Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression.

Pharmacological vitamin C (VC) is a potential natural compound for cancer treatment. However, the mechanism underlying its antitumor effects remains unclear. In this study, we found that pharmacological VC significantly inhibits the mTOR (including mTORC1 and mTORC2) pathway activation and promotes GSK3-FBXW7-mediated Rictor ubiquitination and degradation by increasing the cellular ROS. Moreover, we identified that HMOX1 is a checkpoint for pharmacological-VC-mediated mTOR inactivation, and the deletion of FBXW7 or HMOX1 suppresses the regulation of pharmacological VC on mTOR activation, cell size, cell viability, and autophagy. More importantly, it was observed that the inhibition of mTOR by pharmacological VC supplementation in vivo produces positive therapeutic responses in tumor growth, while HMOX1 deficiency rescues the inhibitory effect of pharmacological VC on tumor growth. These results demonstrate that VC influences cellular activities and tumor growth by inhibiting the mTOR pathway through Rictor and HMOX1, which may have therapeutic potential for cancer treatment.

Multiomics analysis revealed that the metabolite profile of raw milk is associated with lactation stage of dairy cows and could be affected by variations in the ruminal microbiota.

The nutritional components and quality of milk are influenced by the rumen microbiota and its metabolites at different lactation stages. Hence, rumen fluid and milk samples from 6 dairy cows fed the same diet were collected during peak, early mid- and later mid-lactation. Untargeted metabolomics and 16S rRNA sequencing were applied for analyzing milk and rumen metabolites, as well as rumen microbial composition, respectively. The levels of lipid-related metabolites, L-glutamate, glucose-1-phosphate and acetylphosphate in milk exhibited lactation-dependent attenuation. Maltol, N-acetyl-D-glucosamine, and choline, which are associated with milk flavor or coagulation properties, as well as L-valine, lansioside-A, clitocine and ginsenoside-La increased significantly in early mid- and later mid-lactation, especially in later mid-lactation. The obvious increase in rumen microbial diversities (Ace and Shannon indices) were observed in early mid-lactation compared with peak lactation. Twenty-one differential bacterial genera of the rumen were identified, with Succinivibrionaceae_UCG-001, Candidatus Saccharimonas, Fibrobacter, and SP3-e08 being significantly enriched in peak lactation. Rikenellaceae_RC9_gut_group, Eubacterium_ruminantium_group, Lachnospira, Butyrivibrio, Eubacterium_hallii_group, and Schwartzia were most significantly enriched in early mid-lactation. In comparison, only 2 bacteria (unclassified_f__Prevotellaceae and Prevotellaceae_UCG-001) were enriched in later mid-lactation. For rumen metabolites, LPE(16:0), L-glutamate and L-tyrosine had higher levels in peak lactation, whereas PE(17:0/0:0), PE(16:0/0:0), PS(18:1(9Z)/0:0), L-phenylalanine, dulcitol, 2-(methoxymethyl)furan and 3-phenylpropyl acetate showed higher levels in early mid- and later mid-lactation. Multiomics integrated analysis revealed that a greater abundance of Fibrobacter contributed to phospholipid content in milk by increasing ruminal acetate, L-glutamate and LysoPE(16:0). Prevotellaceae_UCG-001 and unclassified_f_Prevotellaceae provide substrates for milk metabolites of the same category by increasing ruminal L-phenylalanine and dulcitol contents. These results demonstrated that milk metabolomic fingerprints and critical functional metabolites during lactation, and the key bacteria in rumen related to them. These findings provide new insights into the development of functional dairy products.

Diet-ruminal microbiome-host crosstalk contributes to differential effects of calf starter and alfalfa hay on rumen epithelial development and pancreatic α-amylase activity in yak calves.

Dietary supplementation of alfalfa hay or calf starter during the preweaning period was beneficial to the gastrointestinal development in dairy calves and lambs. In the present study, we designed 2 experiments using weaning with calf starter and alfalfa hay to investigate the diet-ruminal microbiome-host crosstalk in yak calves by analyzing the ruminal microbiota and rumen epithelial transcriptome. During the preweaning period, supplementation with either alfalfa hay or the starter significantly promoted animal growth and organ development in yak calves, including increases in body weight, body height, body length, chest girth, and development of liver, spleen, and thymus. These improvements could be attributed to increased dry matter intake, rumen fermentation, and development. Butyrate concentration increased in yak calves fed alfalfa hay or the starter, which could further promote ruminal epithelium development. Using 16S rRNA gene amplicon sequencing, we determined that butyrate-producing genera were increased by the supplementation with alfalfa hay or the starter. Transcriptomic analysis of the rumen epithelia revealed that the PI3K-Akt signaling pathway, which is critical in mediating many aspects of cellular function such as cell growth, was upregulated in response to alfalfa hay or the starter supplementation. The starter supplementation also increased the jejunal α-amylase activity, whereas alfalfa hay supplementation reduced the ileal α-amylase activity. Furthermore, the co-supplementation of both the starter and alfalfa hay reduced intestinal α-amylase activity. The starter increased ruminal propionate concentration, whereas alfalfa hay exhibited the opposite trend. The observed opposite effects of the starter and alfalfa hay on rumen propionate concentration corresponded with up- and downregulation, respectively, of the ruminal cholecystokinin involved in pancreatic secretion pathway, and thereby increased and decreased pancreatic α-amylase activity. In conclusion, both alfalfa hay and the starter could promote the growth and ruminal epithelial development of yak calves. The starter and alfalfa hay also differentially affected the intestinal α-amylase activities due to their different chemical components and different effects on ruminal fermentation, especially the ruminal propionate production.

Decreased amylolytic microbes of the hindgut and increased blood glucose implied improved starch utilization in the small intestine by feeding rumen-protected leucine in dairy calves.

Starch digestion in the small intestine in ruminants is relatively lower compared with that in monogastric animals, likely due to low pancreatic α-amylase secretion. Previous studies suggested that leucine could increase pancreatic α-amylase secretion in the small intestine of heifers cannulated with abomasal, duodenal, and ileal catheters. However, the surgical procedures probably have an effect on pancreatic function. Thus, we used rumen-protected leucine (RP-Leu) to explore its effect on small intestinal digestion of starch in calves without any surgery in 3 experiments. The first experiment was to explore whether RP-Leu could improve post-ruminal starch digestion in 5-mo-old calves (158 ± 19 kg body weight ± standard deviation). We found that RP-Leu did not affect rumen fermentation profile or whole-tract starch digestibility, but it increased blood glucose concentration and fecal pH and decreased fecal propionate molar proportion. Additionally, RP-Leu increased fibrolytic genera Ruminiclostridium and Pseudobutyrivibrio and decreased the amylolytic genus of Faecalibacterium. The second experiment compared RP-Leu and rumen-protected lysine (RP-Lys) for their effects on post-ruminal starch digestion in 6-mo-old calves (201 ± 24 kg body weight). The responses of blood glucose concentration, fecal pH, fecal propionate proportion, and starch digestibility to RP-Leu supplementation were similar to those observed in experiment 1. Cellulolytic family Ruminococcaceae and Bacteroidales BS11 gut group tended to be increased by RP-Leu. In contrast, RP-Lys showed no significant influence on the above measurements. The third experiment determined the interaction between RP-Leu and rumen-escape starch (RES) on the small intestinal digestion of starch in 8-mo-old calves (289 ± 26 kg body weight). An interaction between RP-Leu and RES levels was observed in fecal butyrate concentration and the relative abundance of family Bacteroidaceae, and genera Ruminococcaceae UCG-005 and Bacteroides. We found that RP-Leu tended to increase the abundance of fecal Firmicutes and decrease Spirochaetae. In conclusion, RP-Leu, but not RP-Lys, increased blood glucose concentration and decreased the amount of starch fermented in the hindgut in a RES dose-dependent manner, suggesting that RP-Leu might stimulate starch digestion in the small intestine.

Paternal chronic folate supplementation induced the transgenerational inheritance of acquired developmental and metabolic changes in chickens.

Increasing evidence indicates that paternal diet can result in metabolic changes in offspring, but the definite mechanism remains unclear in birds. Here, we fed breeder cocks five different diets containing 0, 0.25, 1.25, 2.50 and 5.00 mg kg-1 folate throughout life. Paternal folate supplementation (FS) was beneficial to the growth and organ development of broiler offspring. Most importantly, the lipid and glucose metabolism of breeder cocks and broiler offspring were affected by paternal FS, according to biochemical and metabolomic analyses. We further employed global analyses of hepatic and spermatozoal messenger RNA (mRNA), long non-coding RNA (lncRNA) and micro RNA (miRNA). Some key genes involved in the glycolysis or gluconeogenesis pathway and the PPAR signalling pathway, including PEPCK, ANGPTL4 and THRSP, were regulated by differentially expressed hepatic and spermatozoal miRNAs and lncRNAs in breeder cocks and broiler offspring. Moreover, the expression of ANGPTL4 could also be regulated by differentially expressed miRNAs and lncRNAs in spermatozoa via competitive endogenous RNA (ceRNA) mechanisms. Overall, this model suggests that paternal folate could transgenerationally regulate lipid and glucose metabolism in broiler offspring and the epigenetic transmission may involve altered spermatozoal miRNAs and lncRNAs.

Identification and characterization of long noncoding RNAs and mRNAs expression profiles related to postnatal liver maturation of breeder roosters using Ribo-zero RNA sequencing.

BACKGROUND: The liver is mainly hematopoietic in the embryo, and converts into a major metabolic organ in the adult. Therefore, it is intensively remodeled after birth to adapt and perform adult functions. Long non-coding RNAs (lncRNAs) are involved in organ development and cell differentiation, likely they have potential roles in regulating postnatal liver development. Herein, in order to understand the roles of lncRNAs in postnatal liver maturation, we analyzed the lncRNAs and mRNAs expression profiles in immature and mature livers from one-day-old and adult (40 weeks of age) breeder roosters by Ribo-Zero RNA-Sequencing. RESULTS: Around 21,939 protein-coding genes and 2220 predicted lncRNAs were expressed in livers of breeder roosters. Compared to protein-coding genes, the identified chicken lncRNAs shared fewer exons, shorter transcript length, and significantly lower expression levels. Notably, in comparison between the livers of newborn and adult breeder roosters, a total of 1570 mRNAs and 214 lncRNAs were differentially expressed with the criteria of log2fold change > 1 or < - 1 and P values < 0.05, which were validated by qPCR using randomly selected five mRNAs and five lncRNAs. Further GO and KEGG analyses have revealed that the differentially expressed mRNAs were involved in the hepatic metabolic and immune functional changes, as well as some biological processes and pathways including cell proliferation, apoptotic and cell cycle that are implicated in the development of liver. We also investigated the cis- and trans- regulatory effects of differentially expressed lncRNAs on its target genes. GO and KEGG analyses indicated that these lncRNAs had their neighbor protein coding genes and trans-regulated genes associated with adapting of adult hepatic functions, as well as some pathways involved in liver development, such as cell cycle pathway, Notch signaling pathway, Hedgehog signaling pathway, and Wnt signaling pathway. CONCLUSIONS: This study provides a catalog of mRNAs and lncRNAs related to postnatal liver maturation of chicken, and will contribute to a fuller understanding of biological processes or signaling pathways involved in significant functional transition during postnatal liver development that differentially expressed genes and lncRNAs could take part in.

Variation in proteomics and metabolomics of chicken hepatocytes exposed to medium with or without folic acid.

Hepatocytes are suitable models for metabolism study. Combined proteomics and metabolomics approaches should provide a comprehensive understanding for the effect of folic acid on hepatic metabolism in vitro. Primary chicken liver cells were exposed to medium with or without folic acid. The combined analyses uncovered 61 differential proteins and 43 differential metabolites between groups with or without folic acid in culture medium. Further pathway annotations revealed that RNA transport, protein processing, TCA cycle, glycolysis, pyruvate metabolism, and so on were significantly enriched. Meanwhile, lipid metabolism was enhanced in no folic acid group along with higher adipose triglyceride lipase, and 2-hydroxybutyric acid level. Concomitantly, amino acid, and carbohydrates metabolism were disturbed. Some amino acids level were changed as well as sugar-acids and sugar-alcohols. In addition, antioxidant function was altered resulting from perturbation of glutathione metabolism, glutamate, and cysteine metabolism. In conclusion, our results indicated that folic acid might affect antioxidant function and metabolism of lipid, amino acid, and carbohydrates in primary chicken hepatocytes via integrating proteomics, and metabolomics analyses method. These results may provide an insight into the effect of folic acid on hepatic metabolism in future research direction.

SNP and haplotype analysis reveal IGF2 variants associated with growth traits in Chinese Qinchuan cattle.

Insulin-like growth factor 2 (IGF2) is a potent cell growth and differentiation factor and is implicated in mammals' growth and development. The objective of this study was to evaluate the effects of the mutations in the bovine IGF2 with growth traits in Chinese Qinchuan cattle. Four single nucleotide polymorphisms (SNPs) were detected of the bovine IGF2 by DNA pool sequencing and forced polymerase chain reaction-restriction fragment length polymorphism (forced PCR-RFLP) methods. We also investigated haplotype structure and linkage disequilibrium (LD) coefficients for four SNPs in 817 individuals representing two main cattle breeds from China. The result of haplotype analysis showed eight different haplotypes and 27 combined genotypes within the study population. The statistical analyses indicated that the four SNPs, combined genotypes and haplotypes are associated with the withers height, body length, chest breadth, chest depth and body weight in Qinchuan cattle population (P < 0.05 or <0.01). The mutant-type variants and mutant haplotype (Hap 8: ATGG; likely to be the beneficial QTN allele) was superior for growth traits; the heterozygote diplotype was associated with higher growth traits compared to wild-type homozygote. Our results provide evidence that polymorphisms in the IGF2 gene are associated with growth traits, and may be used for marker-assisted selection in beef cattle breeding program.

Understanding host immune responses in Clostridioides difficile infection: Implications for pathogenesis and immunotherapy.

Clostridioides difficile (C. difficile) is the predominant causative agent of nosocomial diarrhea worldwide. Infection with C. difficile occurs due to the secretion of large glycosylating toxin proteins, which can lead to toxic megacolon or mortality in susceptible hosts. A critical aspect of C. difficile's biology is its ability to persist asymptomatically within the human host. Individuals harboring asymptomatic colonization or experiencing a single episode of C. difficile infection (CDI) without recurrence exhibit heightened immune responses compared to symptomatic counterparts. The significance of these immune responses cannot be overstated, as they play critical roles in the development, progression, prognosis, and outcomes of CDI. Nonetheless, our current comprehension of the immune responses implicated in CDI remains limited. Therefore, further investigation is imperative to elucidate their underlying mechanisms. This review explores recent advancements in comprehending CDI pathogenesis and how the host immune system response influences disease progression and severity, aiming to enhance our capacity to develop immunotherapy-based treatments for CDI.

Dietary fat and carbohydrate-balancing the lactation performance and methane emissions in the dairy cow industry: A meta-analysis.

For the agroecosystems of the dairy cow industry, dietary carbohydrate (starch, neutral detergent fiber [NDF]) and fat could directly affect rumen methane emissions and host energy utilization. However, the relationships among diet, lactation performance, and methane emissions need to be further determined to assist dairy farms to adjust diet formulations and feeding strategies for environmental and production management. A meta-analysis was conducted in the current study to explore quantitative patterns of dietary fat and carbohydrate at different levels in balancing lactation performance and environment sustainability of dairy cows, and to establish a methane emission prediction model using the artificial neural network (ANN) model. The results showed that the regression relationship between dietary fat, carbohydrate and methane emissions could be shown by the following models: methane = 106.78 + (14.86 × DMI), R2 = 0.80; methane = 443.17 - (46.41 × starch/NDF), R2 = 0.76; and methane = 388.91 + (31.40 × fat) - (5.42 × fat2), R2 = 0.80. The regression relationships between dietary fat, carbohydrate and lactation performance could be shown by the following models: milk fat yield = 1.08 + (0.43 × starch/NDF) - [0.34 × (starch/NDF)2], R2 = 0.79; milk protein yield = 0.68 + (0.15 × fat) - (0.016 × fat2), R2 = 0.82. In the structural equation model, we found that when formulating dietary carbohydrates and fats, it was necessary to balance the relationship between methane emissions and lactation performance. Specifically, dietary starch/NDF was lower than 0.63 (extremum point) and dietary fat was between 2.89% and 4.69% (extremum point), it could ensure that the aim of methane emission reduction (methane emissions decrease with increasing dietary starch/NDF and fat) was achieved without losing lactation performance of dairy cows (lactation performance increase with increasing dietary starch/NDF and fat). Finally, we established the ANN model to predict methane emissions (training set: R2 = 0.62; validation set: R2 = 0.61).

Multi-omics reveal mechanisms of high enteral starch diet mediated colonic dysbiosis via microbiome-host interactions in young ruminant.

BACKGROUND: Although rumen development is crucial, hindgut undertakes a significant role in young ruminants' physiological development. High-starch diet is usually used to accelerate rumen development for young ruminants, but always leading to the enteral starch overload and hindgut dysbiosis. However, the mechanism behind remains unclear. The combination of colonic transcriptome, colonic luminal metabolome, and metagenome together with histological analysis was conducted using a goat model, with the aim to identify the potential molecular mechanisms behind the disrupted hindgut homeostasis by overload starch in young ruminants. RESULT: Compared with low enteral starch diet (LES), high enteral starch diet (HES)-fed goats had significantly higher colonic pathology scores, and serum diamine oxidase activity, and meanwhile significantly decreased colonic mucosal Mucin-2 (MUC2) protein expression and fecal scores, evidencing the HES-triggered colonic systemic inflammation. The bacterial taxa Prevotella sp. P4-67, Prevotella sp. PINT, and Bacteroides sp. CAG:927, together with fungal taxa Fusarium vanettenii, Neocallimastix californiae, Fusarium sp. AF-8, Hypoxylon sp. EC38, and Fusarium pseudograminearum, and the involved microbial immune pathways including the "T cell receptor signaling pathway" were higher in the colon of HES goats. The integrated metagenome and host transcriptome analysis revealed that these taxa were associated with enhanced pathogenic ability, antigen processing and presentation, and stimulated T helper 2 cell (TH2)-mediated cytokine secretion functions in the colon of HES goats. Further luminal metabolomics analysis showed increased relative content of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), and decreased the relative content of hypoxanthine in colonic digesta of HES goats. These altered metabolites contributed to enhancing the expression of TH2-mediated inflammatory-related cytokine secretion including GATA Binding Protein 3 (GATA3), IL-5, and IL-13. Using the linear mixed effect model, the variation of MUC2 biosynthesis explained by the colonic bacteria, bacterial functions, fungi, fungal functions, and metabolites were 21.92, 20.76, 19.43, 12.08, and 44.22%, respectively. The variation of pathology scores explained by the colonic bacterial functions, fungal functions, and metabolites were 15.35, 17.61, and 57.06%. CONCLUSIONS: Our findings revealed that enteral starch overload can trigger interrupted hindgut host-microbiome homeostasis that led to impaired mucosal, destroyed colonic water absorption, and TH2-mediated inflammatory process. Except for the colonic metabolites mostly contribute to the impaired mucosa, the nonnegligible contribution from fungi deserves more future studies focused on the fungal functions in hindgut dysbiosis of young ruminants. Video Abstract.

Beyond faecal microbiota transplantation, the non-negligible role of faecal virome or bacteriophage transplantation.

Intestinal microbiota, which contains bacteria, archaea, fungi, protists, and viruses including bacteriophages, is symbiotic and evolves together with humans. The balanced intestinal microbiota plays indispensable roles in maintaining and regulating host metabolism and health. Dysbiosis has been associated with not only intestinal diseases but other diseases such as neurology disorders and cancers. Faecal microbiota transplantation (FMT) or faecal virome or bacteriophage transplantation (FVT or FBT), transfers faecal bacteria or viruses, with a focus on bacteriophage, from one healthy individual to another individual (normally unhealthy condition), and aims to restore the balanced gut microbiota and assist in subduing diseases. In this review, we summarized the applications of FMT and FVT in clinical settings, discussed the advantages and challenges of FMT and FVT currently and proposed several considerations prospectively. We further provided our understanding of why FMT and FVT have their limitations and raised the possible future development strategy of FMT and FVT.

Promotion of intestinal epithelial cell apoptosis by enterotoxigenic Escherichia coli via PKA-mediated inhibition of mTORC1 activation.

Enterotoxigenic Escherichia coli (ETEC) is the main causative pathogen of diarrhea. It causes acute watery diarrhea that leads to rapid dehydration and prostration within hours. ETEC is still an important cause of neonatal and post-weaning diarrhea in pigs. However, the mechanism underlying ETEC-induced diarrhea is not yet clear. In this study, we investigated these mechanisms and found that the mTORC1 pathway plays a role in the host response to ETEC F4 infection. Specifically, we found that ETEC F4 treatment significantly repressed mTORC1 activity as well as cell proliferation, promoted apoptosis and regulated the expression of diarrhea-related genes via the promotion of PKA-mediated phosphorylation of SIN1, which plays a critical role in the assembly of mTORC2. These findings indicate that PKA is a checkpoint for ETEC-induced diarrhea. In terms of potential therapeutic strategies, we found that ZnSO4 dramatically rescued ETEC F4-induced the inhibition of mTORC1 activity and cell viability and the induction of apoptosis and alterations in the expression of diarrhea-related genes. Thus, the present findings demonstrate that ETEC F4 influences mTORC1 activation by inhibiting the assembly of mTORC2 through PKA-mediated phosphorylation of SIN1. Further, supplementation with ZnSO4 is an effective strategy for blocking the effect of ETEC F4 on mTORC1 activation, and it may have potential clinical applications in the treatment of ETEC F4-induced diarrhea.

Farnesoid X Receptor (FXR) Regulates mTORC1 Signaling and Autophagy by Inhibiting SESN2 Expression.

SCOPE: The mechanistic target of rapamycin complex 1 (mTORC1), as a link between nutrients and autophagy, senses many nutrients in the microenvironment. A growing body of recent literature describes the function of bile acids (BAs) as versatile signaling molecules, while it remains largely unclear whether mTORC1 can sense BAs and the mechanism has not been studied. METHODS AND RESULTS: After treating LO2 cells with indicated concentration of chenodeoxycholic acid (CDCA) and farnesoid X receptor (FXR) inhibitor/activator for 6 h, it finds that CDCA and FXR significantly accelerate mTORC1 activation. The results of immunofluorescence indicate that CDCA and FXR inhibit cellular autophagy through activating mTORC1 pathway. In particular, these findings show that CDCA and FXR promote the lysosomal translocation and activation of mTORC1 in an amino acid-sensitive manner. Mechanistically, the transcriptomics data indicate that SESN2 is a checkpoint for mTORC1 lysosome translocation and activation induced by FXR, and knockdown SESN2 with siRNA suppresses the regulation of FXR on autophagy. CONCLUSION: These results indicate that FXR-induced decrease in SESN2 expression and activation of the mTORC1 pathway can control autophagy and be explored as potential therapeutic targets for enterohepatic and metabolic disorders.

Multi-omics reveals that the host-microbiome metabolism crosstalk of differential rumen bacterial enterotypes can regulate the milk protein synthesis of dairy cows.

BACKGROUND: Dairy cows' lactation performance is the outcome of the crosstalk between ruminal microbial metabolism and host metabolism. However, it is still unclear to what extent the rumen microbiome and its metabolites, as well as the host metabolism, contribute to regulating the milk protein yield (MPY). METHODS: The rumen fluid, serum and milk of 12 Holstein cows with the same diet (45% coarseness ratio), parity (2-3 fetuses) and lactation days (120-150 d) were used for the microbiome and metabolome analysis. Rumen metabolism (rumen metabolome) and host metabolism (blood and milk metabolome) were connected using a weighted gene co-expression network (WGCNA) and the structural equation model (SEM) analyses. RESULTS: Two different ruminal enterotypes, with abundant Prevotella and Ruminococcus, were identified as type1 and type2. Of these, a higher MPY was found in cows with ruminal type2. Interestingly, [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae (the differential bacteria) were the hub genera of the network. In addition, differential ruminal, serum and milk metabolome between enterotypes were identified, where the cows with type2 had higher L-tyrosine of rumen, ornithine and L-tryptophan of serum, and tetrahydroneopterin, palmitoyl-L-carnitine, S-lactoylglutathione of milk, which could provide more energy and substrate for MPY. Further, based on the identified modules of ruminal microbiome, as well as ruminal serum and milk metabolome using WGCNA, the SEM analysis indicated that the key ruminal microbial module1, which contains the hub genera of the network ([Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae) and high abundance of bacteria (Prevotella and Ruminococcus), could regulate the MPY by module7 of rumen, module2 of blood, and module7 of milk, which contained L-tyrosine and L-tryptophan. Therefore, in order to more clearly reveal the process of rumen bacterial regulation of MPY, we established the path of SEM based on the L-tyrosine, L-tryptophan and related components. The SEM based on the metabolites suggested that [Ruminococcus] gauvreauii group could inhibit the energy supply of serum tryptophan to MPY by milk S-lactoylglutathione, which could enhance pyruvate metabolism. Norank_f_Ruminococcaceae could increase the ruminal L-tyrosine, which could provide the substrate for MPY. CONCLUSION: Our results indicated that the represented enterotype genera of Prevotella and Ruminococcus, and the hub genera of [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae could regulate milk protein synthesis by affecting the ruminal L-tyrosine and L-tryptophan. Moreover, the combined analysis of enterotype, WGCNA and SEM could be used to connect rumen microbial metabolism with host metabolism, which provides a fundamental understanding of the crosstalk between host and microorganisms in regulating the synthesis of milk composition.

The salivary microbiota is altered in cervical dysplasia patients and influenced by conization.

This study supports the correlation between the salivary microbiota and cervical dysplasia and suggests that smoking influences the salivary microbiota.

An overview of host-derived molecules that interact with gut microbiota.

The gut microbiota comprises bacteria, archaea, fungi, protists, and viruses that live together and interact with each other and with host cells. A stable gut microbiota is vital for regulating host metabolism and maintaining body health, while a disturbed microbiota may induce different kinds of disease. In addition, diet is also considered to be the main factor that influences the gut microbiota. The host could shape the gut microbiota through other factors. Here, we reviewed the mechanisms that mediate host regulation on gut microbiota, involved in gut-derived molecules, including gut-derived immune system molecules (secretory immunoglobulin A, antimicrobial peptides, cytokines, cluster of differentiation 4+ effector T cell, and innate lymphoid cells), sources related to gut-derived mucosal molecules (carbon sources, nitrogen sources, oxygen sources, and electron respiratory acceptors), gut-derived exosomal noncoding RNA (ncRNAs) (microRNAs, circular RNA, and long ncRNA), and molecules derived from organs other than the gut (estrogen, androgen, neurohormones, bile acid, and lactic acid). This study provides a systemic overview for understanding the interplay between gut microbiota and host, a comprehensive source for potential ways to manipulate gut microbiota, and a solid foundation for future personalized treatment that utilizes gut microbiota.

Metagenomic and single-cell RNA-Seq survey of the Helicobacter pylori-infected stomach in asymptomatic individuals.

Helicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. To deeply characterize the host-microbiota environment in H. pylori-infected (HPI) stomachs, we collected human gastric tissues and performed metagenomic sequencing, single-cell RNA-Seq (scRNA-Seq), flow cytometry, and fluorescent microscopy. HPI asymptomatic individuals had dramatic changes in the composition of gastric microbiome and immune cells compared with noninfected individuals. Metagenomic analysis uncovered pathway alterations related to metabolism and immune response. scRNA-Seq and flow cytometry data revealed that, in contrast to murine stomachs, ILC2s are virtually absent in the human gastric mucosa, whereas ILC3s are the dominant population. Specifically, proportion of NKp44+ ILC3s out of total ILCs were highly increased in the gastric mucosa of asymptomatic HPI individuals, and correlated with the abundance of selected microbial taxa. In addition, CD11c+ myeloid cells and activated CD4+ T cells and B cells were expanded in HPI individuals. B cells of HPI individuals acquired an activated phenotype and progressed into a highly proliferating germinal-center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria. Our study provides a comprehensive atlas of the gastric mucosa-associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.

Multi-omics revealed the long-term effect of ruminal keystone bacteria and the microbial metabolome on lactation performance in adult dairy goats.

BACKGROUND: The increased growth rate of young animals can lead to higher lactation performance in adult goats; however, the effects of the ruminal microbiome on the growth of young goats, and the contribution of the early-life rumen microbiome to lifelong growth and lactation performance in goats has not yet been well defined. Hence, this study assessed the rumen microbiome in young goats with different average daily gains (ADG) and evaluated its contribution to growth and lactation performance during the first lactation period. RESULTS: Based on monitoring of a cohort of 99 goats from youth to first lactation, the 15 highest ADG (HADG) goats and 15 lowest ADG (LADG) goats were subjected to rumen fluid microbiome and metabolome profiling. The comparison of the rumen metagenome of HADG and LADG goats revealed that ruminal carbohydrate metabolism and amino acid metabolism function were enhanced in HADG goats, suggesting that the rumen fluid microbiome of HADG goats has higher feed fermentation ability. Co-occurrence network and correlation analysis revealed that Streptococcus, Candidatus Saccharimonans, and Succinivibrionaceae UCG-001 were significantly positively correlated with young goats' growth rates and some HADG-enriched carbohydrate and protein metabolites, such as propionate, butyrate, maltoriose, and amino acids, while several genera and species of Prevotella and Methanogens exhibited a negative relationship with young goats' growth rates and correlated with LADG-enriched metabolites, such as rumen acetate as well as methane. Additionally, some functional keystone bacterial taxa, such as Prevotella, in the rumen of young goats were significantly correlated with the same taxa in the rumen of adult lactation goats. Prevotella also enriched the rumen of LADG lactating goats and had a negative effect on rumen fermentation efficiency in lactating goats. Additional analysis using random forest machine learning showed that rumen fluid microbiota and their metabolites of young goats, such as Prevotellaceae UCG-003, acetate to propionate ratio could be potential microbial markers that can potentially classify high or low ADG goats with an accuracy of prediction of > 81.3%. Similarly, the abundance of Streptococcus in the rumen of young goats could be predictive of milk yield in adult goats with high accuracy (area under the curve 91.7%). CONCLUSIONS: This study identified the keystone bacterial taxa that influence carbohydrate and amino acid metabolic functions and shape the rumen fluid microbiota in the rumen of adult animals. Keystone bacteria and their effects on rumen fluid microbiota and metabolome composition during early life can lead to higher lactation performance in adult ruminants. These findings suggest that the rumen microbiome together with their metabolites in young ruminants have long-term effect on feed efficiency and animal performance. The fundamental knowledge may allow us to develop advanced methods to manipulate the rumen microbiome and improve production efficiency of ruminants. Video Abstract.

The right bug in the right place: opportunities for bacterial vaginosis treatment.

Bacterial vaginosis (BV) is a condition in which the vaginal microbiome presents an overgrowth of obligate and facultative anaerobes, which disturbs the vaginal microbiome balance. BV is a common and recurring vaginal infection among women of reproductive age and is associated with adverse health outcomes and a decreased quality of life. The current recommended first-line treatment for BV is antibiotics, despite the high recurrence rate. Live biopharmaceutical products/probiotics and vaginal microbiome transplantation (VMT) have also been tested in clinical trials for BV. In this review, we discuss the advantages and challenges of current BV treatments and interventions. Furthermore, we provide our understanding of why current clinical trials with probiotics have had mixed results, which is mainly due to not administering the correct bacteria to the correct body site. Here, we propose a great opportunity for large clinical trials with probiotic strains isolated from the vaginal tract (e.g., Lactobacillus crispatus) and administered directly into the vagina after pretreatment.