Human gut microbiota and healthy aging: Recent developments and future prospective

Abstract

The human gut microbiota alters with the aging process. In the first 2-3 years of life, the gut microbiota varies extensively in composition and metabolic functions. After this period, the intestine microbiota demonstrates adult-like more stable and divers microbial species. however, at old old age, deterioration of physiological functions of the homo consistency enforces the decrease in reckon of beneficial species ( e.g. Bifidobacteria ) in the catgut microbiota, which promotes versatile gut-related diseases ( e.g. inflammatory intestine disease ). use of plant-based diets and probiotics/prebiotics may elevate the abundance of beneficial species and prevent gut-related diseases. still, the connections between diet, microbes, and host are alone partially known. To this end, genome-scale metabolic model can help to explore these connections a well as to expand the understanding of the metabolic capability of each species in the gut microbiota. This systems biology approach can besides predict metabolic variations in the gut microbiota during senesce, and hereby help to design more effective probiotics/prebiotics. Keywords:

Human gut microbiota, aging, diets, probiotics/prebiotics, genome-scale metabolic modeling

1. Introduction

Aging is defined as deterioration of physiological functions accompanied by the development of age [ 18 ]. Based on several studies a connection between the human gut microbiota and age is becoming discernible [ 5, 19– 21 ]. A meaning number of studies have elucidated that human health needs a beneficial intestine microbiota for physical and mental development at every historic period [ 22 ] and alteration in physiologic functions during the aging process can affect the composition and functions of species in the intestine microbiota. A major negative consequence of aging is immunosenescence, which can be defined as a refuse in the functionality of the immune system [ 23 ], which can cause a chronic low-grade incendiary condition in the gut. Immunosenescence can therefore campaign unfavorable changes in the constitution and structure of the catgut microbiota in older people. furthermore, perturbation in the gut microbiota is associated with assorted metabolic and incendiary disorders such as fleshiness [ 24 ], incendiary intestine disease [ 25, 26 ], cranky intestine syndrome [ 27, 28 ] type 1 and type 2 diabetes [ 29– 32 ], atherosclerosis [ 33, 34 ], allergy [ 35 ], autism [ 36 ], and familial Mediterranean fever [ 37 ]. wholly, deterioration in gut-related functions and development can affect the gut microbiota during aging [ 38 ]. Diet, which has been investigated in human subjects and model host [ 39– 44 ], is a major modulator for the catgut microbiota [ 45 ]. however, it is ill known how diet influences composition and function of the gut microbiota and how diet-microbe, microbe-microbe, and microbe-host interact [ 20 ]. here we review holocene research developments in exploring the association between the catgut microbiota and aging. We besides highlight the contribution of diet and probiotics/prebiotics to maintain a beneficial catgut microbiota, and thus contribute to healthy aging. In regulate to design a healthy diet and fresh probiotics/prebiotics, this follow-up includes information about effective approaches that can be employed to acquire better understanding of ( one ) metabolic capability of microbial species in the catgut microbiota and ( two ) interactions between diet, microbes and horde in aging .

2. Variability in the gut microbiota during early life among healthy subjects

Culture-independent techniques for microbiome examen have suggested that there is not a core laid of species-level phylotypes for healthy or normal gut microbiota in humans at individual- and inter-individual-level [ 46 ]. The microbial community composition in the gut differs at inter-individual-level largely on the footing of region-specific diet, geography, health, host genetics, early microbial exposure and old age [ 26, 30, 47– 49 ] and these factors are besides responsible for inducing variability in the gut microbiota over time at the individual-level [ 50 ]. It is believed that during parentage, the baby gut contains no microbial residential district or at least very few species. subsequently, the gut microbiota alters drastically during different stages such as colonization, development, and festering within the first two years of life. Along with the factors described above, there are more factors such as mode of delivery ( vaginal or cesarean delivery ), photograph to antibiotics, feeding type, hospital environment and habit of prebiotic/probiotic, which play meaning roles in the variability of microbial community at the early age of life ( ) [ 51 ]. comparative studies on mode of rescue have demonstrated that colonization of microbes in the catgut differs in vaginal and cesarean manner of speaking, which impacts the exploitation of the immune system in early age of infants [ 52– 54 ]. These studies demonstrated that the intestine microbiota in children delivered by cesarean section contains a lower abundance of Bifidobacteria, Bacteroides Staphylococcus, Corynebacterium, and Propionibacterium spp. and higher abundance of Lactobacillus, Prevotella, Sneathia spp., and Clostridium difficile compared to children delivered vaginally. high abundance of C. difficile represents can cause dysbiosis and increased risk for developing fleshiness [ 22, 55 ]. similarly, vulnerability to antibiotics in infancy directly alters the gut microbiota ( ), which enforces unusual weight advance in infants and contributes to autoimmune diseases such as incendiary intestine disease, asthma, allergies, arthritis and multiple sclerosis, but the mechanism behind this variation remains unclear [ 56– 58 ]. furthermore, the type of feed was besides found as a critical component for variability in the catgut microbiota of infants [ 59 ]. Human breast milk contains a building complex and dynamic constitution influenced by gestational long time, lactation period and mother ’ mho diet, which differs from general convention feed in the concentration and constitution of nutrients, particularly for the bearing of hormones, increase factors, immunoglobins and enzymes [ 60 ]. A discipline suggested that formula-fed infants contain higher abundance of Escherichia coli, C. difficile, Bacteroides, and Lactobacilli than breast-fed infants ( ). all in all, vaginal rescue and breast-feeding were suggested as being optimum for maintaining a healthy intestine microbiota ( higher abundance of Bifidobacteria and lower abundance of C. difficile and E. coli ) [ 61 ] .Open in a separate window

Table 1

FactorsHigh-abundance bacteriaReferencesVaginal deliveryBifidobacteria, Bacteroides Staphylococcus,[55]   Corynebacterium, and Propionibacterium spp.Cesarean deliveryLactobacillus, Prevotella, Sneathia spp., and Clostridium difficile[55]Formula feedingEscherichia coli, C. difficile, Bacteroides, and Lactobacilli[61]Breast feedingBifidobacteria[61]Open in a separate window

4. Impact of diet on the human gut microbiota

Through decades of research on the gut microbiota it has been postulated that dietary substrates play critical roles in altering the intestine microbiota composition and its functional capabilities [ 88, 89 ]. however, the accurate mechanism behind changes in the gut microbiota due to consumption of different diets, is placid an open research question. More precisely, short-run and long-run dietary patterns act differently to trigger the variations in constitution and functional modules of the microbiota [ 90 ]. A late study has revealed the capability of the intestinal microbiota to alter and reshape its composition quickly by mutant in diet for a short time ( five consecutive days ) [ 45 ]. In this study, animal- and plant-based diets were selected to examine the variations and reproducibility in the gut microbiota of 10 american volunteers between the age of 21 and 33. Results demonstrated that the abundance of bile-tolerant microorganisms such as Alistipes, Bilophila and Bacteroides increased during animal-based diet consumption, while a decrease was noticed in the abundance of Firmicutes involved in metabolizing dietary plant polysaccharides ( Roseburia, Eubacterium rectale and Ruminococcus bromii ) ( ). however, it was found that short-run dietary patterns remained ineffective in triggering meaning changes in ‘ enterotypes ’ [ 90 ], which are defined as three clusters of genus dominated by Bacteroides, Prevotella, and Ruminococcus. This study besides suggested that introduction of high-fat/low-fiber or low-fat/high-fiber diet initialized changes in the gut microbiota within 24 hours, but the enterotype of the subjects remained stable for up to 10 days. Further, examinations of long-run dietary interventions have demonstrated strong association with change in enterotypes.

Open in a separate window Capabilities of the human intestine microbiota for rapid shift in its composition and metabolic functionality could be connected with human development over the inaccessibility of similar food sources over clock time [ 92 ]. possibly, handiness of animal-based food was always dependent on success in hunting, whereas alternate sessional plant-based foods were consumed more frequently. These rapid changes in diets would have increased the selective pressure for enhancing the flexibility of running modules of the gut microbiota [ 93 ]. In advanced diet patterns, several studies have suggested that variations in the catgut microbiota due to animal-based diets could be responsible for revision in bile acid biosynthesis [ 94– 96 ]. experimental studies, using shiner as a model host, showed that animal-based/high-fat diets initiate a high production of a especial secondary coil bile acid, namely, deoxycholic acid, which is involved in promoting liver cancer. It has besides been noticed that high-fat diets may stimulate the increase of Bilophila wadsworthia ( a sulphite-reducing bacteria ), which is one of the cues for causing Inflammatory Bowel Disease ( IBD ) [ 97– 99 ]. In contrast, plant-based diets have a higher roughage content than animal-based diets and microbial agitation of dietary polysaccharides can provide up to 10 % of the energy consumption by human [ 100, 101 ]. furthermore, a high-fiber subject diet stimulates variations in the gut microbiota towards performing severalbeneficial functions such as security from inflammation, fleshiness, diabetes, heart disease, and high lineage blackmail [ 102, 103 ]. Turnbaugh et aluminum. have performed a comparative cogitation to determine the impingement of diet on host physiology by switching the low-fat, plant polysaccharides-rich diet to a high-fat, high-sugar diet in germ-free mice colonized with a human catgut microbiome. Results of this survey demonstrated that variety in the diet within a day altered gene expressions of the gut microbiome and metabolic pathways. It has been reported that diets with high-fiber message enrich the abundance of Bacteroidetes and decrease the abundance of Firmicutes [ 41, 89 ]. In a cogitation by Filippo et al., the faecal microbiota of children from Europe and an african village of Burkina Faso ( BF ) were compared, considering the significant differences in diets of both cohorts. interestingly, a alone abundance of genus Prevotella and Xylanibacter was noticed during the consumption of high-fiber containing food. These genus express genes involved in cellulose and xylan hydrolysis. Findings of this discipline besides postulated that fiber-containing diets can help in developing the catgut microbiota towards protecting the host from inflammation and noninfectious colonic diseases, due to the gamey abundance of Faecalibacterium prausnitzii along with early Short Chain Fatty Acids ( SCFAs ) producing bacteria [ 41, 104 ]. Similarly, some studies have shown that abject abundance of F. prausnitzii correlated with Crohn Disease ( compact disk ) and IBD [ 25, 105 ]. Furthermore, assorted studies have suggested that butyrate, one of the products of SCFAs-producing bacteria, could play several beneficial roles to improve the health in aged [ 67, 106 ]. For exemplify, Govindarajan et aluminum. have noticed that sodium butyrate enhances the memory function in mouse models of Alzheimer ’ s disease at an promote stage of long time progress [ 107 ] .

5. Effect of age-related alteration in gut microbiota on human health

One of the austere effects of the age-related changes in composition of catgut microbiota is increase in the abundance of gram-negative bacteria, like Enterobacteriaceae and other pathogens [ 1 ]. These gram-negative bacteria have capability to secrete lipopolysaccharides, which may act as endotoxin. Lipopolysaccharide is a carbohydrate-fat building complex, that may cause excitement in intestine [ 2– 4 ]. It has been postulated that the charge of SCFAs, particularly acetate rayon, butyrate, and propionate, in the intestine of age people is reduced compared to young subjects [ 5 ]. This may lead to secretion of mucins by the intestinal epithelial cells, which, in change by reversal, allows entrance of pathogens easily into the intestinal mucous membrane [ 1 ]. consequently, the deduction of SCFAs by catgut microbiota is considered as anti-inflammatory activity to reduce the causes of diseases like compact disk and IBD [ 6 ]. To this end, diet interventions using fiber-rich diets or indigestible-carbohydrates promote the output of SCFAs through agitation by intestine bacteria. several studies have suggested that acetate rayon is chiefly steep and metabolized in mind, kidney, muscles, and kernel [ 7, 8 ]. Propionate is metabolized by liver and might play a role as an inhibitor for cholesterol synthesis, which is connected to rule of adipose tissue deposition [ 9, 10 ]. On the other hand, butyrate is largely absorbed by the colonic epithelial cell and work as an energy source. It besides plays an significant function in cell increase and specialization vitamin a well as in reducing the risk of colon cancer by stimulating apoptosis [ 11, 12 ]. The age-related decline in SCFAs product by the gut microbiota of aged can hamper the immune system, which cause respective gut-related diseases in aged homo subjects. In this direction, Arpaia et al., demonstrated that butyrate improves the anti-inflammatory activeness of the immune system [ 13 ]. In another study, it has been noticed that epigenetic modifications in immune cells i.e. macrophages by butyrate reduces the secretion of inflammatory factors such as IL-6 [ 14 ]. This leads to a decrease of the permeability of the mucosal membrane to lessen the infiltration of harmful molecules, like lipopolysaccharides from the colon [ 15 ]. Similarly, some studies have demonstrated the anti-inflammatory activities of acetate and propionate [ 16, 17 ]. furthermore, more research efforts are required in this area to fill the cognition gaps between age-related changes in the microbial ecology of gut and human health. such studies will reveal more specific targets for therapeutic interventions to treat or delay the gut-related diseases in aged .

7. Recent research efforts to understand the functionality of the gut microbiota

previous studies on the intestine microbiota have chiefly analyzed the abundance at phylum/genus-level and to some extent at species-level in different age groups ( infants, adults, and elders ) in respective countries during health and diseases. holocene studies, however, are focused on investigating the species-level running behaviors of microbes in the gut microbiota. Due to limitations of current experimental techniques, computer-based methods can help to understand the metabolic demeanor of intestinal bacterial species vitamin a well as microbe-microbe, microbe-host, and diet-microbe interactions in the community level. One direction to study the homo gut microbiota is constraint-based modeling [ 132, 133 ]. In constraint-based modeling, the metabolic information of a particular organism is presented by a genome-scale metabolic model ( GEM ). The core element of a GEM is a stoichiometric matrix representing data about the stoichiometry of all metabolic reactions in the organism. furthermore, each reaction is linked to an enzyme and its correspond gene, and GEMs hereby provide a gene-protein-reaction connectivity. There is besides a biomass reaction in GEMs, which describes how metabolites required for build macromolecules forming the basis of the biomass are being consumed. Through the stoichiometric matrix metamorphosis is represented in a machine-readable form and different computational analysis can be carried out using the matrix. By optimizing the cellular biomass output it is possible to calculate the metabolic flux through each reaction using the concept of magnetic field balance analysis ( FBA ) which in turn enables cellular phenotypical predictions in the context of the organism ’ s genic and environmental boundaries [ 134, 135 ]. GEMs have been used in order to get a deeper reason of the interplay between genotype and phenotype. These mathematical models can besides be used to simulate microbial communities like the human gut microbiota. In this management, genome-scale metabolic modeling approaches have demonstrated potential capabilities towards enhancement in sympathy of phenotypical characteristics of the gut microbiota [ 136, 137 ]. Since the population of the gut relate bacteria is very large, more efforts are required to develop high-quality GEMs in this area. furthermore, research efforts towards exploring uncharacterized genomes of bacterial species in gut microbiome, will be easy to incorporate into this GEMs approach path for predicting the metabolic behavior of members of intestine microbiota as model of the microbial community can easily be expanded to consider metamorphosis besides of newly identified species [ 138 ].

Metabolic models have been widely used to decipher the genotype-phenotype relationships in single species. These models can besides be used to study microbial communities, although in ordering to simulate a multispecies system like the human catgut microbiota, formulating the inter-species interactions and the objective officiate is of all-important importance. One way to simulate a microbial consortium is to consider each member of the residential district as a separate compartment. These compartments interact with each other in terms of metabolite exchanges through a shared compartment. Another element that greatly influences in silico predictions is the objective function. When dealing with a one species metabolic network, the objective routine is normally defined as the flux density through a reaction, which is considered to represent cellular growth. The objective function of a community, however, is more complicate. Another way to simulate a community is to separate the organism-level and community-level objective functions, as implemented in a late discipline using a method called CASINO [ 82 ]. The CASINO optimization algorithm integrates well with diet psychoanalysis and can hereby be used to understand the metabolic microbe-microbe, diet-microbe and host-microbe interactions. In a recent discipline, CASINO was used to elucidate metabolic interactions between the microbiota in the small intestine of mice and different tissues [ 139 ]. The goal was to investigate the metabolic differences in the little intestine of conventionally raised mouse compared to the germ-free ones. The amount of consumed amino acids and produced short-chain fatty acids by the bacteria were calculated and found to be reproducible with the experimentalobservations [ 139 ] .

8. Conclusions and future perspectives

Aging is defined as deterioration of physiological functions accompanied by the development of age [ 18 ]. Older people ( > 65 years ) are more susceptible to age-related diseases and disabilities. presently, one of the goals for scientific and social communities is to explore novel strategies for improving health in old aging, which can be achieved by preventing age-associated diseases. This measure could aid in improving socio-economic conditions and reducing the cost of healthcare in an aging population. The homo gastrointestinal tract harbors a huge ensemble of microbes, which benefit the horde through its metabolic phenotypes. The influences of aging summons on the alterations of intestine microbiota writing and officiate is of particular sake in gut microbiota studies, ampere well as the effects of aging on the human horde in genetics or epigenetics. recently, correlations between the intestine microbiota and ripening was investigated in several studies and these show that aging can affect the composition and metabolic functions of gut bacterial species, and further that this alteration can be associated with numerous gut-related disease in the host. therefore, maintaining a beneficial microbial community in the gut may help to prevent or delay age-associated diseases. Increased understanding of the contributions of the gut microbiota to human healthy had resulted in attempts to manipulate its composition by the use of prebiotics/probiotics or introduce raw gut microbial species by faecal microbiota transplant. Furthermore, a healthy diet is one of the strategies that can be employed to improve health during aging and some preliminary reports, based on impression of plant-based diets on intestine microbiota [ 111, 112 ], has shown a path to design more effective diets to maintain healthy aging. Genome-scale metabolic model driven modeling can be used to simulate the effects of diet on the gut microbiota composition and its interaction with human metamorphosis, and can hereby provide an effective and quick way to screen putative diet components desirable for older people. furthermore, the government of probiotics/probiotics to elderly had been shown to alter the writing and functionality of the catgut microbiota. GEM-driven mold can besides be used to identify candidate species for probiotic design by in-silico analysis of metabolic capacities and interactions of gut microbial species [ 140 ]. lotion of these mathematical mold approaches have the likely to become a useful support to develop individualized probiotics or nutritional strategies [ 141 ] to maintain the healthy condition of the aging people. In this focus, the independent vault is ailing known metabolic connections between diet, microbes, and host. To study these building complex connections, computational tools, such as genome scale metabolic model, can be employed .

Acknowledgments

This work was financially supported by the Knut and Alice Wallenberg Foundation and the Bill & Melinda Gates Foundation .