Muhmmd Shhid Riz RjokJunling ShiH fiz Mhreen MehwishJing ZhuQi LiDongyn ShoQingsheng HungHui Yng

aKey Laboratory for Space Bioscience and Space Biotechnology,School of Life Sciences,Northwestern Polytechnical University,Xi’an 710072,Shaanxi,People’s Republic of China

bDepartment of Biotechnology,University of Agriculture,Faisalabad,Pakistan

Abstract

Keywords:Gut microbiota;Dysbiosis;Probiotics;Human health

1.Introduction

Over the past decades,the interaction between nutrition and the gut microbiota and its impact on human health has gathered increasing interest.Initial studies were primarily focused on the classification of microbial species forming the gut microbiota and the relationship of gut microbiota composition with the host health status[1].Recent studies started to investigate the interaction between food and gut microbiota relative to the health of the host[2].Current exciting research is beginning to unravel how the composition of food modulates the gut microbiota[3].It has been found that the human-associated microbial communities are crucial for proper development of human and various hypotheses have been proposed to understand such relationship.One hypothesis is that the microbial communities of the mother affect fet al development and,consequently, the health of the offspring[4].As a result,therapeutic interventions and diagnostic measurements which target the microbiota of the mother could prevent a negative impact on offspring health and premature birth[5].Another assumption is that,after birth,the changing pattern of microbial populations relative to human development can be used to determine the importance of the microbiota in the development of individuals with healthy growth phenotypes.Therefore,it could be deduced that deviancies from normal microbial communities lead to abnormal development such as precocious maturation or immaturity[6].

The human body hosts at least 1014microorganism and harbors more microbes than body cells[3,7].All human-associated microbes are collectively known as microbiota and the microbiota encoding genes form the microbiome[6,8].It is estimated that the human gastrointestinal tract has 10 million genes which are associated with different microbial species and all genes have some beneficial impact on the health of the host,with possible effects on the homeostasis of the immune system,conversion of food into useful nutrients and protection against pathogenic microorganisms invading.However,due to the differences of diets,the microbiota differs widely from individual to individual and each person carries hundreds of microbial species that remain unchanged throughout adulthood[9–11].

The gut microbiota consists of bacteria,archaea,fungi,protozoa and viruses[12].The microbial communities interact with each other and with their host,causing influence on the physiology and health of the host.The human gut microbiota is composed of both anaerobic and aerobic microbial communities[13].Most gut microorganisms are strictly anaerobic bacteria and difficult to be culturedin vitro.At present,it is estimated that less than 30% of the gut microbial populations have been successfully cultured.However,this does not imply that all other bacterial species are unculturtable,but rather that the optimal growth conditions for these microbes have not yet been discovered[14].The development of high-throughput sequencing techniques has revolutionized the research process on currently uncultured microbes providing an insight into their mechanisms[15].The dominant bacterial species in the human gastrointestinal tract are divided into three phyla:thephylum Bacteroidetes(e.g.Porphyromonas,Prevotella etc.),thephylum Firmicutes(e.g.Ruminococcus,Clostridium,Eubacteria etc.)and thephylum Actinobacteria(Bifidobacterium).Other bacteria such asLactobacilli,StreptococciandEscherichia coli(E.coli)are found in small numbers.Based on the evidence from genomic technologies,theBacteroidetesandFirmicutes phylawere found to be the dominant bacterial populations in the gastrointestinal(GI)tract(Fig.1)[16,17].

Fig.1.Composition of gut microbiota.

The GI tract is currently reported to be sterile during gestationand become colonized after birth. Colonization of bacteria in the GI tract depends upon various factors such as type of childbirth and method of postnatal feeding[18].The gut microbial population is transferred from mother to child and its composition is affected by various genetic factors[19,20].The microbiota populations are also affected by diet and can be involved in the development of various diseases such as cancer,metabolic diseases and obesity.High-carbohydrate diets favor thePrevotellagenus,whereas high-fat and high-protein diets promote the development ofBacteroidetes microbialspecies[21–23].

A disturbance in the interaction between nutrition,metabolism and microbiome may constitute an important factor in the deregulation of normal host homeostasis.Such disturbances in the structure and function of microbiota have been found to be related to the development of various diseases.It is,therefore,necessary to clearly define the range and composition of a normal,healthy microbiota.MetaHit and the Human Microbiome Project are conducting an in-depth analysis of the human-associated microbial communities and their function in maintaining the host homeostasis using various techniques[24–28].

After analyzing the currently available data, this review gives a comprehensive summary on the reports to illustrate how the interaction between microbiota and food affects human physiology and,thus,generate useful information for the prevention of multiple diseases.

2.Impact of diet on GIT microbiota

Protein,fat and carbohydrates are the most comment and major components in diets of human.The type and amount of protein,fat and carbohydrates present in the diet have been widely found to influence the composition of the gut microbiota in the host.This effect is related to the metabolites of the components present in diets.Short chain fatty acids,acetate and butyrate are reported as the end products of microbial-mediated degradation of protein and carbohydrates in the GI tract(GIT).Short chain fatty acids produced by GIT microbiota are the most extensively studied metabolites of diets and have been found to have a physiological effect on the health of the host[29].

Degradation of the protein in diets normally happens at the distal end of the colon,where the conditions are suitable for the secretion of proteolytic bacteria.The normal end products of protein degradation are amino acids, ammonia, amines and short chain fatty acids.High concentrations of ammonia have been found to be related to the development of malignant growths[30–33].Gathered results showed that the rats feeding on diets consisting of protein isolated from whey cheese or containing cysteine or threonine resulted in a significant increase in bifidobacteria or lactobacilli counts in their feces[34–36].Also of note,the protein isolated from whey cheese could alter the microbiota composition in a dose-dependent manner.Furthermore,it was observed that the mice that were fed high fat diets along with the whey-isolated protein tended to have an increase inLactobacillaceaecounts and a decrease inClostridiaceaecounts compared with the mice fed on a normal diet[37].

Dietary fiber is an important food component derived from plants.However,fiber concentration is lower in processed foods than in raw vegetables.Dietary fibers pass from the small intestine to the colon where they are partially metabolized by bacterial species and the remaining fibers are then excreted through feces.Some polysaccharides such as insulin,starch and oligosaccharides are the typical examples of dietary fibers which can be degraded by bacteria.However,certain fibers,such as cellulose,cannot be completely degraded by bacteria when passing through the colon[38].In the GI tract,some carbohydrates,such as starch and non-starch polysaccharides,cannot be directly metabolized by the host.These complex carbohydrates normally act as an important energy resource for microbial growth and can be degraded by proteolytic enzymes into short chain fatty acids and various gases.These carbohydrates are also referred to as prebiotics that are defined as the non-digestible component of food that benefits the host by stimulating the growth of the microbiota.Prebiotics are very important to induce changes in the composition of the gut microbial populations and confer multiple benefits to the host health.Prebiotics such as insulin,fructooligosaccharides and oligosaccharides act as important stimulants which promote the growth ofbifidobacteriaandlactobacilli[39–41].Recent studies indicate that the consumption of prebiotics can modu-late the gut microbial population and improve the hosts health[42].

It has been widely reported that the consumption of modern western diets containing less fiber and vegetables tended to result in the loss of some important microbial species in the western(urban)communities compared to rural communities.As previously mentioned,diets have a strong impact on the microbial diversity of individuals from different populations.For instance,when comparing an individual whose diet is high in fat and low in fiber with an individual on the opposite diet(e.g.high fiber and low fat),the latter tends to have a smaller amount of pathogenic bacteria and a large amount of beneficial microbes,such asPrevotellaandXylanibacte[43–45].The balance of GIT microbial composition can be achieved as a result of symbiosis which regulates the immune system and protects the host from various diseases(Fig.2).

Fig.2 Microbiota and homeostasis of the immune system.

The Mediterranean diet,which is based on a balanced intake of fruits,grains,monounsaturated fat,vegetables and polyunsaturated fats,is considered the standard for a healthy life style.It has been found that such diets have anti-inflammatory capabilities and can be used to reduce inflammation in diseases.Individuals fed on the Mediterranean diet have lower numbers ofBacillaceae,Proteobacteriaand acute phase C-reactive proteins,but higherClostridiumandBacteroidetespopulations[46,47].Vegetarian diets are also recognized as healthy and benefic diets because they can protect the host from various chronic,metabolic and inflammatory disorders.Recent investigations showed that vegetarian diets could increase the number ofFaecalibacterium prausnitzii,Clostridium clostridioformeandBacteroides Prevotella,but decrease the ratio ofClostridium clusterXIVa species[48–50].

Small amounts of dietary fat can be digested and absorbed but some fat components cannot be metabolized and pass to the colon where they affect the microbial composition and are then excreted in feces.Consequently,the consumption of high-fat foods tends to induce substantial changes in the composition of GI tract microbiota[51,52].Mice fed on high-fat diets have different microbiota composition from those that have been fed control or balanced diets[53].High fat content and increased calorie consumption have the capability to induce changes in the microbial composition of the GI tract[54,55].Table 1highlights the impact of various dietary components on host microbiota and health status.

Table 1Influence of dietary components on host health and GIT microbiota.

It has been also found that the children feeding on vegetarian diets rich in plant-based polysaccharides, fibers and starches had a significant increase in the number ofFirmicutes,Xylanibacter,BacteroidetesandPrevotellacompared with those consuming a carbohydrate rich European diet.Therefore,it was suggested that children should be provided with a plant-based polysaccharide rich diet which confers protection against inflammatory disease[44].

Currently,it is clear that the composition of the microbiota differs among individuals living in different geographic regions and also depends on the long-term diet pattern.However,further investigation is required to identify the effects of long term and short term dietary patterns on the microbiota composition.

3.Impact of GIT microbiota on various diseases

The GIT microbiota has recently become a major subject of clinical research.Various studies have described the role of microbiota in ameliorating liver disease,irritable bowel syndrome,chronic inflammation,constipation,food allergies and cancers[43,60–64].The gut microbiota interacts with the lymphoid tissue and epithelium,and,thus,plays an important role in the regulation and development of the host defense system[65,66].The gut microbiota is involved in the regulation of antimicrobial peptides,mucin gene expression and paracellular permeability of the paneth cells of the small intestine.Moreover,a healthy microbiota is necessary for the maturation of the B cells and T cells,and the maintenance of proper immunoglobulin levels in the serum[67–69].Recent studies showed that several diseases might be associated with the change in composition and metabolic activities of gut microbiota[70–72].Changes in the composition and function of GI tract microbiota have also been linked to aging,obesity,neurodevelopmental disorders,cirrhosis,cardiovascular diseases and cancer[73–83].

3.1.GIT microbiota and cancer prevention

The intestinal microbiota has been increasingly recognized to be involved in the pathogenesis of diseases,even some kind of cancers[84].It was supposed that the disturbance of GIT microbiota may promote carcinogenesis through three mechanisms:increasing bacterial translocation and consequently increasing inflammation,producing bacterial genotoxins that tend to induce DNA damage in organs,producing metabolites that can active carcinogens.The microbiota is also found to mediates tumor suppressive effects through inactivation of carcinogens,currently known as through the generation of short-chain fatty acids such as butyrate and through the biological activation of cancer-preventing phytochemicals[85].Lactic acid bacteria are the most extensively reported components of GIT microbiota.

Various clinical studies have reported the effect of lactic acid bacteria(LAB)on preventing complication and alleviating symptoms of gastrointestinal cancer but LAB can also be used to inhibit intestinal carcinogenesis[86].In the past year,various strains of LAB were reported to inhibit the proliferation and induce apoptosis of colon and gastric cancer cells as summarized in Table 2[87].Lactic acid bacteria(LAB)can be used for prevention of colon cancer due to their ability to modulate host immunity,intestinal microbiota,gut barrier function,anti-inflammatory and antipathogenic activity,and to suppress the bacterial translocation in the gut[88].The beneficial effect of LAB is species specific,implying that different species have different effects on varying types of cancer.It is also suggested that the combination of two or more lactic acid bacteria might be more beneficial than a single LAB strain[88].Concerning the mechanism of action of LAB,recent studies reported that such suppressive effect was dependent on short chain fatty acid production and upregulation of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)[89].

Table 2Effect of lactic acid bacteria on gastrointestinal cancer cells.

In addition,it was also reported that LAB are useful to treat cancer induced in various animal models through the administration of carcinogens,for example,azoxymethane.In one study,the administration ofLactobacillus casei BL23protected the mice against colon cancer and facilitated the generation of T-helper Th-17-biased immune responses,as shown by the changes in cytokines levels and T-cells population.Furthermore,it was shown that the administration ofPediococcus pentosaceus GS4suppresses the nuclear factor-kB activity,which is associated with chronic cell proliferation and inflammation.

3.2.GIT microbiota and obesity

Obesity is a physiological state that arises in a population consuming western diets [92]. Obesity is linked to various metabolic disorders such as cardiovascular and liver diseases.The genetic makeup of the host, together with lifestyle and diet has been identified as major risk factors that tend to induce obesity.Common treatment options for obese individuals focus on decreasing the weight and include physical activity,calorie intake restriction and weight loss medication[93].In obese hosts,theFirmicutesmicrobial population tends to increase,whilst theBacteroidetespopulation tends to decrease[58].However,a decrease inBacteroidetesand an increase in theActinobacteriumpopulation,with normal levels ofFirmicuteshas recently been reported[74].These microbial communities have a higher capacity to harvest food energy and produce low levels of inflammation.The decrease in microbiota composition in obese individuals is thought to be related to the reduction in insulin sensitivity and the stimulation of inflammation[23,74].Research based on animal models found that host genetics and some environmental factors alter the microbiota composition and induce obesity[57,94].The increase in harvesting food energy in the obese individuals is due to the hydrogen transfer between the microbiota phyla,since there is a consequent increase in hydrogen-using and hydrogen-producing microbes in those individuals[95].The low level of chronic inflammation is found to be a major factor which causes obesity and enhances the level of macrophages,T cells,tumor necrosis factor,interleukin and mast cells[96].

In obese mice,Bifidobacteriumspecies increase significantly and,thus,modulate the inflammation by producing glucagon peptide-2 and reducing lipopolysaccharide translocation[97].The first finding demonstrating the role of microbiota in stimulating obesity came from a study that used germ free mice and showed the resistance to diets.Here,induced obesity depended on the macronutrient composition of the diets and improved the fat storage on microbiota colonization from the conventional donor[98–100].

Overall,the results of these studies indicate a link between dysbiosis and obesity,and suggest that the microbiota can enhance the host fat storage.However,the mechanisms responsible for the induction of obesity are very complex and still not completely understood.

3.3.GIT microbiota and type 2 diabetes

Type 2 diabetes alters the composition of gut microbiota and microbiota function such as the secondary metabolite bile acid and butyrate products.These functions are crucial for insulin sensitivity.The status of gut microbiota can be used to successfully distinguish between type 2 diabetes patients and healthy individuals in Chinese and European populations.Type 2 diabetes was linked to higher amounts ofLactobacilliand lower amounts ofRoseburiawhen comparing the two populations[77,78,101–103].However,the current understanding of the effect of GIT microbiota on type 2 diabetes is very limited.Further research is necessary to elucidate the interaction between the microbiota and the metabolism of the host,as well as to determine its impact on type 2 diabetes.

3.4.GIT microbiota and cardiovascular diseases

Cardiovascular diseases are the leading cause of death worldwide.The first indication of a link between GIT microbiota and cardiovascular diseases came from studies concerned with impaired dental health,cardiovascular diseases,infectious agents and atherosclerosis.Recent studies showed that certain bacterial strains used for the prevention of cardiovascular diseases exhibited antimicrobial activities[104–106].Bacterial DNA identified from atherosclerotic plaques demonstrated the presence of a microbial load in the plaques which was,therefore,associated with influencing the development of cardiovascular diseases[107,108].However,Metagenomic analysis of the fecal microbiome of healthy individuals and atherosclerosis patients showed a decrease in beta-carotene production gene(anti-inflammatory)and an increase in the peptidoglycan synthesis gene(proinflammatory)in the afflicted population[109].

3.5.GIT microbiota and parkinson’s disease

Parkinson’s disease is the most common neurodegenerative disease,affecting 1%–2% of the population over the age of 65 years.In recent decades,it was discovered that changes in neurodegenerative disorders occur through bidirectional communication in the gut-brain axis[110–112].The gut-brain axis,or interaction,is developed during stress responses and it is believed that neuronal degeneration in conjunction with cognition and gastrointestinal disorders occur together.Hence,the neuro-hormonal factors and the gut microbiota influence the gut and brain function.It has been accepted that the gut microbiota influences the function of the central nervous system by establishing the pathway known as microbiota-gut-brain axis[113].Dysfunctions in the microbiota-gut-brain axis result in the development of Parkinson’s disease as evidenced by various disease symptoms[114,115].Pain is experienced by approximately 45%–85% of Parkinson’s disease patients.However,it has been noted that changes in the microbiota are associated with different types of pain such as migraines,autoimmune related pain,inflammatory pain and visceral pain in patients with rheumatoid arthritis[116–118].The communication pathways are very complex involving neurochemical signaling molecules which are used to facilitate this communication process.The gut microbiota stimulates the production of short-chain fatty acids and certain neurotransmitters.These factors contribute to the development of Parkinson’s disease and the associated pains[119,120].Therefore the microbiota has the potential to modulate the pain in Parkinson’s disease patients.

4.Conclusions

Over the past decades,researchers have established a link between the alteration of gut microbial composition and various diseases.Diet affects the host health status by modulating the composition of the gut microbiota.It has been found that normal gut microbiota affects the development of the immune system,nutrient absorption,tissue generation,morphogenesis,and bone homeostasis metabolism.In this paper, we summarized the recent developments concerning the relationship between diseases and the gut microbiota.The modulation of the gut microbiota is a hot topic of interest and may benefit the health of the host(Fig.3).However,there is still a substantial gap in our understanding of how diet modulates the microbiota and how microbiota modulates the immunity of the host.New tools and new approaches are needed for further investigations,as the modulation of the GIT microbiota represents a promising new method for the prevention,management and treatment of various diseases.

Fig.3.Interaction between diet,Gut microbiota and host.

Disclosure statement

The authors declare that there are no conflicts of interest.

Acknowledgements

This study was supported by the National Key Technology R&D Program(grant number 2015BAD16B02)and the National Natural Science Foundation of China(NSFC)(grant number 31201408 and 31471718).