Microbial Genetic Composition Tunes Host Longevity.

Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.

Feeding live yeast (Saccharomyces cerevisiae) improved performance of mid-lactation dairy cows by altering ruminal bacterial communities and functions of serum antioxidation and immune responses.

BACKGROUND: The utilization of live yeast (Saccharomyces cerevisiae, YE) in dairy cows is gaining traction in dairy production as a potential strategy to improve feed efficiency and milk yield. However, the effects of YE on dairy cow performance remain inconsistent across studies, leaving the underlying mechanisms unclear. Hence, the primary aim of this study was to investigate the impact of YE supplementation on lactation performance, ruminal microbiota composition and fermentation patterns, as well as serum antioxidant capacity and immune functions in dairy cows. RESULTS: Supplementation with YE (20 g/d/head) resulted in enhancements in dairy cow's dry matter intake (DMI) (P = 0.016), as well as increased yields of milk (P = 0.002) and its components, including solids (P = 0.003), fat (P = 0.014), protein (P = 0.002), and lactose (P = 0.001) yields. The addition of YE led to significant increases in the concentrations of ammonia nitrogen (NH3-N) (P = 0.023), acetate (P = 0.005), propionate (P = 0.025), valerate (P = 0.003), and total volatile fatty acids (VFAs) (P < 0.001) in rumen fermentation parameters. The analysis of 16s rRNA gene sequencing data revealed that the administration of YE resulted in a rise in the relative abundances of three primary genera including Ruminococcus_2 (P = 0.010), Rikenellaceae_RC9_gut_group (P = 0.009), and Ruminococcaceae_NK4A214_group (P = 0.054) at the genus level. Furthermore, this increase was accompanied with an enriched pathway related to amino acid metabolism. Additionally, enhanced serum antioxidative (P < 0.05) and immune functionalities (P < 0.05) were also observed in the YE group. CONCLUSIONS: In addition to improving milk performance, YE supplementation also induced changes in ruminal bacterial community composition and fermentation, while enhancing serum antioxidative and immunological responses during the mid-lactation stage. These findings suggest that YE may exert beneficial effects on both rumen and blood metabolism in mid-lactation dairy cows.

A g-type lysozyme from the scallop Argopecten purpuratus participates in the immune response and in the stability of the hemolymph microbiota.

Lysozymes are antimicrobial acid hydrolases widely distributed in nature. They are located inside the cells in lysosomes, or they are secreted to the extracellular space, where they can lyse the cell wall of certain species of bacteria via hydrolysis of the peptidoglycan. Thus, lysozymes are bacteriolytic enzymes and play a major biological role in biodefense, as these enzymes can act as antibacterial and immune-modulating agents. In this study, we characterized a g-type lysozyme from the scallop Argopecten purpuratus named ApGlys. The cDNA sequence comprises an open reading frame (ORF) of 600 nucleotides, codifying for a putative protein of 200 amino acids with a signal peptide of 18 amino acids. The deduced mature protein sequence displays a molecular weight of 20.07 kDa and an isoelectric point (pI) of 6.49. ApGlys deduced protein sequence exhibits conserved residues associated with catalytic activity and substrate fixation in other g-type lysozymes. The phylogenetic analysis revealed a high degree of identity of ApGlys with other mollusk g-type lysozymes, which form a restricted and separated clade from the vertebrate lysozymes. ApGlys transcripts were constitutively and highly expressed in the digestive gland, and it was induced in hemocytes and gills of scallops after an immune challenge. Furthermore, the ApGlys protein was located inside hemocytes of immunostimulated scallops, determined by immunofluorescence analysis. Finally, the transcript silencing of ApGlys by RNA interference led to an increase of total culturable bacteria from the scallop hemolymph. Furthermore, we detected a higher diversity of the bacterial community in ApGlys-silenced scallops and an imbalance of certain bacterial groups present in the hemolymph by 16S rDNA deep amplicon sequencing. Overall, our results showed that ApGlys is a new member of scallop lysozymes that is implicated in the immune response and in the microbial homeostasis of A. purpuratus hemolymph.

Interactions between bile salts, gut microbiota, and hepatic innate immunity.

Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.

Short-chain fatty acids: Bacterial messengers modulating the immunometabolism of T cells.

Short-chain fatty acids (SCFAs) are mainly generated by bacterial fermentation of non-digestible carbohydrates such as dietary fiber. In the last decade, new investigations have revealed that SCFAs have a very specific function and serve as active microbial metabolites, which are able to modulate the function of immune cells in the intestine and other tissues. Recent studies have highlighted the immunomodulatory potential of SCFAs in several autoimmune and inflammatory disorders such as multiple sclerosis, colitis, type 1 diabetes and rheumatoid arthritis. While the SCFA-mediated activation of GPR41/GPR43 signalling pathways and their inhibitory activity on histone deacetylases have been extensively investigated, the impact of SCFAs on the T cell metabolism is poorly understood. SCFAs induce metabolic alterations in T cells by enhancing the activity of the mTOR complex and by regulating their glucose metabolism. Once taken up into T lymphocytes, SCFA-derived acetyl groups contribute to the cellular acetyl-CoA pool, which influences the histone acetylation and cytokine gene expression. This article reviews how SCFAs modulate the metabolic status of T cells, thereby impacting on epigenetic modifications and T cell function. We will also discuss how the recent findings from SCFA biology might be utilized for potential immune therapies of various autoimmune diseases.

Metabolic networks of the human gut microbiota.

The human gut microbiota controls factors that relate to human metabolism with a reach far greater than originally expected. Microbial communities and human (or animal) hosts entertain reciprocal exchanges between various inputs that are largely controlled by the host via its genetic make-up, nutrition and lifestyle. The composition of these microbial communities is fundamental to supply metabolic capabilities beyond those encoded in the host genome, and contributes to hormone and cellular signalling that support the dynamic adaptation to changes in food availability, environment and organismal development. Poor functional exchange between the microbial communities and their human host is associated with dysbiosis, metabolic dysfunction and disease. This review examines the biology of the dynamic relationship between the reciprocal metabolic state of the microbiota-host entity in balance with its environment (i.e. in healthy states), the enzymatic and metabolic changes associated with its imbalance in three well-studied diseases states such as obesity, diabetes and atherosclerosis, and the effects of bariatric surgery and exercise.

Microbiota and cancer: host cellular mechanisms activated by gut microbial metabolites.

In recent years, more and more data indicate the effect of human microbiota on carcinogenesis. Despite the numerous studies on the relationship between gut microbiota and carcinogenesis, the exact mechanisms of this interaction are not well studied. It becomes apparent that this relationship can be mediated by microbial metabolites. Mechanisms of some well-known bacterial genotoxins and oncogenes, such as colibactin, CagA, IpgD, VirA, P37, have been studied in detail. At the same time, a role in carcinogenesis of a large group of gut microbial metabolites, including short-chain fatty acids, polyamines, and products of polyphenol and tryptophan catabolism, is less well understood. However, more and more evidence data show the effect of bacterial metabolites on cancer development and progression. In this review, we summarize relevant data regarding the possible mechanisms that can account for the effects of gut microbial metabolites mentioned above in carcinogenesis.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

BACKGROUND: It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. OBJECTIVE: We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. METHODS: Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment. RESULTS: Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. CONCLUSIONS: Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

Maternal milk and fecal microbes guide the spatiotemporal development of mucosa-associated microbiota and barrier function in the porcine neonatal gut.

BACKGROUND: The early-life microbiota exerts a profound and lifelong impact on host health. Longitudinal studies in humans have been informative but are mostly based on the analysis of fecal samples and cannot shed direct light on the early development of mucosa-associated intestinal microbiota and its impact on GI function. Using piglets as a model for human infants, we assess here the succession of mucosa-associated microbiota across the intestinal tract in the first 35 days after birth. RESULTS: Although sharing a similar composition and predicted functional profile at birth, the mucosa-associated microbiome in the small intestine (jejunum and ileum) remained relatively stable, while that of the large intestine (cecum and colon) quickly expanded and diversified by day 35. Among detected microbial sources (milk, vagina, areolar skin, and feces of sows, farrowing crate, and incubator), maternal milk microbes were primarily responsible for the colonization of the small intestine, contributing approximately 90% bacteria throughout the first 35 days of the neonatal life. Although maternal milk microbes contributed greater than 90% bacteria to the large intestinal microbiota of neonates upon birth, their presence gradually diminished, and they were replaced by maternal fecal microbes by day 35. We found strong correlations between the relative abundance of specific mucosa-associated microbes, particularly those vertically transmitted from the mother, and the expression levels of multiple intestinal immune and barrier function genes in different segments of the intestinal tract. CONCLUSION: We revealed spatially specific trajectories of microbial colonization of the intestinal mucosa in the small and large intestines, which can be primarily attributed to the colonization by vertically transmitted maternal milk and intestinal microbes. Additionally, these maternal microbes may be involved in the establishment of intestinal immune and barrier functions in neonates. Our findings strengthen the notion that studying fecal samples alone is insufficient to fully understand the co-development of the intestinal microbiota and immune system and suggest the possibility of improving neonatal health through the manipulation of maternal microbiota.

Do oral and gut microbiota communicate through redox pathways? A novel asset of the nitrate-nitrite-NO pathway.

Nitrate may act as a regulator of •NO bioavailability via sequential reduction along the nitrate-nitrite-NO pathway with widespread health benefits, including a eubiotic effect on the oral and gut microbiota. Here, we discuss the molecular mechanisms of microbiota-host communication through redox pathways, via the production of •NO and oxidants by the family of NADPH oxidases, namely hydrogen peroxide (via Duox2), superoxide radical (via Nox1 and Nox2) and peroxynitrite, which leads to downstream activation of stress responses (Nrf2 and NFkB pathways) in the host mucosa. The activation of Nox2 by microbial metabolites is also discussed. Finally, we propose a new perspective in which both oral and gut microbiota communicate through redox pathways, with nitrate as the pivot linking both ecosystems.

The Colonization of Rumen Microbiota and Intervention in Pre-Weaned Ruminants.

In pre-weaned ruminants, the microbiota colonizes rapidly in the rumen after birth and constantly interacts with the host to sustain health and metabolism. The developing microbial community is more malleable, so its manipulation may improve ruminant health and productivity as well as may have long-term effects on ruminants. Hence, understanding the process of rumen microbiota establishment is helpful for nutritional interventions of rumen microbiota in pre-weaned ruminants. This paper reviews the latest advances in the colonization of rumen microbiota while providing insights into the most suitable time for manipulating rumen microbial colonization in early life. In addition, different factors that affect rumen microbiota establishment during the pre-weaned ruminants are discussed in the current manuscript. The purpose of this review is to aid in the development of guidelines for manipulating rumen microbiota to improve animal productivity and health.

Serratia marcescens in the intestine of housefly larvae inhibits host growth by interfering with gut microbiota.

BACKGROUND: The structure of gut microbiota is highly complex. Insects have ubiquitous associations with intestinal symbiotic bacteria, which play essential roles. Thus, understanding how changes in the abundance of a single bacterium interfere with bacterial interactions in the insect's gut is important. METHODS: Here, we analyzed the effects of Serratia marcescens on the growth and development of housefly larvae using phage technology. We used 16S rRNA gene sequencing technology to explore dynamic diversity and variation in gut bacterial communities and performed plate confrontation assays to study the interaction between S. marcescens and intestinal microorganisms. Furthermore, we performed phenoloxidase activity assay, crawling assay, and trypan blue staining to explore the negative effects of S. marcescens on housefly larvae's humoral immunity, motility, and intestinal organization. RESULTS: The growth and development of housefly larvae were inhibited after feeding on S. marcescens, and their intestinal bacterial composition changed with increasing abundance of Providencia and decreasing abundance of Enterobacter and Klebsiella. Meanwhile, the depletion of S. marcescens by phages promoted the reproduction of beneficial bacteria. CONCLUSIONS: In our study, using phage as a tool to regulate the abundance of S. marcescens, we highlighted the mechanism by which S. marcescens inhibits the growth and development of housefly larvae and illustrated the importance of intestinal flora for larval development. Furthermore, by studying the dynamic diversity and variation in gut bacterial communities, we improved our understanding of the possible relationship between the gut microbiome and housefly larvae when houseflies are invaded by exogenous pathogenic bacteria.

Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism.

Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways via the "gut microbiota-brain axis" (GMBA). Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.

Does the Gut Microbiota Modulate Host Physiology through Polymicrobial Biofilms?

Microbes inhabit various environments, such as soil, water environments, plants, and animals. Humans harbor a complex commensal microbial community in the gastrointestinal tract, which is known as the gut microbiota. The gut microbiota participates not only in various metabolic processes in the human body, it also plays a critical role in host immune responses. Gut microbes that inhabit the intestinal epithelial surface form polymicrobial biofilms. In the last decade, it has been widely reported that gut microbial biofilms and gut microbiota-derived products, such as metabolites and bacterial membrane vesicles, not only directly affect the host intestinal environment, but also indirectly influence the health of the host. In this review, we discuss the most recent findings from human and animal studies on the interactions between the gut microbiota and hosts, and their associations with various disorders, including inflammatory diseases, atopic dermatitis, metabolic disorders, and psychiatric and neurological diseases. The integrated approach of metabologenomics together with biofilm imaging may provide valuable insights into the gut microbiota and suggest remedies that may lead to a healthier society.

The effects of cigarettes and alcohol on intestinal microbiota in healthy men.

Human intestinal microbiota is affected by the exogenous microenvironment. This study aimed to determine the effects of cigarettes and alcohol on the gut microbiota of healthy men. In total, 116 healthy male subjects were enrolled and divided into four groups: non-smoking and non-drinking (Group A), smoking only (Group B), drinking only (Group C), and smoking and drinking combined (Group D). Fecal samples were collected and sequenced using 16S rRNA to analyze the microbial composition. Short-chain fatty acid (SCFAs) levels in feces were determined by gas chromatography. We found that cigarette and alcohol consumptions can alter overall composition of gut microbiota in healthy men. The relative abundances of phylum Bacteroidetes and Firmicutes and more than 40 genera were changed with cigarette and alcohol consumptions. SCFAs decreased with smoking and alcohol consumption. Multivariate analysis indicated that when compared with group A, group B/C/D had higher Bacteroides, and lower Phascolarctobacterium, Ruminococcaceae_UCG-002, Ruminococcaceae_UCG-003, and Ruminiclostridium_9 regardless of BMI and age. Additionally, the abundance of Bacteroides was positively correlated with the smoking pack-year (r = 0.207, p < 0.05), the abundance of predicted pathway of bacterial toxins (r = 0.3672, p < 0.001) and the level of carcinoembryonic antigen in host (r = 0.318, p < 0.01). Group D shared similar microbial construction with group B, but exerted differences far from group C with lower abundance of Haemophilus. These results demonstrated that cigarette and alcohol consumption separately affected the intestinal microbiota and function in healthy men; furthermore, the co-occurrence of cigarette and alcohol didn't exacerbate the dysbiosis and cigarette played the predominated role on the alteration.