European Review for Medical and Pharmacological Sciences 2016; 20: 4742-4749 The role of diet on composition

S. BIBBÒ1,2, G. IANIRO1, V. GIORGIO3, F. SCALDAFERRI1, L. MASUCCI4, A. GASBARRINI1, G. CAMMAROTA1

1Internal Medicine, Gastroenterology and Liver Unit, Catholic University of the Sacred Heart, School of Medicine, A. Gemelli Foundation, Rome, Italy 2Department of Clinical and Experimental Medicine, University of Sassari, Italy 3Division of Pediatrics, Catholic University of the Sacred Heart, School of Medicine A. Gemelli Foundation, Rome, Italy 4Institute of , Catholic University of the Sacred Heart, A. Gemelli Foundation, School of Medicine, Rome, Italy

Abstract. – Gut microbiota is characterized In health, gut microbiota plays a relevant role by an inter-individual variability due to genet- within our body, mainly being involved in the ic and environmental factors. Among the envi- development and growth of immunity and in the ronmental ones, dietary habits play a key role in regulation of several fundamental metabolic pa- the modulation of gut microbiota composition. thways3-5. There are main differences between the intes- tinal microbiota of subjects fed with prevalent Quantitative and/or qualitative alterations of Western diet and that of subjects with a diet rich gut microbiota bring to the impairment of this ho- in fibers. Specific changes in the composition of meostasis, leading to the development of several gut microbiota have been demonstrated among gut microbiota-related diseases6,7, such as functio- subjects according to a different dietary intake. nal gastrointestinal diseases8, intestinal infectious A particular diet may promote the growth of spe- diseases9,10, inflammatory bowel disease11,12, liver cific bacterial strains, driving hosts to a con- diseases13,14, gastrointestinal malignancies15, obe- sequent alteration of fermentative metabolism, 16 with a direct effect on intestinal pH, which can sity and metabolic syndrome , diabetes melli- 17 18 19 be responsible for the development of a patho- tus , allergic diseases , autism , and others. genic . Moreover, a high-fat diet can pro- Since a large part of , in parti- mote the development of a pro-inflammatory gut cular, anaerobes, is not cultivable through conven- microbiota, with a consequent increase of intes- tional microbiology techniques, our understan- tinal permeability and, consequently, of circulat- ding of gut microbiota is substantially limited. ing levels of lipopolysaccharides. In this review, we discuss the direct role of However, the development of culture-independent the diet in the composition of gut microbiota and tools, based on technologies, has about the possible clinical consequences. led us to take a step forward in the assessment of gut microbiota composition20. Key Words: Currently, four major microbial phyla are Gut microbiota, Diet, , Lipopolysac- known to represent over 90% of the bacterial charide, Fiber, High-fat. component of gut microbiota: , Bacte- roides, Proteobacteria and Actinobacteria. The majority of “good” harbouring the human Introduction gut microbiota are represented by Firmicutes and Cytophaga-Flavobacterium-Bacteroides (CFB). Our organism is colonized by an enormous Firmicutes are sub-grouped in Clostridium coc- number of micro-organisms, both on its surface coides (Clostridium cluster XIVa) and Clostri- and inside. They amount for more than 1 kg of dium leptum (Clostridium cluster IV); whereas weight, and outnumber human eukaryotic cells at CFB group is represented mainly by Bacteroides least ten times. The majority of them live in our phyla with a great number of Prevotella and Por- gut, constituting the so-called gut microbiota1. As phyromonas10,21. gut microbiota and human beings are in a symbio- Moreover, our gut microbiota includes , tic relationship, the idea of a combined “super-or- especially phages, Eukarya, as Fungi, Blastocy- ganism” has been recently developed2. stis, Amoebozoa, and Archaea22,23,24.

4742 Corresponding Author: Stefano Bibbò, MD; e-mail: [email protected] Diet and gut microbiota

Gut microbiota has been classified into three Large variations in gut microbiota among main enterotypes, each one owning specific me- Americans, Europeans and Africans have also tabolic features25. Each enterotype is characteri- been documented in other studies. Gut microbio- zed by the relative abundance of one of the fol- me of Africans clustered with that of South Ame- lowing genera: Bacteroides (more represented in rican people, correlating with large consumption enterotype 1), Prevotella (more abundant in ente- of plant-based polysaccharides, but were diffe- rotype 2), Ruminococcus (prevalent in enterotype rent from North Americans (which have mainly a 3). Prevalence of a specific enterotype can depend low-fiber diet). intake from the diet on long-term dietary habits, indeed high-fat and could, therefore, contribute to the large variation protein diet enhances the growth of enterotypes 1 observed in gut microbiota composition35. Indeed, and 3, while a diet rich in carbohydrates supports a high-fiber diet seems to be positively correla- the raise of enterotype 226. Recent findings sug- ted with bacterial richness. Therefore, permanent gest that gut microbiota composition is influenced changes in gut microbiota composition might be also by short-term dietary changes27. achieved through dietary modifications26,36. Both genetic and environmental factors are in- While Western diet, typically constituted by volved in influencing the inter-individual diversi- high consumption of red meat, animal fat, high ty of gut microbiota. Among environmental ones, sugar and low fiber food37, was therefore asso- the interest of the scientific community in dietary ciated with an increased number of Bacteroides factors has progressively increased, and the role phyla (mainly mucin-degrading bacteria) and also of diet on the composition of gut microbiota has Ruminococcus38. been particularly emphasized over the last ye- Specific changes in the gut microbiota have ars28-31. been associated with long-term or short-term die- tary modifications. Wu and colleagues found that Relationship Between Diet the microbiota composition is strongly associa- and Gut Microbiota ted with long-term dietary habits. Prevalence of Diet is known to have a strong influence on the Bacteroides and Actinobacteria is positively as- composition of intestinal microbiota31. To con- sociated with high-fat diet, but is negatively asso- firm this hypothesis, some researchers sequen- ciated with fiber intake, whereas Firmicutes and ced oral microbiota from skeleton teeth of people Proteobacteria show the opposite association. who lived over the various eras. They showed -predominant enterotype is strictly that the most significant changes in human gut associated with animal protein and saturated fats, microbiota had occurred during two socio-die- suggesting its prevalence in Western countries. In tary breakthroughs over the human history: the contrast, Prevotella-prevailing enterotype is as- passage from the hunter-gatherer Paleolithic era sociated with high consumption of carbohydrates to the farming Neolithic era (10000 years ago), and simple sugars, indicating a correlation with a with a diet rich in carbohydrates, and the begin- based diet more typical of agrarian ning of the industrialized period, characterized societies and vegetarians26. by processed flour and sugar diet (about two cen- Also, a short-term dietary alterations can mo- turies ago)32,33. dify the microbial communities of our body. An Further studies identified also differences in animal-based diet increased the abundance of gut microbiota composition among different po- bile-tolerant microorganisms (such as Alistipes, pulations of our planet, probably due to variability Bilophila and Bacteroides) and decreased the in both diet and genetics of each population. levels of Firmicutes metabolizing dietary plant De Filippo et al34 have compared the gut micro- polysaccharides (Roseburia, Eubacterium recta- biota of children from rural Africa (Burkina Faso) le and Ruminococcus bromii). Such data confirm with that of Italian children living in urban areas the existing differences between gut microbiota showing that these two populations have radically of vegetarians and mainly carnivorous subjects, different diets; in particular, open children have a that are fundamental respectively for carbohydra- lower dietary intake of fibers. The bacterial profi- te and protein fermentation27. les of the two groups of children clustered separa- tely: microbiota of the African children is domi- High-fiber diet and gut microbiota nated by Bacteroidetes, whereas among European Dietary fibers are divided into complex car- children there is a prevalence of Enterobacteria- bohydrates (digestible and non-digestible) and ceae and a decrease in Bacteroides. oligosaccharides. They exert a strong influence

4743 S. Bibbò, G. Ianiro, V. Giorgio, F. Scaldaferri, L. Masucci, A. Gasbarrini, G. Cammarota

Table I. Effect of carbohydrates on gut microbiota composition.

Resistant starch 2 ↑ Ruminococcus spp, Eubacterium rectale, adolescentis Resistant starch 3 ↑ Eubacterium rectale, Roseburia spp, Ruminococcus bromii Resistant starch 4 ↑ Parabacteroides diastasonis ↓ Eubacterium rectale, Ruminococcus bromii High soluble fiber diet ↑ Bacteroides spp., C. leptum group, and E. rectale Complex carbohydrates ↑ Bifidobacteria spp, Prevotella spp Low fiber diet ↓ Roseburia spp, Eubacterium rectale on the composition of the gut microbiota and Furthermore, the consumption of high quanti- consequently on the gut fermentative metabo- ties of soluble diet leads to increase in Bacteroi- lism. des spp., Clostridium leptum group bacteria, and Eubacterium rectale group45. Soluble fibers are Complex carbohydrates indeed associated with an increased proportion A fraction of normal human dietary intake of butyrate-producing bacteria, that mainly be- remains undigested in the small intestine and long to the Clostridium leptum and Eubacterium passes through to the to be elimi- rectale groups46. Moreover, complex carbohydra- nated. Non-digestible components include plant tes also increase levels of beneficial bacteria, in cell wall polysaccharides (such as cellulose and particular, Bifidobacteria spp., such as B. longum, pectin) and certain storage polysaccharides (such B. breve and B. thetaiotaomicron47. Finally, Pre- as inulin and oligosaccharides). Dietary starch in- votella spp. are the most represented bacteria in corporates a resistant component that is not fully vegetarian subjects48. digested in the small intestine39,40. There are four On the other hand, a decrease in total carbohy- types of resistant starch (RS1 to RS4) consumed drate dietary content leads to a significant decre- with diet29. Resistance features of dietary starch ase in the proportion of the Roseburia/E. rectale are respectively the protection from plant cell group (Table I)49. wall polymers (type 1), granular structure (type 2), retro-gradation resulting from heating and co- Oligosaccharides oling (type 3) or chemical cross-linking (type 4)41. Not only complex carbohydrates, but also oli- Several studies have analyzed the role of dif- gosaccharides (such as fructans, inulin, fructo-o- ferent types of resistant starch in gut microbio- ligosaccharides (FOSs), Galacto-oligosaccharides ta regulation. Leitch et al42 showed that subjects (GOS) and Arabinoxylan-oligosaccharides) have fed with resistant starch type 2 (RS2) from high shown a role in modifying gut microbiota. Inulin amylose maize showed an increased abundance and FOSs promote the growth of Bifidobacterium of Ruminococcus spp. and Eubacterium rectale, spp and, Lactobacillus spp., whereas fructan sup- while consumption of RS 3 promoted the growth plementation decreases levels of Bacteroides spp of Eubacterium rectale, Roseburia spp. and Ru- and Clostridium spp.50. Furthermore, fructans can minococcus bromii42. promote the growth of beneficial butyrate-produ- Additionally, RS2 have been shown to promote cing bacteria, such as Faecalibacterium prausnit- an enrichment of Bifidobacterium adolescentis, zii51,52. Eubacterium rectale, and Ruminococcus bromii. Galacto-oligosaccharides (GOS) supplemen- These last two species are increased during RS3 tation can stimulate the growth of Bifidobacte- consumption. Moreover, RS4 is positively corre- ria spp (especially B. adolescentis and B. cate- lated with Parabacteroides distasonis abundan- nulatum) and also increase the Faecalibacterium ce and negatively correlated with Eubacterium prausnitzii population, but with inter-individual rectale and Ruminococcus bromii prevalence. variability53,54. Arabinoxylan-oligosaccharides di- Strikingly, RS4 also leads to phylum level alte- splay a similar behavior, and additionally increase rations, decreasing the proportion of Firmicutes total bacterial population (Table II)55. while increasing Bacteroides and Actinobacte- ria43. Walker et al44 confirmed that Firmicutes High-fat diet and gut microbiota bacteria related to Ruminococcus bromii and Eu- The role of fatty acids in the regulation of gut mi- bacterium rectale are commonly stimulated by crobiota has been extensively assessed. Dietary fatty the RS diet. acids are grouped into three main categories: satura-

4744 Diet and gut microbiota

Table II. Effect of oligosaccharides on gut microbiota composition.

Fructo-oligosaccharides ↑ Bifidobacterium spp, Lactobacillus spp Inulin ↑ Bifidobacterium spp, Lactobacillus spp Fructans ↓ Bacteroides spp, Clostridium spp Galacto-oligosaccharides ↑ Bifidobacterium spp, F. prausnitzii Arabinoxylan-oligosaccharides ↑ Bifidobacterium spp

ted (SFA), monounsaturated (MUFA), polyunsatu- Metabolic effects rated (PUFA). Essential PUFAs are represented by two important families56: ω-6 and ω-3. The effect of dietary induced changes of gut Several papers explain the role of specific fat- microbiota on local and systemic inflamma- ty acids. A high-fat diet rich in safflower oil (that tion has also been extensively investigated. In- contains ω-6 PUFA) reduces the populations of testinal barrier plays an important role in the Bacteroides while enriching the populations of regulation of the , in particular Firmicutes, Actinobacteria and Proteobacteria57. through gut microbiota6,7. Gut microbiota can In vitro studies have assessed the effect of alter the function and feedbacks of intestinal PUFAs on the growth and adhesion of different immune cells, by regulating systemic and mu- Lactobacillus strains (L. rhamnosus GG, L. casei cosal immunity63. For this reason, there is a Shirota and L. delbrueckii ssp bulgaricus), with growing interest for factors, such as diet, that different results depending on the strain. High can modulate gut microbiota itself56,64. concentrations of PUFA inhibit both adhesion to High fiber diet alters fermentative metabolites mucus and growth of all tested bacterial strains, and intestinal pH. Colonic microbiota is able to whereas small quantities of gamma-linolenic acid metabolize complex carbohydrates and sugars and arachidonic acid promote growth and mucus into short-chain fatty acids (SCFAs), such as ace- adhesion of L. casei Shirota58,59. tate, butyrate and propionate. Such metabolites In humans, high intake of MUFA was associa- play a role in regulating intestinal pH30. ted with lower levels of Bifidobacteria spp and For instance, in vegetarian subjects, the high slightly higher numbers of Bacteroides spp. In the amounts of fiber result in an increase of SCFAs same study higher ω-6 PUFA intake was associa- production by microbes, which lower the local ted with a decreased number of Bifidobacteria45. pH65. Little variation of acid concentrations may Some studies have shown the effect of high-fat exert important consequences. A one-unit de- dietary pattern. For instance, a regular consump- crease in pH (from 6.5 to 5.5) has been shown to tion of red meat is responsible of a major con- have a profound selective effect on the colonic mi- centration of Bacteroides60. Moreover, a diet rich crobial population, with a prevalent decrease of in saturated fats (for example milk) has shown Bacteroides spp. and a growth of butyrate-produ- ability in triggering the growth of delta-Proteo- cing gram-positive bacteria66. bacteria, specifically Bilophila wadsworthia61. The decrease of pH caused by high concentration Interestingly, a high-fat diet generates , of SCFAs prevents the growth of potentially patho- leading to a significant reduction in numbers of genic bacteria, such as E. coli and other members Roseburia species (Table III)62. of the Enterobacteriaceae65,67. Moreover, SCFAs

Table III. Effect of high-fat diet on gut microbiota composition.

Safflower oil (ω-6 PUFA) ↑ Firmicutes, Actinobacteria, Proteabacteria ↓ Bacteroides PUFA ↓ Lactobacillus spp ω -6 PUFA ↓ Bifidobacteria spp ↓PUFA ↑ L. casei Shirota MUFA ↓ Bifidobacteria spp High-fat diet ↑ delta-proteabacteria spp, Bilophila wadsworthia ↓ Roseburia spp

4745 S. Bibbò, G. Ianiro, V. Giorgio, F. Scaldaferri, L. Masucci, A. Gasbarrini, G. Cammarota production can be a potential modulator of intestinal bacterial wall LPS, through the impairment in flora. Several gut bacteria, such as some Firmicutes gastrointestinal barrier function and the changes spp, especially those belonging to Clostridium clu- of the microbiota. Endotoxemia is associated with ster XIVa, are tolerant of lower, while Bacteroides systemic inflammation and with the metabolic spp. and Bifidobacterium spp are not63,66. syndrome71,75. Western diet was considered responsible of the intestinal dysbiosis that triggers local inflammation, causing an increase of intestinal permeability37. It is Conclusions known that certain types of intestinal flora may pro- mote inflammation. The exact mechanism is, howe- In this review, we analyzed how dietary fac- ver, not completely understood. Besides, metabolic tors can modify the gut microbiota. Recent disco- adaptation to high-fat diet is associated to a change veries have allowed us to set aside the idea that in gut microbiota composition68,69. only individual genetics play a role in determi- It was observed that high fat diet induces the ning the composition of the intestinal flora. It is proliferation of certain gram-negative bacteria, evident how the food choice of every individual, such as Enterobacteriaceae, which can ultimately both because of survival needs and taste prefe- result in increased intestinal lipopolysaccharide rence, causes a substantial and significant varia- (LPS)70. To confirm this Pendyala et al71 reported bility in gut microbiota. As increasing evidence is that only 1 month of western diet is responsible of showing us, diet can be definitely included, as it is an important increase of LPS plasma levels. for antibiotics, among the microbiota modulators, Furthermore, increased gut permeability is as- with a two-faced behavior toward gastrointestinal sociated with a decrease in Bifidobacteria spp, disorders76,77. bacteria that are known to reduce LPS levels and We have briefly discussed how a diet rich in also improve gut barrier function. Interestingly, fats may favor an “inflammatory” flora. Diet prebiotic treatment with non-digestible carbohy- rich in fats and low in fibers, typical of Western drates increases Bifidobacteria, reduces intestinal Countries, is rapidly spreading around the wor- permeability, LPS concentrations, and metabolic ld. Similarly, inflammatory diseases are increa- endotoxaemia72. sing in prevalence even in areas where were less In a mouse model, consumption of a high-fat common until a few years ago. Between these two diet increased the incidence of colonic inflamma- observations maybe there is a link, which could tion; this effect seems to be induced by the se- be represented by the diet. It is still too early to cretion of bile acid, in particular taurine, promo- comprise whether this is only a suggestion or ted by fat food. Such phenomenon stimulates the if behind this observation there is a precise pa- growth of sulphite-reducing pathobionts such as thophysiological mechanism. For this reason, fur-

Bilophila wadsworthia, whose production of H2S ther studies are needed to understand the role of is thought to inflame intestinal mucosa. Bilophila the intestinal barrier, and in particular of gut mi- wadsworthia is promoted by a high-fat diet also crobiota, in the development of systemic and lo- in human beings27,61. Moreover, high-fat diet cau- cal immune response. Full understanding of this ses low-grade inflammation in the gut, leading to issue will provide the medical community with increased levels of plasma markers of inflamma- new therapeutic targets for gastrointestinal and tion, and higher levels of circulating LPS73. extraintestinal disorders. A decreased numbers of Bifidobacteria was associated with the higher ω-6 PUFA intake45. Interestingly, high ω-6 PUFA intake decreases Conflicts of interest certain immune functions, such as T-helper Th1 The authors declare no conflicts of interest. and Th2 responses, adhesion molecule expression and proinflammatory cytokines74. Moreover, hi- gh-protein diet stimulates the activity of bacterial References enzymes such as B-glucorinidase, azoreductase and nitroreductase, which produce toxic metabo- 1) Rajilic-Stojanovic M, de Vos WM. The first 1000 lites that trigger inflammatory response31. cultured species of the human gastrointestinal mi- crobiota. FEMS Microbiol Rev 2014; 38: 996-1047. Consequently, the Western diet can therefore 2) Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett create the favorable conditions for chronic en- CM, Knight R, Gordon JI. The human dotoxiemia, defined as an excess of circulating project. Nature 2007; 449: 804-810.

4746 Diet and gut microbiota

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