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The human oral cavity and upper airway serves as an early barrier and reservoir in the transmission of SARS-CoV-2. Saliva in this microenvironment may serve as a key host factor that can modulate susceptibility to infection and eventual infection of the lower respiratory tract. We sought to analyze the content and composition of heparan sulfate, a glycosaminoglycan identified as an important co-receptor for viral entry, and whether there is any correlation with SARS-CoV-2 infection. We enlisted 98 participants stratified by age, gender, race, and COVID-19 history. Notably, the concentration of heparan sulfate in saliva increased with age, and its composition showed a wide range of variability within each age group independently of age. Heparan sulfate concentration and composition did not differ significantly with gender, ethnicity or race. Compared to patients with no COVID-19 history, patients with previous infection had a similar salivary heparan sulfate concentration, but significant increases in overall sulfation were noted. Moreover, in a subset of participants, for which data was available pre- and post- infection, significant elevation in N-sulfoglucosamine in heparan sulfate was observed post- COVID-19. Examination of salivary bacterial 16S rRNA, showed a significant reduction in species predicted to possess heparan sulfate-modifying capacity among participants >60 years old, which correlates with the increase in heparan sulfate content in older individuals. These findings demonstrate a surprisingly wide variation in heparan sulfate content and composition in saliva across the sampled population and confirm other findings showing variation in content and composition of glycosaminoglycans in blood and urine. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD‐mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low‐fat‐diet intervention. METHODS: Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low‐fat American Heart Association diet or high‐fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6‐week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals' microbiome and metabolome throughout the dietary interventions. RESULTS: Participants with MCI on the MMKD had lower levels of GABA‐producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA‐regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase‐containing microbes and an altered bile acid pool, suggesting reduced gut motility. DISCUSSION: Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut‐transit time. [ABSTRACT FROM AUTHOR]

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15+HLADRhi and CD48highS100A2pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens. Periodontal disease and rheumatoid arthritis: The incidence of periodontal disease is high in individuals with rheumatoid arthritis (RA) who also have anti-citrullinated protein antibodies (ACPAs), suggesting a link between these two diseases. Brewer et al. carried out a paired analysis of human and bacterial transcriptomes from blood samples collected longitudinally from RA patients with and without periodontal disease. They identified transcriptional signatures within inflammatory monocyte subsets that correlated with repeated oral bacteremias and clinical arthritis flares in patients with RA and periodontal disease. These oral bacteria were broadly citrullinated, and some of these citrullinated epitopes were the targets of ACPA expressed by RA blood plasmablasts that have undergone affinity maturation. These results confirm that periodontal disease can cause breaches in oral mucosa that release citrullinated bacteria into the blood, which activates inflammatory monocytes and ACPA-specific B cells. —CF [ABSTRACT FROM AUTHOR]

The microbiome and faecal metabolome beta-diversity also showed differences between responders and non-responders (Figure 3D-F), likely reflecting the baseline differences in diet and gut microbiome. (A-C) Comparison of average Shannon diversity of the microbiome (A), faecal metabolome (B) or plasma metabolome (C) across three timepoints; paired samples Wilcoxon tests were performed to compare means of the Shannon diversity between the different timepoints. Changes in diet might modify the faecal microbiome and metabolomic profile, affecting pain in rheumatoid arthritis (RA). [Extracted from the article]

Obstructive sleep apnea (OSA), a common sleep disorder characterized by intermittent hypoxia and hypercapnia (IHC), increases atherosclerosis risk. However, the contribution of intermittent hypoxia (IH) or intermittent hypercapnia (IC) in promoting atherosclerosis remains unclear. Since gut microbiota and metabolites have been implicated in atherosclerosis, we examined whether IH or IC alters the microbiome and metabolome to induce a pro-atherosclerotic state. Apolipoprotein E deficient mice (ApoE−/−), treated with IH or IC on a high-fat diet (HFD) for 10 weeks, were compared to Air controls. Atherosclerotic lesions were examined, gut microbiome was profiled using 16S rRNA gene amplicon sequencing and metabolome was assessed by untargeted mass spectrometry. In the aorta, IC-induced atherosclerosis was significantly greater than IH and Air controls (aorta, IC 11.1 ± 0.7% vs. IH 7.6 ± 0.4%, p < 0.05 vs. Air 8.1 ± 0.8%, p < 0.05). In the pulmonary artery (PA), however, IH, IC, and Air were significantly different from each other in atherosclerotic formation with the largest lesion observed under IH (PA, IH 40.9 ± 2.0% vs. IC 20.1 ± 2.6% vs. Air 12.2 ± 1.5%, p < 0.05). The most differentially abundant microbial families (p < 0.001) were Peptostreptococcaceae, Ruminococcaceae, and Erysipelotrichaceae. The most differentially abundant metabolites (p < 0.001) were tauro-β-muricholic acid, ursodeoxycholic acid, and lysophosphoethanolamine (18:0). We conclude that IH and IC (a) modulate atherosclerosis progression differently in distinct vascular beds with IC, unlike IH, facilitating atherosclerosis in both aorta and PA and (b) promote an atherosclerotic luminal gut environment that is more evident in IH than IC. We speculate that the resulting changes in the gut metabolome and microbiome interact differently with distinct vascular beds. [ABSTRACT FROM AUTHOR]

C‐type regenerating islet derived‐3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol‐induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down‐regulated in animal models of diet‐induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was induced by a Western‐style fast‐food diet in mice deficient for Reg3g or Reg3b and in transgenic mice overexpressing Reg3g in intestinal epithelial cells (Reg3gTg). Glucose tolerance was assessed after 18 weeks and insulin resistance after 19 weeks of feeding. After 20 weeks, mice were assessed for features of the metabolic syndrome. Obesity was not different in genetically modified mice compared with their respective wild‐type littermates. Glucose intolerance, liver injury, hepatic inflammation, steatosis, fibrosis, and bacterial translocation to mesenteric lymph nodes and to the liver were not different in Reg3g‐deficient mice compared with wild‐type littermates. Plasma endotoxin levels were higher in Reg3g‐deficient mice. Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild‐type littermates. Absence of either REG3G or REG3B protein in the ileum was not compensated for by up‐regulation of the respective other REG3 protein. Transgenic Reg3g mice also developed liver injury, steatosis, and fibrosis similar to their wild‐type littermates. Conclusion: In contrast to alcoholic liver disease, loss of intestinal Reg3 lectins is not sufficient to aggravate diet‐induced obesity and NASH. This supports a multi‐hit pathogenesis in NASH. Only glucose metabolism is affected by Reg3b deficiency. (Hepatology Communications 2018;2:393‐406) [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments. [Display omitted] • Microbiome and metabolome changes during colorectal cancer (CRC) progression • High-fat diet is a dominant determinant of cecal microbiome in CRC-susceptible APC min/+ mice • Microbially conjugated bile acids increase with high-fat diet Fu et al. identify high-fat diet as a dominant determinant of the cecal microbiome and metabolome in a mouse model of colorectal cancer and implicate microbially conjugated bile acids as potential drivers of disease progression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean-ketogenic diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier., Competing Interests: Conflicts of interest Dr. Krumsiek holds equity in Chymia LLC and iollo, owns intellectual property in PsyProtix, and serves as an advisor for celeste. Annalise Schweickart is a co-founder of celeste. Dr. Kaddurah-Daouk in an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix.

Introduction: The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD-mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low-fat-diet intervention., Methods: Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low-fat American Heart Association diet or high-fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6-week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals' microbiome and metabolome throughout the dietary interventions., Results: Participants with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility., Discussion: Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut-transit time., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilized whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalized models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management., Competing Interests: Declaration of interests GK and MA are co-inventors of several patent applications on the use of metabolomics in Alzheimer’s disease and own equity and IP in Chymia LLC and IP in PsyProtix unrelated to this work. RKD is an inventor of a series of patents on the use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. ST has served on national and international advisory boards of Roche, Eisai, Grifols, and Biogen, and is a member of the independent data safety and monitoring board of the study ENVISION (Biogen). HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care.

Quantifying the differential abundance (DA) of specific taxa among experimental groups in microbiome studies is challenging due to data characteristics (e.g., compositionality, sparsity) and specific study designs (e.g., repeated measures, meta-analysis, cross-over). Here we present BIRDMAn ( B ayesian I nferential R egression for D ifferential M icrobiome An alysis), a flexible DA method that can account for microbiome data characteristics and diverse experimental designs. Simulations show that BIRDMAn models are robust to uneven sequencing depth and provide a >20-fold improvement in statistical power over existing methods. We then use BIRDMAn to identify antibiotic-mediated perturbations undetected by other DA methods due to subject-level heterogeneity. Finally, we demonstrate how BIRDMAn can construct state-of-the-art cancer-type classifiers using The Cancer Genome Atlas (TCGA) dataset, with substantial accuracy improvements over random forests and existing DA tools across multiple sequencing centers. Collectively, BIRDMAn extracts more informative biological signals while accounting for study-specific experimental conditions than existing approaches., Competing Interests: Conflicts of interest G.D.S.-P. and R.K. are inventors on a US patent application (PCT/US2019/059647) submitted by The Regents of the University of California and licensed by Micronoma; that application covers methods of diagnosing and treating cancer using multi-domain microbial biomarkers in blood and cancer tissues. G.D.S.-P. and R.K. are founders of and report stock interest in Micronoma. G.D.S.-P. has filed several additional US patent applications on cancer bacteriome and mycobiome diagnostics that are owned by The Regents of the University of California or Micronoma. R.K. additionally is a member of the scientific advisory board for GenCirq, holds an equity interest in GenCirq, and can receive reimbursements for expenses up to US $5,000 per year.

Microbial communities contain a broad phylogenetic diversity of organisms; however, the majority of methods center on describing bacteria and archaea. Fungi are important symbionts in many ecosystems and are potentially important members of the human microbiome, beyond those that can cause disease. To expand our analysis of microbial communities to include data from the fungal internal transcribed spacer (ITS) region, five candidate DNA extraction kits were compared against our standardized protocol for describing bacteria and archaea using 16S rRNA gene amplicon- and shotgun metagenomics sequencing. The results are presented considering a diverse panel of host-associated and environmental sample types and comparing the cost, processing time, well-to-well contamination, DNA yield, limit of detection and microbial community composition among protocols. Across all criteria, the MagMAX Microbiome kit was found to perform best. The PowerSoil Pro kit performed comparably but with increased cost per sample and overall processing time. The Zymo MagBead, NucleoMag Food and Norgen Stool kits were included.

Dimensionality reduction techniques are a key component of most microbiome studies, providing both the ability to tractably visualize complex microbiome datasets and the starting point for additional, more formal, statistical analyses. In this review, we discuss the motivation for applying dimensionality reduction techniques, the special characteristics of microbiome data such as sparsity and compositionality that make this difficult, the different categories of strategies that are available for dimensionality reduction, and examples from the literature of how they have been successfully applied (together with pitfalls to avoid). We conclude by describing the need for further development in the field, in particular combining the power of phylogenetic analysis with the ability to handle sparsity, compositionality, and non-normality, as well as discussing current techniques that should be applied more widely in future analyses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Armstrong, Rahman, Martino, McDonald, Gonzalez, Mishne and Knight.)