Microbiome Ecosystem Research Articles

The Contribution of Intestinal Barrier and Microbiome Ecosystem in Progression of Chronic Kidney Disease

Abstract Background The introduction of concepts such as “Intestinal renal syndrome” and “The gut-kidney axis” has opened the door to the study of gut microbiota and intestinal barrier integrity. Aim This study is to focus on these two keys which link the interaction between CKD and intestine. Material and Methods This study was carried out on 20 adult male albino rats initially weighing 180 - 193 grams that were divided into sham operated (control) and 5/6th nephrectomized rats. After 8 weeks, all rats were subjected to anthropometric studies, measurement of serum level of creatinine, urea, NGAL, indoxyl sulphate, urine volume, eGFR, aIb/Cr ratio and arterial blood pressure. Serum SCFA an indicator for microbiome disturbances and tissue occludine an indicator for intestinal barrier as well as histological study to the wall of colon were determined. Also, serum TNF α, MDA, glutathione peroxidase was measured as possible interactive mechanism. Results In the present study, nephrectomy group showed significant decrease in body weight and body mass index gain compared to control group. In addition, 5/6th nephrectomy showed significant increase in mean arterial blood pressure and the levels of serum creatinine, urea, NGAL, indoxyl sulphate, alb / cr ratio, malondialdehyde and TNF- α. While volume of urine, eGFR and level of serum GPx were significantly decreased. Moreover, with nephrectomy SCFA in serum and intestinal tissue level of occludine were significantly reduced and the histological studies showed decreased thickness of mucosa, reduced number of goblet cell and increased inflammatory cell infiltration. Conclusion CKD could be considered as one of the chronic stressors affecting gut microbiota production of SCFA and intestinal barrier integrity marker and histology through the induction of gut inflammation and oxidative stress. This study provides a theoretical basis for subsequent targeted treatment.

Affective symptoms in pregnancy are associated with the vaginal microbiome

BackgroundComposition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Therefore, identifying sources of individual differences in the vaginal microbiome is of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure. MethodsData were based on a prospective longitudinal study of a medically healthy community sample of 275 mother-infant pairs. Affective symptoms and stress exposure and select measures of associated biomarkers (diurnal salivary cortisol, serum measures of sex hormones) were collected at each trimester; self-report, clinical, and medical records were used to collect detailed data on socio-demographic factors and health behavior, including diet and sleep. Vaginal microbiome samples were collected in the third trimester (34–40 weeks) and characterized by 16S rRNA sequencing. Identified taxa were clustered into three community clusters (CC1–3) based on dissimilarity of vaginal microbiota composition. ResultsResults indicate that depressive symptoms during pregnancy were reliably associated with individual taxa and CC3 in the third trimester. Prediction of functional potential from 16S taxonomy revealed a differential abundance of metabolic pathways in CC1–3 and individual taxa, including biosynthetic pathways for serotonin and dopamine. We did not find robust evidence linking symptom- and stress-related biomarkers and CCs. ConclusionsOur results provide further evidence of how prenatal psychological distress during pregnancy alters the maternal-fetal microbiome ecosystem that may be important for understanding maternal and child health outcomes.

Reduction of product composition variability using pooled microbiome ecosystem therapy and consequence in two infectious murine models.

Growing evidence demonstrates the key role of the gut microbiota in human health and disease. The recent success of microbiotherapy products to treat recurrent Clostridioides difficile infection has shed light on its potential in conditions associated with gut dysbiosis, such as acute graft-versus-host disease, intestinal bowel diseases, neurodegenerative diseases, or even cancer. However, the difficulty in defining a "good" donor as well as the intrinsic variability of donor-derived products' taxonomic composition limits the translatability and reproducibility of these studies. Thus, the pooling of donors' feces has been proposed to homogenize product composition and achieve higher taxonomic richness and diversity. In this study, we compared the metagenomic profile of pooled products to corresponding single donor-derived products. We demonstrated that pooled products are more homogeneous, diverse, and enriched in beneficial bacteria known to produce anti-inflammatory short chain fatty acids compared to single donor-derived products. We then evaluated pooled products' efficacy compared to corresponding single donor-derived products in Salmonella and C. difficile infectious mouse models. We were able to demonstrate that pooled products decreased pathogenicity by inducing a structural change in the intestinal microbiota composition. Single donor-derived product efficacy was variable, with some products failing to control disease progression. We further performed in vitro growth inhibition assays of two extremely drug-resistant bacteria, Enterococcus faecium vanA and Klebsiella pneumoniae oxa48, supporting the use of pooled microbiotherapies. Altogether, these results demonstrate that the heterogeneity of donor-derived products is corrected by pooled fecal microbiotherapies in several infectious preclinical models.IMPORTANCEGrowing evidence demonstrates the key role of the gut microbiota in human health and disease. Recent Food and Drug Administration approval of fecal microbiotherapy products to treat recurrent Clostridioides difficile infection has shed light on their potential to treat pathological conditions associated with gut dysbiosis. In this study, we combined metagenomic analysis with in vitro and in vivo studies to compare the efficacy of pooled microbiotherapy products to corresponding single donor-derived products. We demonstrate that pooled products are more homogeneous, diverse, and enriched in beneficial bacteria compared to single donor-derived products. We further reveal that pooled products decreased Salmonella and Clostridioides difficile pathogenicity in mice, while single donor-derived product efficacy was variable, with some products failing to control disease progression. Altogether, these findings support the development of pooled microbiotherapies to overcome donor-dependent treatment efficacy.

Abstract 6687: Evaluation of a new co-cultured microbiome ecosystem therapy candidate (MaaT034) for clinical testing as adjuvant/neoadjuvant to immune checkpoint inhibitors in solid tumors

Abstract Background: Increasing evidence suggests that gut microbiome composition modulates tumor response to therapies, including immune checkpoint inhibitors (ICI). Clinical proofs of concept were obtained in pilot studies using healthy or ICI-responder donor-derived fecal matter transplants to modulate the gut microbiome of non-responding cancer patients and improve their response to ICI. These results support the development of Microbiome Ecosystem TherapiesTM (MET) replicating at large industrial scale the effects of ICI-responders gut microbiome. MaaT Pharma, a clinical-stage biotech, has developed a unique, ground-breaking, patented co-culture process (MET-C). MaaT034, the first-in-class co-cultured microbiome product, has been selected for optimizing intestinal homeostasis and to activate immune functions alone and in combination with an ICI treatment. Method: We combined metagenomic analysis, metabolite quantification by LC-MRM/MS, Caco-2/THP-1 leaky gut model, PBMC assay and mixed lymphocyte reaction (MLR) to assess the impact of MaaT034 on gut homeostasis and immune activation. Results: Metagenomic analysis demonstrates that MaaT034 replicates the richness and diversity of native-based microbiome ecosystems. Metabolite quantification also revealed that MaaT034 microbes secrete anti-inflammatory metabolites such as short chain fatty acids and indoles, as well as metabolites associated with ICI response such as secondary biliary acids. Using a Caco-2/THP-1 leaky gut model, we then demonstrate that MaaT034 conditioned medium was able to restore the integrity of a THP-1-induced damaged gut barrier. This was associated with and a reduction of inflammatory signals. We further performed a human PBMC assay to evaluate the impact of MaaT034 on immune cell activation. We observed the secretion of immunostimulatory cytokines associated with myeloid cell activation in response to MaaT034 conditioned medium. Notably, anti-CD3 mediated T-cells activation was further increased in response to MaaT034 conditioned medium as evidenced by increased IFNγ release associated with increased Granzyme B and CD25. Finally, MLR was performed to determine the immunomodulatory potential of MaaT034 through the interaction between T-cells and monocytes-derived dendritic cells (moDC). Interestingly, MaaT034 conditioned medium improved moDC maturation as well as moDC-induced T-cell activation. MaaT034 conditioned medium further increased anti-PD-1 mediated T-cell activation, as evidenced by IFNγ release. Conclusion: Altogether, these results highlight the potential of MaaT034 to produce metabolites involved in the restoration of gut barrier integrity and stimulation of immune cell response to ICI therapy, with potential benefit for solid tumors treatment. Citation Format: Bastien Laperrousaz, Julie Reygner, Cyrielle Gasc, Charlotte Petitjean, Aurore Duquenoy, Lora Martin, Vincent Bonnaud, Marianne Robin, Sophie Declomesnil, Carole Schwintner, Nathalie Corvaïa. Evaluation of a new co-cultured microbiome ecosystem therapy candidate (MaaT034) for clinical testing as adjuvant/neoadjuvant to immune checkpoint inhibitors in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6687.

Interactions Between Oral Microbiota and Cancers in the Aging Community: A Narrative Review.

The oral microbiome potentially wields significant influence in the development of cancer. Within the human oral cavity, an impressive diversity of more than 700 bacterial species resides, making it the second most varied microbiome in the body. This finely balanced oral microbiome ecosystem is vital for sustaining oral health. However, disruptions in this equilibrium, often brought about by dietary habits and inadequate oral hygiene, can result in various oral ailments like periodontitis, cavities, gingivitis, and even oral cancer. There is compelling evidence that the oral microbiome is linked to several types of cancer, including oral, pancreatic, colorectal, lung, gastric, and head and neck cancers. This review discussed the critical connections between cancer and members of the human oral microbiota. Extensive searches were conducted across the Web of Science, Scopus, and PubMed databases to provide an up-to-date overview of our understanding of the oral microbiota's role in various human cancers. By understanding the possible microbial origins of carcinogenesis, healthcare professionals can diagnose neoplastic diseases earlier and design treatments accordingly.

Oropharyngeal microbial ecosystem perturbations influence the risk for acute respiratory infections in common variable immunodeficiency.

The respiratory tract microbiome is essential for human health and well-being and is determined by genetic, lifestyle, and environmental factors. Patients with Common Variable Immunodeficiency (CVID) suffer from respiratory and intestinal tract infections, leading to chronic diseases and increased mortality rates. While CVID patients' gut microbiota have been analyzed, data on the respiratory microbiome ecosystem are limited. This study aims to analyze the bacterial composition of the oropharynx of adults with CVID and its link with clinical and immunological features and risk for respiratory acute infections. Oropharyngeal samples from 72 CVID adults and 26 controls were collected in a 12-month prospective study. The samples were analyzed by metagenomic bacterial 16S ribosomal RNA sequencing and processed using the Quantitative Insights Into Microbial Ecology (QIME) pipeline. Differentially abundant species were identified and used to build a dysbiosis index. A machine learning model trained on microbial abundance data was used to test the power of microbiome alterations to distinguish between healthy individuals and CVID patients. Compared to controls, the oropharyngeal microbiome of CVID patients showed lower alpha- and beta-diversity, with a relatively increased abundance of the order Lactobacillales, including the family Streptococcaceae. Intra-CVID analysis identified age >45 years, COPD, lack of IgA, and low residual IgM as associated with a reduced alpha diversity. Expansion of Haemophilus and Streptococcus genera was observed in patients with undetectable IgA and COPD, independent from recent antibiotic use. Patients receiving azithromycin as antibiotic prophylaxis had a higher dysbiosis score. Expansion of Haemophilus and Anoxybacillus was associated with acute respiratory infections within six months. CVID patients showed a perturbed oropharynx microbiota enriched with potentially pathogenic bacteria and decreased protective species. Low residual levels of IgA/IgM, chronic lung damage, anti antibiotic prophylaxis contributed to respiratory dysbiosis.

A Multicentre, Randomized, Double-Blinded, Phase 2b Study Evaluating the Efficacy and Safety of MaaT033, an Oral, Pooled Microbiome Ecosystem Therapy in Patients Undergoing Allogenic Hematopoietic Cell Transplantation to Improve Overall Survival: The Phoebus Trial

Background and significance: Allogenic hematopoietic cell transplantation (alloHCT) is a well-established therapy for various life-threatening hematologic malignancies. The use of alloHCT is constantly increasing, with nearly 20 000 transplantations reported to the European Society for Blood and Marrow Transplantation (EBMT) per year. However, this treatment is limited by high morbidity and mortality, mainly related to relapse, infection, graft-versus-host disease (GvHD), and conditioning-related toxicity. Several pioneering studies have shown that the diversity of the gut microbiota of patients not only correlates with the occurrence of medical complications after alloHCT, including GvHD (Jenq et al. 2012, Stein-Thoeringer et al. 2019) and bloodstream infections (Taur et al. 2012), but also with relapse of the underlying disease (Peled et al. 2017). Gut microbiota diversity restoration with fecal microbiotherapy could be an effective treatment to improve patients' clinical outcomes including overall survival (OS) after alloHCT, through the prevention and resolution of gut microbiota dysbiosis. MaaT033 is a freeze-dried, full-ecosystem, high-diversity, fecal microbiota medicinal product, formulated as delayed-release capsules and derived from pooled allogenic human fecal material. The PHOEBUS trial is a phase 2b study to evaluate the efficacy of MaaT033 in improving survival of adult alloHCT patients (Clinicaltrials.gov identifier: NCT05762211) Study design and Methods: 387 subjects aged ≥ 50 years with hematologic malignancies for which an alloHCT is indicated will be randomized 1:1 to receive either MaaT033 (experimental arm) or placebo (control arm) before initiation of the conditioning regimen and after hematopoietic recovery following alloHCT. Stratification of patients will be performed based on disease risk index (low-intermediate versus high-very high) and donor-host compatibility (HLA-identical versus HLA-mismatch). Inclusion criteria include age ≥ 50 years, alloHCT with a reduced-toxicity or reduced-intensity conditioning regimen, neutrophils > 0.5 G/L, and administration of broad-spectrum antibiotics within the last 90 days prior to inclusion. Exclusion criteria comprise non-myeloablative conditioning regimen, conventional myeloablative conditioning regimen, in-vitro T-cell depletion, alloHCT with cord blood cells, alloHCT from an unrelated donor with ≥ 3/10 HLA-mismatches, use of alemtuzumab, vedolizumab or abatacept for GvHD prophylaxis, history of chronic digestive disease. The primary endpoint is to evaluate OS at 12 months after randomization. Secondary endpoints will include evaluation of the safety of MaaT033, GvHD-free survival, cumulative incidence of acute GvHD and chronic GvHD, non-relapse mortality, relapse-free survival, GvHD-free, relapse-free survival, the proportion of patients with severe infections, gut microbiota composition, and quality of life. Exploratory endpoints will describe the impact of MaaT013 on immune recovery, the nutritional status of the patients, and resource utilization. Patients will receive MaaT033 or placebo (3 capsules per day) for 1 week before the start of the conditioning regimen. Experimental treatment (3 capsules per day) will be resumed at neutrophil recovery and pursued up to 90 days after alloHCT. Patients will be followed monthly up to 6 months post alloHCT and then every 3 months up to 12 months. The study is approved in France and Germany; expansion to other countries is planned for 2024. Study start is expected in September 2023.

Development of Gut Microbiota in the First 1000 Days after Birth and Potential Interventions.

The first 1000 days after birth represent a critical window for gut microbiome development, which is essential for immune system maturation and overall health. The gut microbiome undergoes major changes during this period due to shifts in diet and environment. Disruptions to the microbiota early in life can have lasting health effects, including increased risks of inflammatory disorders, autoimmune diseases, neurological disorders, and obesity. Maternal and environmental factors during pregnancy and infancy shape the infant gut microbiota. In this article, we will review how maintaining a healthy gut microbiome in pregnancy and infancy is important for long-term infant health. Furthermore, we briefly include fungal colonization and its effects on the host immune function, which are discussed as part of gut microbiome ecosystem. Additionally, we will describe how potential approaches such as hydrogels enriched with prebiotics and probiotics, gut microbiota transplantation (GMT) during pregnancy, age-specific microbial ecosystem therapeutics, and CRISPR therapies targeting the gut microbiota hold potential for advancing research and development. Nevertheless, thorough evaluation of their safety, effectiveness, and lasting impacts is crucial prior to their application in clinical approach. The article emphasizes the need for continued research to optimize gut microbiota and immune system development through targeted early-life interventions.

The Gut Microbiome and Mental Health.

The gut microbiome has been well researched in the past few years and may be a target for treating mental illness. Trillions of bacteria in the digestive system work with the brain, immune function, and endocrine pathways. This gut microbiome ecosystem mediates the interaction between the human being and the environment making its inclusion in holistic nursing essential. Changes in normal balance of the gut microbiome occur with diet, antibiotics and other medications, stress, cancer treatment, geography and environment, and current illnesses. When the microbiome is challenged a "dysbiotic" state leads to inadequate production of needed neurotransmitters such as serotonin and dopamine. Research has shown links between the dysbiosis, and the inflammatory response system that are known to contribute to depression, anxiety, and schizophrenia. Understanding the role of the gut microbiome can be beneficial to holistic nurses, providing a new tool to prevent, treat, or reduce symptoms of mental illness and improve general immune function. This innocuous holistic approach to mental wellness is becoming an important evidenced-based approach.

Antifungal Activity and Alleviation of Salt Stress by Volatile Organic Compounds of Native Pseudomonas Obtained from Mentha piperita.

As salt stress has a negative impact on plant growth and crop yield, it is very important to identify and develop any available biotechnology which can improve the salt tolerance of plants. Inoculation with plant-growth-promoting rhizobacteria (PGPR) is a proven environmentally friendly biotechnological resource for increasing the salt stress tolerance of plants and has a potential in-field application. In addition, bacterial volatile organic compounds (mVOCs) are signal molecules that may have beneficial roles in the soil-plant-microbiome ecosystem. We investigated the effects of mVOCs emitted by Pseudomona putida SJ46 and SJ04 on Mentha piperita grown under different levels of NaCl stress by evaluating their growth-promoting potential and capacity to increase salt tolerance effects. Furthermore, we evaluated under control and salt stress conditions the biocontrol ability of VOCs emitted by both these strains to inhibit the growth of Alternaria alternata and Sclerotium rolfsii. The VOCs emitted by both strains under control conditions did not lead to an significant improvement in peppermint growth. However, under salt stress conditions (75 or 100 mM NaCl), an amelioration of its physiological status was observed, with this effect being greater at 100 mM NaCl. This led to an enhancement of the number of leaves and nodes and, increased the shoot fresh and root dry weight by approximately twice in relation to control stressed plants. Moreover, the VOCs released by the two bacteria grown in control or saline media showed a significant reduction in the mycelial growth of A. alternata. In contrast, S. rolfsii growth was reduced 40% by the mVOCs released only under control conditions, with no effects being observed under salt stress. We also explored the composition of the bacterial volatile profiles by means of a solid-phase microextraction/gas chromatography-mass spectrometry (SPME/GC-MS) analysis. From the headspace of SJ46, three VOCs were identified: n-octanol, decane and tetradecane. The emission of SJ04 had the same chromatographic profile, with the addition of two more compounds: 1-(N-phenyl carbamyl)-2-morpholino cyclohexene and tridecane. Only compounds that were not present in the headspace of the control groups were recorded. The salt stress conditions where the bacteria were grown did not qualitatively modify the mVOC emissions. Taken together, our results suggest that plant-associated rhizobacterial VOCs play a potentially important role in modulating plant salt tolerance and reducing fungal growth. Thus, biological resources represent novel tools for counteracting the deleterious effects of salt stress and have the potential to be exploited in sustainable agriculture. Nevertheless, future studies are necessary to investigate technological improvements for bacterial VOC application under greenhouse and open field conditions.

Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma.

The rate at which obesity is becoming an epidemic in many countries is alarming. Obese individuals have a high risk of developing elevated intraocular pressure and glaucoma. Additionally, glaucoma is a disease of epidemic proportions. It is characterized by neurodegeneration and neuroinflammation with optic neuropathy and the death of retinal ganglion cells (RGC). On the other hand, there is growing interest in microbiome dysbiosis, particularly in the gut, which has been widely acknowledged to play a prominent role in the etiology of metabolic illnesses such as obesity. Recently, studies have begun to highlight the fact that microbiome dysbiosis could play a critical role in the onset and progression of several neurodegenerative diseases, as well as in the development and progression of several ocular disorders. In obese individuals, gut microbiome dysbiosis can induce endotoxemia and systemic inflammation by causing intestinal barrier malfunction. As a result, bacteria and their metabolites could be delivered via the bloodstream or mesenteric lymphatic vessels to ocular regions at the level of the retina and optic nerve, causing tissue degeneration and neuroinflammation. Nowadays, there is preliminary evidence for the existence of brain and intraocular microbiomes. The altered microbiome of the gut could perturb the resident brain-ocular microbiome ecosystem which, in turn, could exacerbate the local inflammation. All these processes, finally, could lead to the death of RGC and neurodegeneration. The purpose of this literature review is to explore the recent evidence on the role of gut microbiome dysbiosis and related inflammation as common mechanisms underlying obesity and glaucoma.

Stool energy density is positively correlated to intestinal transit time and related to microbial enterotypes

BackgroundIt has been hypothesised that the gut microbiota causally affects obesity via its capacity to extract energy from the diet. Yet, evidence elucidating the role of particular human microbial community structures and determinants of microbiota-dependent energy harvest is lacking.ResultsHere, we investigated whether energy extraction from the diet in 85 overweight adults, estimated by dry stool energy density, was associated with intestinal transit time and variations in microbial community diversity and overall structure stratified as enterotypes. We hypothesised that a slower intestinal transit would allow for more energy extraction. However, opposite of what we expected, the stool energy density was positively associated with intestinal transit time. Stratifications into enterotypes showed that individuals with a Bacteroides enterotype (B-type) had significantly lower stool energy density, shorter intestinal transit times, and lower alpha-diversity compared to individuals with a Ruminococcaceae enterotype (R-type). The Prevotella (P-type) individuals appeared in between the B- and R-type. The differences in stool energy density between enterotypes were not explained by differences in habitual diet, intake of dietary fibre or faecal bacterial cell counts. However, the R-type individuals showed higher urinary and faecal levels of microbial-derived proteolytic metabolites compared to the B-type, suggesting increased colonic proteolysis in the R-type individuals. This could imply a less effective colonic energy extraction in the R-type individuals compared to the B-type individuals. Notably, the R-type had significantly lower body weight compared to the B-type.ConclusionsOur findings suggest that gut microbial energy harvest is diversified among individuals by intestinal transit time and associated gut microbiome ecosystem variations. A better understanding of these associations could support the development of personalised nutrition and improved weight-loss strategies.94Sar5PFK32y4TFUjWsEvSVideo

Soil Layers Impact Lithocarpus Soil Microbial Composition in the Ailao Mountains Subtropical Forest, Yunnan, China

Plant litter decomposition is a complex, long-term process. The decomposition of litterfall is a major process influencing nutrient balance in forest soil. The soil microbiome is exceptionally diverse and is an essential regulator of litter decomposition. However, the microbiome composition and the interaction with litterfall and soil remain poorly understood. In this study, we examined the bacterial and fungal community composition of Lithocarpus across soil samples from different sampling seasons. Our results displayed that the microbiome assembly along the soil layer is influenced predominantly by the soil layer rather than by the sampling season. We identified that the soil layer strongly affected network complexity and that bacterial and fungal microbiomes displayed different patterns in different soil layers. Furthermore, source tracking and community composition analysis indicated that there are significantly different between soil and litter. Moreover, our results demonstrate that few dominant taxa (2% and 4% of bacterial and fungal phylotypes) dominated in the different soil layers. Hydnodontaceae was identified as the most important biomarker taxa for humic fragmented litter fungal microbiome and Nigrospora and Archaeorhizomycetaceae for organic soil and the organic mineral soil layer, and the phylum of Acidobacteria for the bacteria microbiome. Our work provides comprehensive evidence of significant microbiome differences between soil layers and has important implications for further studying soil microbiome ecosystem functions.

Host innate and adaptive immunity shapes the gut microbiota biogeography.

The gut microbiota has a fundamental role in the development and the maturation of the host immune system. Both innate and adaptive immune cells have critical functions in microbial pathogen containment and clearance, but the regulation of the commensal microbiome ecosystem in the gastrointestinal tract by these major immune cell populations is incompletely defined. The role of specific innate and adaptive immune cell in the regulation of the microbiota in the intestinal tract biogeographically was investigated. Dendritic cells, macrophages, CD4+ T-cells, CD8+ T-cells, and B-cells were depleted using monoclonal antibodies and clodronate liposomes, and the microbial communities were determined by 16S rRNA gene sequencing. With specific immune cell depletion, distinct microbiota changes were observed. In general, immune cell depleted mice had higher microbiota richness and evenness at all gut anatomical sites. At each gut segment, samples from immune cell-depleted animals clustered away from the isotype/liposome control mice. This was especially dramatic for the small intestinal microbiota. Specifically, Enterobacteriaceae, Bacteroides acidifaciens, and Mucispirillum schaedleri were highly enriched in the mucosa and lumen of the small intestine in immune cell-deficient animals. Further, the mucosal microbiota had higher microbiota evenness compared with luminal microbiota at all gut segments, and the UniFrac distance between B cell depleted and isotype control mice was the largest in the duodenum followed by the ileum and colon. Taken together, the data suggest that innate and adaptive immune cells specifically contribute to the regulation of the gut microbiota's biogeographical distribution along the gastrointestinal tract, and microbiota in the duodenum mucosa are more responsive to host immune changes compared with other anatomical sites.

A randomized controlled trial for response of microbiome network to exercise and diet intervention in patients with nonalcoholic fatty liver disease

Exercise and diet are treatments for nonalcoholic fatty liver disease (NAFLD) and prediabetes, however, how exercise and diet interventions impact gut microbiota in patients is incompletely understood. We previously reported a 8.6-month, four-arm (Aerobic exercise, n = 29; Diet, n = 28; Aerobic exercise + Diet, n = 29; No intervention, n = 29) randomized, singe blinded (for researchers), and controlled intervention in patients with NAFLD and prediabetes to assess the effect of interventions on the primary outcomes of liver fat content and glucose metabolism. Here we report the third primary outcome of the trial—gut microbiota composition—in participants who completed the trial (22 in Aerobic exercise, 22 in Diet, 23 in Aerobic exercise + Diet, 18 in No Intervention). We show that combined aerobic exercise and diet intervention are associated with diversified and stabilized keystone taxa, while exercise and diet interventions alone increase network connectivity and robustness between taxa. No adverse effects were observed with the interventions. In addition, in exploratory ad-hoc analyses we find that not all subjects responded to the intervention in a similar manner, when using differentially altered gut microbe amplicon sequence variants abundance to classify the responders and low/non-responders. A personalized gut microbial network at baseline could predict the individual responses in liver fat to exercise intervention. Our findings suggest an avenue for developing personalized intervention strategies for treatment of NAFLD based on host-gut microbiome ecosystem interactions, however, future studies with large sample size are needed to validate these discoveries. The Trial Registration Number is ISRCTN 42622771.

Lower Genital Tract Microbiome—A Work in Progress

The lower genital tract microbiome is composed of millions upon millions of microbes colonizing this unique anatomical niche reflecting the influence of genetic, biologic, and behavioral factors. Over the last decade, as a result of ever advancing technology and research investment, our knowledge of this complex microbiome ecosystem has grown enormously. All too often such progress remains invisible to practitioners. In this special issue, clinical scientists, in a unique contribution, have bridged the ever-increasing distance between vaginal microbiota science and clinical disease. Approaching a myriad of pathologic entities, authors describe the clinical application of recent molecular laboratory findings encouraging diagnostic, prognostic, and therapeutic advances. Nevertheless, challenges are recognized and the authors outline vulvovaginal disease management opportunities. Above all, exposing the dynamism of vaginal microbiota affords a better understanding of pathogenesis of lower genital tract disease.

Microbiome research potential for developing holistic approaches to improve refugee health

Morbidity from disease is increasingly being understood as dependent on wellbeing of the ecosystem, as opposed to an isolated element. However, the combined burden of disequilibrium of the gut microbiome ecosystem – which can facilitate proliferation of antimicrobial resistance (AMR) – is not well understood. The gap in knowledge grows when considering regions, such as the Gaza Strip, where the population continues to experience recurrent conflicts, movement restrictions, and high rates of poverty, food insecurity and unemployment.1 The concurrent rise of gut microbiome disequilibrium, AMR proliferation, and displacement of populations globally – combined with lack of data – poses significant but unknown risk to public health, in displaced and host communities alike. Examining the current landscape of research, and existing gaps solidifies the need for interdisciplinary perspectives to address AMR through exploration of the gut microbiome. This holistic approach can help account for the political, socio-economic, and material factors, in the context of regions experiencing conflict/war. The growing role of microbiota in health may hold answers to questions surrounding understudied conditions such as AMR, and even non-communicable or chronic diseases.

The role of oral microbiome in respiratory health and diseases

The oral cavity (mouth) has various microbial habitats, including, teeth, gingival sulcus, gingiva, tongue, inner cheek, hard palate, and soft palate. The human oral cavity houses the second most diverse microbiome in the body harboring over 700 bacterial species. The fine-tuned equilibrium of the oral microbiome ecosystem maintains oral health. Oral dysbiosis caused by food habits and poor oral hygiene leads to various oral diseases such as periodontitis, caries, gingivitis, and oral cancer. Recent advances in technology have revealed the correlation between the oral microbiome and systemic diseases such as pulmonary diseases, cardiovascular diseases, rheumatoid arthritis, Alzheimer's disease, and other metabolic diseases. Since the oral cavity directly connects with the upper respiratory tract, the oral microbiome has easier access to the respiratory system compared to other organ systems. Direct aspiration of oral microflora in the respiratory system and oral dysbiosis-induced host immune reaction and inflammation are mainly responsible for various pulmonary complications. Numbers of literature have reported the correlation between oral diseases and pulmonary diseases, suggesting the possible role of the oral microbiome in respiratory diseases such as chronic obstructive pulmonary diseases, pneumonia, lung cancer, etc. This paper reviews the current evidence in establishing a link between the oral microbiome and pulmonary diseases. We also discuss future research directions focusing on the oral microbiome to unravel novel therapeutic approaches that could prevent or treat the various pulmonary complications.

Abstract PS5-41: Machine learning model of gut microbiota predicts neratinib induced diarrhea in patients with breast cancer

Abstract Background: Neratinib is a potent small molecule tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (HER1,2,4). One of the major side effects of neratinib is diarrhea. The human gut contains a dense microbiome ecosystem that is essential in maintaining a healthy host physiology, and its disruption may lead to increased risk of toxicities from cancer therapy. In this study, we aimed to develop a machine learning model based on analysis of gut microbiota data to predict neratinib-induced diarrhea. Methods: Patients were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Neratinib was administered as single agent, 240 mg oral daily in a 28-day cycle. Stool samples were collected at baseline and during treatment for 16S rRNA gene sequencing. Using microbial relative abundance data, we developed gradient-boosted tree models with two nested loops of cross validations to classify whether diarrhea would occur or not after treatment onset. For the inner validation loop, we used ten-fold cross validation to determine the optimal model from hyper-parameters including regularization. For the outer validation loop, we utilized a leave-one-patient-out cross validation to test this model on the hold-out patient’s baseline data and the predictions were used for model assessment. Results: A total of 11 patients and 50 longitudinal stool samples were collected. The median age was 66 years. 73% developed grade ≥ 1 diarrhea attributed to neratinib. Shannon diversity index of gut microbiome was not associated with diarrhea. For predictive modeling, the outer validation loop Area Under the Receiver Operating Characteristic Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC) were 0.92 and 0.97, respectively. The two most important taxa predictive of protection from diarrhea were Ruminiclostridium 9, and Bacteroides sp. HPS0048. We found that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 have reduced risk of neratinib-related diarrhea. Conclusions: The machine learning model can identify breast cancer patients at risk of diarrhea prior to neratinib use. Future studies are required to validate this finding. Citation Format: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, John D. Gillece, Megan Folkerts, Lauren Reining, Sarah K. Highlander, Zahra Eftekhari, Joanne Mortimer, Yuan Yuan. Machine learning model of gut microbiota predicts neratinib induced diarrhea in patients with breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-41.

Gut microbiome and Mediterranean diet in the context of obesity. Current knowledge, perspectives and potential therapeutic targets

Mediterranean Diet has been recognized as one of the healthiest and sustainable dietary patterns worldwide, based on the food habits of people living in the Mediterranean region. It is focused on a plant-based cuisine combining local agricultural products and moderate intake of fish. As eating habits seem to exert a major impact on the composition of gut microbiota, numerous studies show that an adherence to the Mediterranean diet positively influences the microbiome ecosystem network. This has a profound effect on multiple host metabolic pathways and plays a major role in immune and metabolic homeostasis. Among metabolic disorders, obesity represents a major health issue where Mediterranean Dietary regime could possibly slowdown its spread. The aim of this review is to emphasize the interaction between diet and gut microbiota and the potential beneficial effects of Mediterranean diet on metabolic disorders like obesity, which is responsible for the development of many noncommunicable diseases.