Gut microbiota and fecal metabolites in sustained unresponsiveness by oral immunotherapy in school-age children with cow's milk allergy.

BACKGROUND: Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. METHODS: We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. RESULTS: During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41-0.93 and 0.42-0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10-2.03), and these associations were observed until the end of OIT. CONCLUSIONS: In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

Assessment of metagenomic workflows using a newly constructed human gut microbiome mock community.

To quantify the biases introduced during human gut microbiome studies, analyzing an artificial mock community as the reference microbiome is indispensable. However, there are still limited resources for a mock community which well represents the human gut microbiome. Here, we constructed a novel mock community comprising the type strains of 18 major bacterial species in the human gut and assessed the influence of experimental and bioinformatics procedures on the 16S rRNA gene and shotgun metagenomic sequencing. We found that DNA extraction methods greatly affected the DNA yields and taxonomic composition of sequenced reads, and that some of the commonly used primers for 16S rRNA genes were prone to underestimate the abundance of some gut commensal taxa such as Erysipelotrichia, Verrucomicrobiota and Methanobacteriota. Binning of the assembled contigs of shotgun metagenomic sequences by MetaBAT2 produced phylogenetically consistent, less-contaminated bins with varied completeness. The ensemble approach of multiple binning tools by MetaWRAP can improve completeness but sometimes increases the contamination rate. Our benchmark study provides an important foundation for the interpretation of human gut microbiome data by providing means for standardization among gut microbiome data obtained with different methodologies and will facilitate further development of analytical methods.

Estimation of silent phenotypes of calf antibiotic dysbiosis.

Reducing antibiotic usage among livestock animals to prevent antimicrobial resistance has become an urgent issue worldwide. This study evaluated the effects of administering chlortetracycline (CTC), a versatile antibacterial agent, on the performance, blood components, fecal microbiota, and organic acid concentrations of calves. Japanese Black calves were fed with milk replacers containing CTC at 10 g/kg (CON group) or 0 g/kg (EXP group). Growth performance was not affected by CTC administration. However, CTC administration altered the correlation between fecal organic acids and bacterial genera. Machine learning (ML) methods such as association analysis, linear discriminant analysis, and energy landscape analysis revealed that CTC administration affected populations of various types of fecal bacteria. Interestingly, the abundance of several methane-producing bacteria at 60 days of age was high in the CON group, and the abundance of Lachnospiraceae, a butyrate-producing bacterium, was high in the EXP group. Furthermore, statistical causal inference based on ML data estimated that CTC treatment affected the entire intestinal environment, potentially suppressing butyrate production, which may be attributed to methanogens in feces. Thus, these observations highlight the multiple harmful impacts of antibiotics on the intestinal health of calves and the potential production of greenhouse gases by calves.

An agroecological structure model of compost-soil-plant interactions for sustainable organic farming.

Compost is used worldwide as a soil conditioner for crops, but its functions have still been explored. Here, the omics profiles of carrots were investigated, as a root vegetable plant model, in a field amended with compost fermented with thermophilic Bacillaceae for growth and quality indices. Exposure to compost significantly increased the productivity, antioxidant activity, color, and taste of the carrot root and altered the soil bacterial composition with the levels of characteristic metabolites of the leaf, root, and soil. Based on the data, structural equation modeling (SEM) estimated that amino acids, antioxidant activity, flavonoids and/or carotenoids in plants were optimally linked by exposure to compost. The SEM of the soil estimated that the genus Paenibacillus and nitrogen compounds were optimally involved during exposure. These estimates did not show a contradiction between the whole genomic analysis of compost-derived Paenibacillus isolates and the bioactivity data, inferring the presence of a complex cascade of plant growth-promoting effects and modulation of the nitrogen cycle by the compost itself. These observations have provided information on the qualitative indicators of compost in complex soil-plant interactions and offer a new perspective for chemically independent sustainable agriculture through the efficient use of natural nitrogen.

Fatty acid overproduction by gut commensal microbiota exacerbates obesity.

Although recent studies have highlighted the impact of gut microbes on the progression of obesity and its comorbidities, it is not fully understood how these microbes promote these disorders, especially in terms of the role of microbial metabolites. Here, we report that Fusimonas intestini, a commensal species of the family Lachnospiraceae, is highly colonized in both humans and mice with obesity and hyperglycemia, produces long-chain fatty acids such as elaidate, and consequently facilitates diet-induced obesity. High fat intake altered the expression of microbial genes involved in lipid production, such as the fatty acid metabolism regulator fadR. Monocolonization with a FadR-overexpressing Escherichia coli exacerbated the metabolic phenotypes, suggesting that the change in bacterial lipid metabolism is causally involved in disease progression. Mechanistically, the microbe-derived fatty acids impaired intestinal epithelial integrity to promote metabolic endotoxemia. Our study thus provides a mechanistic linkage between gut commensals and obesity through the overproduction of microbe-derived lipids.

Amendment of a thermophile-fermented compost to humus improves the growth of female larvae of the Hercules beetle Dynastes hercules (Coleoptera: scarabaeidae).

AIMS: Hercules beetle is a popular pet and large adult individuals are considered valuable. Incorporating compost prepared from marine animals and fermented by thermophilic bacteria into the humus benefits the gut microflora of several livestock. Here, we evaluated whether this compost improves the growth of the Hercules beetle (Dynastes hercules hercules) larvae. METHODS AND RESULTS: We mixed the compost grains with the humus at a final concentration of 1% (w/w) and transferred ∼90 days old Hercules beetle larvae to fresh humus with or without the compost. After 72 days rearing period, only the female larvae reared in the humus with compost exhibited superior growth, compared with those grown in compost-free humus. The gut bacterial composition was determined at 0 and 46 day after transferring the larvae to humus with or without compost. Improved growth of the female larvae was associated with increased abundance of Mollicutes and decreased abundance of Gammaproteobacteria. CONCLUSION: The thermophile-fermented compost has a probiotic effect on the female Hercules beetle larvae that is mediated by altered gut microflora.

Computational estimation of sediment symbiotic bacterial structures of seagrasses overgrowing downstream of onshore aquaculture.

Coastal seagrass meadows are essential in blue carbon and aquatic ecosystem services. However, this ecosystem has suffered severe eutrophication and destruction due to the expansion of aquaculture. Therefore, methods for the flourishing of seagrass are still being explored. Here, data from 49 public coastal surveys on the distribution of seagrass and seaweed around the onshore aquaculture facilities are revalidated, and an exceptional area where the seagrass Zostera marina thrives was found near the shore downstream of the onshore aquaculture facility. To evaluate the characteristics of the sediment for growing seagrass, physicochemical properties and bacterial ecological evaluations of the sediment were conducted. Evaluation of chemical properties in seagrass sediments confirmed a significant increase in total carbon and a decrease in zinc content. Association analysis and linear discriminant analysis refined bacterial candidates specified in seagrass overgrown- and nonovergrown-sediment. Energy landscape analysis indicated that the symbiotic bacterial groups of seagrass sediment were strongly affected by the distance close to the seagrass-growing aquaculture facility despite their bacterial population appearing to fluctuate seasonally. The bacterial population there showed an apparent decrease in the pathogen candidates belonging to the order Flavobacteriales. Moreover, structure equation modeling and a linear non-Gaussian acyclic model based on the machine learning data estimated an optimal sediment symbiotic bacterial group candidate for seagrass growth as follows: the Lachnospiraceae and Ruminococcaceae families as gut-inhabitant bacteria, Rhodobacteraceae as photosynthetic bacteria, and Desulfobulbaceae as cable bacteria modulating oxygen or nitrate reduction and oxidation of sulfide. These observations confer a novel perspective on the sediment symbiotic bacterial structures critical for blue carbon and low-pathogenic marine ecosystems in aquaculture.

Integrated Multi-Omics Analysis Reveals Differential Effects of Fructo-Oligosaccharides (FOS) Supplementation on the Human Gut Ecosystem.

Changes in the gut ecosystem, including the microbiome and the metabolome, and the host immune system after fructo-oligosaccharide (FOS) supplementation were evaluated. The supplementation of FOS showed large inter-individual variability in the absolute numbers of fecal bacteria and an increase in Bifidobacterium. The fecal metabolome analysis revealed individual variability in fructose utilization in response to FOS supplementation. In addition, immunoglobulin A(IgA) tended to increase upon FOS intake, and peripheral blood monocytes significantly decreased upon FOS intake and kept decreasing in the post-FOS phase. Further analysis using a metagenomic approach showed that the differences could be at least in part due to the differences in gene expressions of enzymes that are involved in the fructose metabolism pathway. While the study showed individual differences in the expected health benefits of FOS supplementation, the accumulation of "personalized" knowledge of the gut ecosystem with its genetic expression may enable effective instructions on prebiotic consumption to optimize health benefits for individuals in the future.

Dysbiotic human oral microbiota alters systemic metabolism via modulation of gut microbiota in germ-free mice.

Background: The effect of oral microbiota on the intestinal microbiota has garnered growing attention as a mechanism linking periodontal diseases to systemic diseases. However, the salivary microbiota is diverse and comprises numerous bacteria with a largely similar composition in healthy individuals and periodontitis patients. Aim: We explored how health-associated and periodontitis-associated salivary microbiota differently colonized the intestine and their subsequent systemic effects. Methods: The salivary microbiota was collected from a healthy individual and a periodontitis patient and gavaged into C57BL/6NJcl[GF] mice. Gut microbial communities, hepatic gene expression profiles, and serum metabolites were analyzed. Results: The gut microbial composition was significantly different between periodontitis-associated microbiota-administered (PAO) and health-associated oral microbiota-administered (HAO) mice. The hepatic gene expression profile demonstrated a distinct pattern between the two groups, with higher expression of lipid and glucose metabolism-related genes. Disease-associated metabolites such as 2-hydroxyisobutyric acid and hydroxybenzoic acid were elevated in PAO mice. These metabolites were significantly correlated with characteristic gut microbial taxa in PAO mice. Conversely, health-associated oral microbiota were associated with higher levels of beneficial serum metabolites in HAO mice. Conclusion: The multi-omics approach used in this study revealed that periodontitis-associated oral microbiota is associated with the induction of disease phenotype when they colonized the gut of germ-free mice.

Noninvasive fecal metabolic profiling for the evaluation of characteristics of thermostable lactic acid bacteria, Weizmannia coagulans SANK70258, for broiler chickens.

Weizmannia coagulans SANK70258 is a spore-forming thermostable lactic acid bacterium and an effective probiotic for the growth of livestock animals, but its growth-promoting mechanism remains unclear. Here, the composition of fecal metabolites in broilers continuously administered with W. coagulans SANK70258 was assessed under a regular program with antibiotics, which was transiently given for 6 days after birth. Oral administration of W. coagulans to broiler chicks tended to increase the average daily gain of body weights thereafter. The composition of fecal metabolites in the early chick stage (day 10 after birth) was dramatically altered by the continuous exposure. The levels of short-chain fatty acids (SCFAs) propionate and butyrate markedly increased, while those of acetate, one of the SCFAs, and lactate were reduced. Simultaneously, arabitol, fructose, mannitol, and erythritol, which are carbohydrates as substrates for gut microbes to produce SCFAs, also increased along with altered correlation. Correlation network analyses classified the modularity clusters (|r| > 0.7) among carbohydrates, SCFAs, lactate, amino acids, and the other metabolites under the two conditions. The characteristic diversities by the exposure were visualized beyond the perspective associated with differences in metabolite concentrations. Further, enrichment pathway analyses showed that metabolic composition related to biosynthesis and/or metabolism for SCFAs, amino acids, and energy were activated. Thus, these observations suggest that W. coagulans SANK70258 dramatically modulates the gut metabolism of the broiler chicks, and the metabolomics profiles during the early chick stages may be associated with growth promotion.

A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate Lymphoid Cells.

Daikenchuto (DKT) is one of the most widely used Japanese herbal formulae for various gastrointestinal disorders. It consists of Zanthoxylum Fructus (Japanese pepper), Zingiberis Siccatum Rhizoma (processed ginger), Ginseng radix, and maltose powder. However, the use of DKT in clinical settings is still controversial due to the limited molecular evidence and largely unknown therapeutic effects. Here, we investigated the anti-inflammatory actions of DKT in the dextran sodium sulfate (DSS)-induced colitis model in mice. We observed that DKT remarkably attenuated the severity of experimental colitis while maintaining the members of the symbiotic microbiota such as family Lactobacillaceae and increasing levels of propionate, an immunomodulatory microbial metabolite, in the colon. DKT also protected colonic epithelial integrity by upregulating the fucosyltransferase gene Fut2 and the antimicrobial peptide gene Reg3g. More remarkably, DKT restored the reduced colonic group 3 innate lymphoid cells (ILC3s), mainly RORγthigh-ILC3s, in DSS-induced colitis. We further demonstrated that ILC3-deficient mice showed increased mortality during experimental colitis, suggesting that ILC3s play a protective function on colonic inflammation. These findings demonstrate that DKT possesses anti-inflammatory activity, partly via ILC3 function, to maintain the colonic microenvironment. Our study also provides insights into the molecular basis of herbal medicine effects, promotes more profound mechanistic studies towards herbal formulae and contributes to future drug development.

A potential network structure of symbiotic bacteria involved in carbon and nitrogen metabolism of wood-utilizing insect larvae.

Effective biological utilization of wood biomass is necessary worldwide. Since several insect larvae can use wood biomass as a nutrient source, studies on their digestive microbial structures are expected to reveal a novel rule underlying wood biomass processing. Here, structural inferences for inhabitant bacteria involved in carbon and nitrogen metabolism for beetle larvae, an insect model, were performed to explore the potential rules. Bacterial analysis of larval feces showed enrichment of the phyla Chroloflexi, Gemmatimonadetes, and Planctomycetes, and the genera Bradyrhizobium, Chonella, Corallococcus, Gemmata, Hyphomicrobium, Lutibacterium, Paenibacillus, and Rhodoplanes, as bacteria potential involved in plant growth promotion, nitrogen cycle modulation, and/or environmental protection. The fecal abundances of these bacteria were not necessarily positively correlated with their abundances in the habitat, indicating that they were selectively enriched in the feces of the larvae. Correlation and association analyses predicted that common fecal bacteria might affect carbon and nitrogen metabolism. Based on these hypotheses, structural equation modeling (SEM) statistically estimated that inhabitant bacterial groups involved in carbon and nitrogen metabolism were composed of the phylum Gemmatimonadetes and Planctomycetes, and the genera Bradyrhizobium, Corallococcus, Gemmata, and Paenibacillus, which were among the fecal-enriched bacteria. Nevertheless, the selected common bacteria, i.e., the phyla Acidobacteria, Armatimonadetes, and Bacteroidetes and the genera Candidatus Solibacter, Devosia, Fimbriimonas, Gemmatimonas Opitutus, Sphingobium, and Methanobacterium, were necessary to obtain good fit indices in the SEM. In addition, the composition of the bacterial groups differed depending upon metabolic targets, carbon and nitrogen, and their stable isotopes, δ13C and δ15N, respectively. Thus, the statistically derived causal structural models highlighted that the larval fecal-enriched bacteria and common symbiotic bacteria might selectively play a role in wood biomass carbon and nitrogen metabolism. This information could confer a new perspective that helps us use wood biomass more efficiently and might stimulate innovation in environmental industries in the future.

Development of a novel feeding method for Japanese black calves with thermophile probiotics at postweaning.

AIMS: Probiotic effects of compost containing thermophiles on productivity have been reported in domestic animals, although not cattle. We evaluated the effects of administering Caldibacillus hisashii, a thermophile contained in compost, on growth, blood components, faecal organic acid concentrations and microbiota population in Japanese black calves. METHODS AND RESULTS: Calves were administered C. hisashii from 3 to 5 months of age. Administering C. hisashii decreased feed intake without affecting body weight, indicating that feed efficiency is improved by administration. Administering C. hisashii decreased plasma insulin concentration without affecting glucose and non-esterified fatty acid concentrations. Chao1 was decreased by exposure at 5 months of age. Similarly, weighted and unweighted UniFrac distances were affected by treatment at 5 months of age. Faecal abundance of the phylum Bacteroidetes tended to be increased by exposure. Faecal propionic acid concentration was correlated positively with faecal abundance of phylum Bacteroidetes but negatively with that of Firmicutes. Interestingly, the population of the genus Methanobrevibacter, representing the majority of methanogens, was lowered by exposure and was negatively correlated with faecal propionic acid concentration. CONCLUSION: Administration of C. hisashii has the potential to improve growth performance of Japanese black calves and to contribute to reducing environmental load, which may be associated with altered endocrine kinetics and gut microbial populations. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed that isolated thermophiles included in compost may exert probiotic effects on calves.

Impact of dietary fructooligosaccharides (FOS) on murine gut microbiota and intestinal IgA secretion.

Fructooligosaccharides (FOS) are considered as prebiotics and are well known for their health-promoting properties, including antitumor, allergy-preventive, and infection-protective effects. They exert these effects by modulating the gut microbial composition and dynamics. In the present study, we performed a comparative whole metagenome shotgun sequencing analysis (WMGS) to elucidate the gut microbiota and secretary Immunoglobulin A (SIgA) dynamics as a result of 5% (w/w) FOS supplementation over a period of 7 days (fecal samples were collected every day). A number of taxa including Bacteroides, Lactobacillus, Roseburia, Clostridia, Faecalibaculum, and Enterorhabdus were found to be modulated with SIgA production in the murine gut. The process of SIgA production from FOS metabolization was found to be carried out via the production of short-chain fatty acids in the gut. Species of Bacteroides and Roseburia; namely, B. caccae, B. finegoldii, B. ovatus, B. thetaiotamicron, and Roseburia intestinalis, respectively, are predominantly responsible for FOS metabolization in the murine gut. The abundances of these bacterial species and their corresponding functions involved in FOS metabolization decreased over time even though these prebiotics were administered continuously for seven days. This suggests that there is a decrease in FOS metabolization over time. In addition, the present analysis suggests that the administration of FOS may help to reduce the pathogenic bacteria from the gut via SIgA production. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03116-3.

Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice.

Background & Aims: Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology. Methods: C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction. Results: CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different. Conclusions: Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

Bacterial cancer therapy in autochthonous colorectal cancer affects tumor growth and metabolic landscape.

Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT in xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using autochthonous mouse models of intestinal cancer and tumor organoid cultures to assess the effectiveness and consequences of oral treatment with aromatase A-deficient STm (STmΔaroA). STmΔaroA delivered by oral gavage significantly reduced tumor burden and tumor load in both a colitis-associated colorectal cancer (CAC) model and in a spontaneous Apcmin/+ intestinal cancer model. STmΔaroA colonization of tumors caused alterations in transcription of mRNAs associated with tumor stemness, epithelial-mesenchymal transition, and cell cycle. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STmΔaroA-treated tumors, suggesting that STmΔaroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro recapitulated effects seen on tumor stemness, mesenchymal markers, and altered metabolome. Furthermore, live STmΔaroA was required, demonstrating active mechanisms including metabolite usage. We have demonstrated that oral BCT is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium affecting tumor stem cells.

Next-generation prebiotic promotes selective growth of bifidobacteria, suppressing Clostridioides difficile.

Certain existing prebiotics meant to facilitate the growth of beneficial bacteria in the intestine also promote the growth of other prominent bacteria. Therefore, the growth-promoting effects of ß-galactosides on intestinal bacteria were analyzed. Galactosyl-ß1,4-l-rhamnose (Gal-ß1,4-Rha) selectively promoted the growth of Bifidobacterium. Bifidobacterium longum subsp. longum 105-A (JCM 31944) has multiple solute-binding proteins belonging to ATP-binding cassette transporters for sugars. Each strain in the library of 11 B. longum subsp. longum mutants, in which each gene of the solute-binding protein was disrupted, was cultured in a medium containing Gal-ß1,4-Rha as the sole carbon source, and only the BL105A_0502 gene-disruption mutant showed delayed and reduced growth compared to the wild-type strain. BL105A_0502 homolog is highly conserved in bifidobacteria. In a Gal-ß1,4-Rha-containing medium, Bifidobacterium longum subsp. infantis JCM 1222T, which possesses BLIJ_2090, a homologous protein to BL105A_0502, suppressed the growth of enteric pathogen Clostridioides difficile, whereas the BLIJ_2090 gene-disrupted mutant did not. In vivo, administration of B. infantis and Gal-ß1,4-Rha alleviated C. difficile infection-related weight loss in mice. We have successfully screened Gal-ß1,4-Rha as a next-generation prebiotic candidate that specifically promotes the growth of beneficial bacteria without promoting the growth of prominent bacteria and pathogens.

Association of the Maternal Gut Microbiota/Metabolome with Cord Blood CCL17.

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.

Acetate differentially regulates IgA reactivity to commensal bacteria.

The balance between bacterial colonization and its containment in the intestine is indispensable for the symbiotic relationship between humans and their bacteria. One component to maintain homeostasis at the mucosal surfaces is immunoglobulin A (IgA), the most abundant immunoglobulin in mammals1,2. Several studies have revealed important characteristics of poly-reactive IgA3,4, which is produced naturally without commensal bacteria. Considering the dynamic changes within the gut environment, however, it remains uncertain how the commensal-reactive IgA pool is shaped and how such IgA affects the microbial community. Here we show that acetate-one of the major gut microbial metabolites-not only increases the production of IgA in the colon, but also alters the capacity of the IgA pool to bind to specific microorganisms including Enterobacterales. Induction of commensal-reactive IgA and changes in the IgA repertoire by acetate were observed in mice monocolonized with Escherichia coli, which belongs to Enterobacterales, but not with the major commensal Bacteroides thetaiotaomicron, which suggests that acetate directs selective IgA binding to certain microorganisms. Mechanistically, acetate orchestrated the interactions between epithelial and immune cells, induced microbially stimulated CD4 T cells to support T-cell-dependent IgA production and, as a consequence, altered the localization of these bacteria within the colon. Collectively, we identified a role for gut microbial metabolites in the regulation of differential IgA production to maintain mucosal homeostasis.

Obesity-Related Gut Microbiota Aggravates Alveolar Bone Destruction in Experimental Periodontitis through Elevation of Uric Acid.

Obesity is a risk factor for periodontal disease (PD). Initiation and progression of PD are modulated by complex interactions between oral dysbiosis and host responses. Although obesity is associated with increased susceptibility to bacterial infection, the detailed mechanisms that connect obesity and susceptibility to PD remain elusive. Using fecal microbiota transplantation and a ligature-induced PD model, we demonstrated that gut dysbiosis-associated metabolites from high-fat diet (HFD)-fed mice worsen alveolar bone destruction. Fecal metabolomics revealed elevated purine degradation pathway activity in HFD-fed mice, and recipient mice had elevated levels of serum uric acid upon PD induction. Furthermore, PD induction caused more severe bone destruction in hyperuricemic than normouricemic mice, and the worsened bone destruction was completely abrogated by allopurinol, a xanthine oxidase inhibitor. Thus, obesity increases the risk of PD by increasing production of uric acid mediated by gut dysbiosis. IMPORTANCE Obesity is an epidemic health issue with a rapid increase worldwide. It increases the risk of various diseases, including periodontal disease, an oral chronic infectious disease. Although obesity increases susceptibility to bacterial infection, the precise biological mechanisms that link obesity and susceptibility to periodontal disease remain elusive. Using fecal microbial transplantation, experimental periodontitis, and metabolomics, our study demonstrates uric acid as a causative substance for greater aggravation of alveolar bone destruction in obesity-related periodontal disease. Gut microbiota from obese mice upregulated the purine degradation pathway, and the resulting elevation of serum uric acid promoted alveolar bone destruction. The effect of uric acid was confirmed by administration of allopurinol, an inhibitor of xanthine oxidase. Overall, our study provides new insights into the pathogenic mechanisms of obesity-associated periodontal disease and the development of new therapeutic options for the disease.