, MD, Sanofi: Grant/Research Support Navaneeth Narayanan, PharmD, MPH, BCIDP, Astellas: Honoraria|Beckman Coulter: Honoraria|Merck: Grant/Research Support|Shionogi: Grant/Research Support

Engraftment of aging-related human gut microbiota and the effect of a seven-species consortium in a pre-clinical model

ABSTRACT Human aging is characterized by gut microbiome alteration and differential loss of gut commensal species associated with the onset of frailty. The administration of cultured commensal strains to replenish lost taxa could potentially promote healthy aging. To investigate the interaction of whole microbiomes and administered strains, we transplanted gut microbiota from a frail or healthy elderly subject into germ-free mice. We supplemented the frail-donor recipient group with a defined consortium of taxa (the “S7”) that we identified by analyzing healthy aging subjects in our previous studies and whose abundance correlated with health-promoting dietary intervention. Inoculation with a frail or a healthy donor microbiome resulted in differential microbiota compositions in murine recipients 5 weeks post-transplantation. Fecal acetate levels were significantly higher in healthy donor recipient mice than in frail donor recipient mice after 4 weeks. However, the frailty-related phenotype was not replicated in recipient mice with single-dose microbiota transplantation from a healthy and a frail donor. Five S7 species colonized successfully in germ-free mice, with a relatively high abundance of Barnesiella intestinihominis and Eubacterium rectale. The engraftment of five S7 species in germ-free mice increased fecal acetate levels and reduced colon permeability and plasma TNF-ɑ concentration. Supplementation with the S7 in frail-microbiota recipient mice did not increase alpha-diversity but significantly increased the abundance of Barnesiella intestinihominis. S7 supplementation showed the potential for improving spatial reference memory in frail-microbiota recipient mice. Collectively, these data highlight the challenge of elderly microbiota engraftment in the germ-free mouse model but show promise for modulating the gut microbiome of frail elderly subjects by administering an artificial gut microbe consortium associated with healthy aging.

Altered gut microbiome associated with metabolic-associated fatty liver disease in Chinese children

Limited studies have investigated the association between gut microbiota and metabolic dysfunction-associated fatty liver disease (MAFLD) in children and adolescents. We aimed to identify differences in gut microbiota composition and diversity between children with MAFLD and healthy counterparts. Data were collected from a nested case-control study (October to December, 2021) of the "Huantai Childhood Cardiovascular Health Cohort Study" in Huantai County, Zibo City, China. The study included 52 children aged 5-11 years with new-onset MAFLD and 52 healthy children matched by age and sex. Stool samples were collected and analyzed using 16S rRNA gene sequencing. Shannon index and Chao index were used to assess the α diversity of gut microbiota and Principal coordinates analysis (PCoA) was performed to evaluate β diversity between the two groups. The differences in the relative abundance of gut microbiota between MAFLD group and control group were compared by the Wilcoxon rank-sum test after false discovery rate (FDR) correction. Additionally, the gut-microbial metabolic pathways were identified using the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). We found that children with MAFLD had significant different gut microbiota composition and reduced α diversity compared with the control group. PCoA showed that the two groups can be significantly distinguished based on the unweighted unifrac distance algorithm. Gut microbiota at the phylum level such as Verrucomicrobia and Desulfobacterial, genus level such as Blautia, Lachnospiraceae_NK4A136_group, Coprococcus, Erysipelotrichaceae_UCG-003, UCG-002 and Akkermansia, and species level such as Bifidobacterium_longum abundances were significantly decreased in children with MAFLD compared with that in children without MAFLD. Notably, the abundance of these bacteria were found to be associated with HDL-C, SBP, DBP, WC, BMI, etc. In addition, our analysis of gut-microbial metabolic pathways identified differences in carbohydrate transport and metabolism, as well as amino acid transport and metabolism between the two groups. Significant differences in gut microbiota composition are observed between children with and without MAFLD, which indicate that gut microbiota may be a potential contributor to the development of MAFLD in childhood.

Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.

Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70-/- mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70-/- mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70-/- mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (-99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70-/- mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70-/- mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70-/- mice. In conclusion, depletion of gut microbiota in Cyp2c70-/- mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.

15 Effects of the Maternal Gut and Reproductive Microbiome on Postnatal Development in Ruminants

Abstract The microbial communities residing within the gastrointestinal and reproductive tracts are vital to cattle health; not only for their involvement in nutrient metabolism, but also for their ability to influence infectious and metabolic diseases as well as reproductive efficiency. Therefore, harnessing the ruminal and vagino-uterine microbiomes for improved cattle health and productivity have recently become an active area of research in an era where microbiome manipulation holds as much potential as genetic selection and management refinement for enhancing herd productivity. New developments highlight that the maternal gut and reproductive microbiome extend their impact to offspring development and health. These developments include the demonstrations of maternal gut microbiota involvement in developmental programming in murine models, and increased evidence supporting the existence of in utero microbial colonization and the role of maternal nutrition on fetal programming in cattle. Our recent work has focused on understanding the role of the maternal microbiota and feto-maternal microbial crosstalk in fetal programming and offspring microbiome development. Our lab has investigated the impacts of maternal dietary restriction, supplementation of one carbon metabolites or vitamins and minerals during gestation on maternal ruminal and vaginal microbiota; as well as pre- and postnatal microbial colonization in offspring calves. Our results indicate that maternal dietary alterations during pregnancy may influence ruminal and vaginal microbiota of dams, which may subsequently impact early life microbial colonization in calves being gestated. Our findings call for further research in the area of maternal gut and reproductive microbiome alterations and their impacts on fetal programming and offspring development in ruminants.