Int. J. Mol. Sci. 2015, 16, 7493-7519; doi:10.3390/ijms16047493
`
`OPEN ACCESS
`
`International Journal of
`Molecular Sciences
`o modulate gut
`www.mdpi.com/journal/ijms
`
`Review
`Impacts of Gut Bacteria on Human Health and Diseases
`
`Yu-Jie Zhang 1, Sha Li 2, Ren-You Gan 3, Tong Zhou 1, Dong-Ping Xu 1 and Hua-Bin Li 1,*
`
`1 Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health,
`Sun Yat-sen University, Guangzhou 510080, China; E-Mails: zhyujie3@mail2.sysu.edu.cn (Y.-J.Z.);
`zt740359815@163.com (T.Z.); xudongping1989@163.com (D.-P.X.)
`2 School of Chinese Medicine, The University of Hong Kong, Sassoon Road, Hong Kong, China;
`E-Mail: lishasl0308@163.com
`3 School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China;
`E-Mail: ganry@connect.hku.hk
`
`* Author to whom correspondence should be addressed; E-Mail: hbli2000@yahoo.com or
`lihuabin@mail.sysu.edu.cn; Tel.: +86-20-8733-2391; Fax: +86-20-8733-0446.
`
`Academic Editor: Manickam Sugumaran
`
`Received: 5 February 2015 / Accepted: 26 March 2015 / Published: 2 April 2015
`
`
`Abstract: Gut bacteria are an important component of the microbiota ecosystem in the
`human gut, which is colonized by 1014 microbes, ten times more than the human cells. Gut
`bacteria play an important role in human health, such as supplying essential nutrients,
`synthesizing vitamin K, aiding in the digestion of cellulose, and promoting angiogenesis and
`enteric nerve function. However, they can also be potentially harmful due to the change of
`their composition when the gut ecosystem undergoes abnormal changes in the light of the
`use of antibiotics, illness, stress, aging, bad dietary habits, and lifestyle. Dysbiosis of the gut
`bacteria communities can cause many chronic diseases, such as inflammatory bowel
`disease, obesity, cancer, and autism. This review summarizes and discusses the roles and
`potential mechanisms of gut bacteria in human health and diseases.
`
`Keywords: gut bacteria; human health; cancer; obesity
`
`
`
`1. Introduction
`
`The human gut mucosa consists of epithelial cells, lamia propria, and the muscularis mucosae, which
`is colonized by 1014 microbes [1]. The number of these microbes is ten times more than the human cells.
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`Gut bacteria are important components of the microbiota ecosystem in the human gut. Commensal
`bacteria colonize in the gut shortly after birth and comprise approximate 1000 species, most of which are
`unknown species belonging to anaerobic strains [2,3]. The composition and temporal patterns of gut
`microbiota in infants varies widely and is very different from those in adults. Furthermore, the intestinal
`microbiota stabilizes to a more adult-like profile around the age of one year, usually after the
`introduction of solid foods [4]. In addition, the composition of the gut bacteria community in the
`stomach and colon is distinctive, which is mainly due to different physicochemical conditions, such as
`intestinal motility, pH value, redox condition, nutrients, host secretions (e.g., gastric acid, bile, digestive
`enzymes, and mucus), and the presence of an intact ileocaecal valve [5]. Additionally, they can be
`influenced by many factors, such as the use of antibiotics, illness, stress, aging, bad dietary habits and
`lifestyle [5,6].
`Usually, gut bacteria and the host live in a commensal manner. On the one hand, they can supply
`essential nutrients, synthesize vitamin K, aid in the digestion of cellulose, and promote angiogenesis and
`enteric nerve function [7–9]. Bacteroidetes and Firmicutes are the main bacteria in the metabolism
`of undigested food remnants. They help to digest dietary fiber and polyphenols by a complex
`metabolic energy-harvesting mechanism, which is based on cross-feeding and co-metabolism. In return,
`commensal bacteria take advantage of theprotective and nutrient-rich environment of the host [10]. Yet,
`specialized gut bacteria perform reductive reactions such as methanogenesis, acetogenesis, nitrate
`reduction, and sulfate reduction [11]. On the other hand, commensal bacteria and probiotics can
`promote barrier integrity, and prevent antigens and pathogens from entering the mucosal tissues [12].
`Besides, commensal bacteria contribute to the host defense by regulating the homeostasis of the host
`immune system [13]. However, gut bacteria can be potentially harmful when the gut ecosystem
`undergoes abnormal changes. Dysbiosis of the gut bacteria communities in patients or animal models
`may cause allergy, inflammatory bowel disease (IBD), obesity, diabetes, and even cancer [8,9]. The
`composition of gut bacteria can indicate the risk of diseases in each person [14]. Herein, this review
`summarizes and highlights the roles and potential mechanisms of gut bacteria in human health and
`diseases. Understanding of the relationship between gut bacteria and human health can be helpful for
`targeting new probiotic treatments and novel strategies in treating and managing a wide variety of
`human diseases. The literature was sought from the databases PubMed and ISI Web of Knowledge, and
`the references cited were mainly original articles from 2005–2014.
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`2. Gut Bacteria in Health
`
`The main gut bacterial phyla, in the order of numerical importance, are Firmicutes, Bacteroidetes,
`Actinobacteria, Proteobacteria, Verrucomicrobia and Fusobacteria [15]. Firmicutes are gram-positive
`bacteria with a low G + C content, including the large class of Clostridia and the lactic acid bacteria,
`while Actinobacteria are gram-positive bacteria with a high G + C content, including Colinsella
`and Bifidobacterium spp. Lactic acid bacteria and Bifidobacteria are two important types of gut
`bacteria, which are autochthonous ones from birth or acquired from digested food. Lactobacillus and
`Leuconostoc spp. are the main lactic acid bacteria found in the human intestine. Bifidobacterium spp. is
`the predominant bacteria found among the first colonizers of newborns, and persists at a low level in
`adults [16]. Gut bacteria play an important role in human health, including contributing to the host gut
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`defense system and helping the gut to maintain normal function, while its composition can be
`influenced by the host (Figure 1).
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`Stomach (acid)
`
`Small intestine (bile and
`pancreatic secretions)
`
`(space and
`Colon
`nutrients)
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`Bacteria: 103 cells/ml
`contents;
`e.g.,
`Helicobacter pylori
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`Bacteria: 104-106 cells/g
`contents; e.g., lactobacilli,
`Gram positive cocci
`GALT: mucosal adaptive
`immune activity
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`Bacteria: 1012 cells/g contents;
`e.g., bifidobacteria, lactobacilli,
`bacteroides, enterobacteria,
`enterococci, sulphate reducers,
`methanogens
`Major metabolic activity
`Short chain fatty acids
`
`
`
`Figure 1. Reciprocal relationship between human gut bacteria and the host.
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`2.1. Gut Bacteria and Gut Immune System
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`The gut resists pathogenic bacteria through two barriers, the mechanical barrier and the immune
`barrier. The mechanical barrier consists of a single layer of polarized intestinal epithelial cells,
`the enterocytes and mucus. On the other hand, secreted immunoglobulin A (IgA), intraepithelial
`lymphocytes, macrophages, neutrophils, natural killer cells, Peyer’s plaques, and mesenteric lymph
`node compose the immune barrier. Commensal bacteria and probiotics can promote the integrity
`of gut barriers. Commensal bacteria contribute to the host gut defense system mainly by resisting the
`invasion of pathogenic bacteria and helping the development of the host immune system. Gut bacteria
`maintain resistance against the colonization of pathogenic bacteria by competing for nutrients and
`attachment sites on the mucosal surface in the colon, a phenomenon collectively known as “colonization
`resistance” [17]. The invasion of pathogenic bacteria is also prevented by commensal bacteria due to the
`reduction of the intestinal pH by the production of lactate and short-chain fatty acids (SCFAs) [9].
`Another way is by producing toxic or carcinogenic metabolites to inhibit the growth or kill
`potentially pathogenic bacteria, together with volatile fatty acids that can inhibit the colonization of
`pathogenic bacteria. For example, proteolytic fermentation in the distal colon could produce toxic,
`carcinogenic metabolites such as bacteriocins, ammonia, indoles, and phenols by gut bacteria [18].
`Lipopolysaccharides (LPSs) and peptidoglycan (PGN) components in the bacterial cell wall are two
`kinds of pathogen-associated molecular patterns, and they can individually or synergistically activate
`nuclear factor κB (NF-κB) effector and further induce the production of inflammatory cytokines such as
`tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and antimicrobial peptides in the defense
`against foreign pathogens. Chronic stimulation of pattern-recognition receptors (PRRs) by PGN can
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`also minimize excessive tissue injury induced by intestinal antigen-presenting cells, which can
`produce inhibitory cytokines such as transforming growth factor β (TGF-β) and IL-10 via nuclear
`oligomerization domain-2 dependent pathways [19].
`Peyer’s patches, lamina propria lymphocytes, intra-epithelial lymphocytes and mesenteric lymph
`nodes constitute gut-associated lymphoid tissue (GALT), which is the main part of the gut immune
`system. Gut bacteria prime the dendritic cells (belonging to lamina propria lymphocytes) of the immune
`system. L. plantarum was suggested to regulate human intestinal epithelial tight-junction proteins and
`show protective effects against chemical-induced disruption of the epithelial barrier [12]. It has been
`found that antibody repertoire diversification occurred in GALT after birth and was stimulated by gut
`bacteria in sheep, cattle, pigs, and rabbits [20]. It was hypothesized this action may also occur in
`humans. Gut bacteria including Bacteroides fragilis and Bacillus are probably required for the normal
`development of GALT and mucosal immunity in all mammals. They are also required for somatic
`diversification of immunoglobulin (Ig) genes. Gut bacteria colonization induces a conspicuous response
`of the gut immune system to the production of IgA, which plays a critical role in regulation of gut
`bacterial communities in the small intestine. Another factor that may play an active role in the induction
`of local immune responses is the ILs, which may function as sensors of gut bacteria [10].
`Studies of animals bred under germ-free conditions showed that germ-free animals presented
`morphological, structural, and functional abnormalities, including “reduced vascularity, digestive
`enzyme activity, muscle wall thickness, cytokine production and serum immunoglobulin levels, smaller
`Peyer’s patches and fewer intra-epithelial lymphocytes” [21]. Another study showed that animals
`received cells from germ free mice developed an earlier onset of colitis, and CD4+CD62L− cells from
`germ free mice were not able to ameliorate colitis compared with mice reconstituted with lymphocytes
`from conventionally housed animals [22]. The study also assumed a lack of Treg cells within germ
`free mice by observing the higher percentage of CD4+GITR+ expressing lymphocytes and the production
`of IL-10 after priming by dendritic cells, which suggested the presence of Treg cells within the
`CD4+CD62L+ lymphocyte subset derived from conventional housed mice. Butyrate, produced by
`commensal microorganisms during starch fermentation, may facilitate extrathymic generation of Treg
`cells [23].
`
`2.2. Gut Bacteria Benefit the Host
`
`Not only do gut bacteria benefit the host by contributing to the host gut defense system, they also
`help the gut to maintain normal functions. Gut bacteria benefit the host in a variety of ways, such as
`regulating gut motility, producing vitamins, transforming bile acid and steroids, metabolizing xenobiotic
`substances, absorbing minerals, and activating and destroying toxins, genotoxins, and mutagens [24].
`The proximal region of colon produces a great quantity of short-chain organic acids, such as acetic,
`propionic, and butyric acids. Theses organic acids are energy sources for the colonic mucosa and
`peripheral body tissues, and they are metabolites of undigested complex carbohydrates by colonic
`bacteria fermentation. In return, theses organic acids affect bacterial growth in the colon by
`affecting colonic water absorption and decreasing fecal pH. In addition, Oxalibacterium formigenes,
`a betaproteobacterium within the order Burkholderiales, which is among the putative core bacteria,
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`is one of the few colonic bacteria with well-defined health benefits. They regulate the homeostasis of
`oxalic acid and prevent the formation of kidney stones [25].
`Gut bacteria are essential for the transformation of natural compounds (e.g., lignans) to perform their
`bioactivities. Lignans are present in a wide range of foods, such as flaxseed, vegetable, fruit, and
`beverages. Lignans afford protection against cardiovascular diseases, hyperlipidemia, breast cancer,
`colon cancer, prostate cancer, osteoporosis and menopausal syndrome, dependent on the bioactivation of
`these compounds to enterolactone (ENL) and enterodiol [26,27]. Gut bacteria are required for the
`production and bioavailability of these enterolignans. Secoisolariciresinol is one of the most abundant
`dietary lignans, and it can be demethylated and dehydroxylated by two gut bacteria isolated from
`human feces, named Peptostre ptococcus SECO-Mt75m3 and Eggerthella lenta SECO-Mt75m2 [28].
`Gut bacteria also play an essential role in the metabolism of isoflavones, and the metabolites are more
`biologically active than their precursors. Isoflavones are structurally similar to the mammalian estrogen,
`and soy foods are the predominant food sources of them. Isoflavones have protective activity in
`breast cancer, prostate cancer, cardiovascular disease, osteoporosis, and menopausal symptoms [29].
`In addition, De Fillippo et al. [14] reported that gut bacteria protected African children from the risk of
`infectious and noninfectious colonic diseases by coevolving with the polysaccharide-rich diet, which
`also allowed them to maximize energy intake from fibers.
`
`2.3. Dietary Influence on Gut Bacteria
`
`The colonization of gut bacteria is influenced by many factors, such as the living environment and
`diet (Figure 2). The feeding ways of infants was reported to impact the composition of gut bacteria.
`Infants fed with breast milk had higher levels of Bifidobacteria spp., while infants fed with formula had
`higher levels of Bacteroides spp., Clostridium coccoides and Lactobacillus spp. [30–32]. Besides, the
`host physiologic process, the anatomical structure and physiology of the digestive tract are major
`factors [24]. They may cause changes to the disease structure in the host. It was proved that diets could
`impact the composition of gut bacteria. A study showed that mice fed with Western-diet and
`low-fat-chow-diet displayed different structures of gut bacteria. The relative abundance was increased
`about 1.2-fold for Bacteroidetes and 18-fold for Proteobacteria, while was decreased about 1.5-fold
`for Firmicutes in mice fed with Western-diet. Members of the Desulfovibrionaceae family were
`significantly enriched in the cecal contents of healthy mice fed with Western-diet. Lactobacillus gasseri
`species were found representing 4.3% of total bacteria on average, and Ruminococcus and other
`members of Lachnospiraceae and Bacteroidales were also enriched in mice fed with low-fat-chow-diet.
`Lactobacillus gasseri species were even absent in mice receiving Western-diet [33]. There are also
`studies reporting that long-term and short-term diets influence the composition and function of the gut
`microbiota in humans. In a study of diet inventories and 16S rDNA sequencing to characterize fecal
`samples from 98 individuals, enterotypes were strongly associated with long-term diets, particularly
`protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). Microbiome composition
`changed detectably within 24 h of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that
`enterotype identity remained stable during the 10-days in a controlled-feeding study of 10 subjects [34].
`Another study showed the short-term consumption of diets composed entirely of animal meat, eggs, and
`cheeses or plant rich in grains, legumes, fruits, and vegetables, altered microbial community structure
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`and overwhelmed inter-individual differences in microbial gene expression. The animal-based diet
`increased the abundance of bile-tolerant microorganisms and decreased the levels of Firmicutes
`that metabolize dietary plant polysaccharides. The bile-tolerant microorganisms included Alistipes,
`Bilophila, and Bacteroides, and Firmicutes
`included Roseburia, Eubacterium rectale, and
`Ruminococcus bromii. Both diets also altered microbial metabolic activity. The animal-based diet
`resulted in significantly lower levels of the products of carbohydrate fermentation and a higher
`concentration of the products of amino acid fermentation compared with the plant-based diet and
`baseline samples [35].
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`External influences
`
`Diet; Prebiotics;
`Probiotics;
`Antibiotic usage;
`Illness; Lifestyle;
`Living environment
`
`
`Health
`
`homeostasis
`
`Density, diversity
`and activity of
`the gut bacteria
`
`Dysbiosis
`
`Diseases
`
`Internal host properties
`
`Stress;
`Age; Genetics;
`Physiologic processes; The
`anatomical
`structure
`and physiology of
`the
`digestive tract
`
`
`
`
`Figure 2. Several factors influence the density, diversity, and activity of the gut bacteria.
`
`Further study found that dietary factors such as polyphenols, fibers, and carbohydrates had the ability
`to modify the balance of gut bacteria. Phenolic acids and flavonoids are the main polyphenols of our
`dietary intake. It was shown that tea phenolics and their derivatives repressed the growth of certain
`pathogenic bacteria such as Clostridium perfringens, Clostridium difficile, and Bacteroides spp., while
`they less severely affected commensal anaerobes, such as Clostridium spp., Bifidobacterium spp., and
`Lactobacillus sp. [36]. Parkar et al. [37] found dietary polyphenols may modify the gut bacteria balance
`indirectly by their biotransformation products rather than the original plant compounds. In that study,
`fermentation of polyphenols increased proliferation of Bifidobacteria and decreased the ratio of
`Firmicutes to Bacteroidetes, compared to controls. Furthermore, among the polyphenols studied, caffeic
`acid at 100 mg/mL stimulated the greatest absolute increases of gut bacteria. Polyphenols also
`stimulated the production of short chain organic acids by the gut bacteria. Fiber was another dietary
`factor that impacted the composition of gut bacteria. A study showed that subjects on a fiber-blend
`fortified enteral formula had less negative symptoms related to bowel urgency, and decreases in total
`bacteria and Bifidobacteria were less severe compared with the fiber-free formula [38]. Polyphenols
`and fibers were thought to be beneficial dietary factors. Functional foods based on these beneficial
`dietary factors may provide opportunities to modulate the bacteria balance in the gut. In addition,
`a recent study showed the pH of drinking water could also affect the composition and diversity of
`commensal bacteria in the gut [39].
`However, some dietary factors may be harmful, such as dietary iron. Dietary iron mostly from red
`meat and fortified cereals can also change the gut bacteria composition. Other luminal iron is from
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`cigarette smoking. Increased iron availability may increase the proliferation and virulence of gut bacteria
`and increase the permeability of the gut barrier. A study showed that increased iron exposure contributed
`to the colonization of certain bacterial pathogens including Salmonella [40]. It may be a risk factor for
`colorectal cancer. The composition of intestinal bacteria could also be regulated by traditional Chinese
`herbs. The five hydroxyanthraquinone derivatives from Rheum palmatum had inhibitive effects on
`Bifidobacterium adolescentis growth [41]. The most effective component in R. palmatum to restrain the
`growth of B. adolescentis was rhein.
`It was proved that prebiotics could influence the composition of gut bacteria to benefit the host.
`Prebiotics are defined as a non-digestible food ingredient that beneficially affects the host by selectively
`stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus
`improving the hosts’ health [42]. Prebiotics are carbohydrate-like compounds, such as lactulose and
`resistant starch, and have been used in the food industry to modify the composition of the microbiota
`species to benefit human health in recent years [43]. Inulin is one type of prebiotics. These prebiotics
`mostly target bifidobacteria and lactobacilli, which are two kinds of probiotics [44]. Probiotics are
`living non-pathogenic organisms used as food ingredients to benefit the hosts’ health. They may be lactic
`acid bacteria, Bifidobacteria, or yeasts, such as Saccharomyces cerevisiae [45,46]. Furthermore,
`probiotics can be used in the treatment of hepatic encephalopathy, inflammatory bowel diseases,
`infections, hypertension, cancer, and atopic dermatitis in children [46–50].
`
`3. Gut Bacteria and Diseases
`
`Usually, gut bacteria and the host live in a commensal manner. However, gut bacteria
`can be potentially harmful when the ecosystem undergoes abnormal changes. Dysbiosis of the gut
`bacteria communities in patients or animal models may cause many diseases. For example, antibiotic
`treatment and surgery cause pseudomembranous colitis due to toxin production by Clostridium difficile
`and sepsis of Escherichia coli, Enterococcus faecalis and Enterococcus faecium, and intra-abdominal
`abscesses due to Bacteroides fragilis [51]. Imbalance in gut bacteria composition was associated with
`intestinal symptoms, such as bloating, abdominal pain, and diarrhoea. Uncultured phylotypes from
`Clostridium clusters IV and XIVa had statistically significant positive correlation with bloating.
`Anaerotruncus colihominis, Ruminococcus callidus and Lachnospira pectinoschiza were higher when
`bloating was recorded. The abundance of bifidobacteria may have a negative correlation with abdominal
`pain. In addition to bifidobacteria, one phylotype within Ruminococcus lactaris, Clostridium cluster IV,
`was significantly decreased in pain associated samples. Among the positive correlations, uncultured,
`potentially pathogenic phylotypes within uncultured Clostridiales II, Anaerotruncus colihominis and
`Ruminococcus callidus, were increased over ten-fold when pain was recorded [25]. Diarrhea was
`associated with a reduced number of members from the genus Streptococcus, particularly S. alactolyticus [15].
`Besides, many other diseases are related to gut bacteria, such as inflammatory bowel diseases, obesity,
`diabetes, liver diseases, chronic heart diseases, cancers, HIV, and autism.
`
`3.1. Gut Bacteria and Inflammatory Bowel Diseases
`
`Inflammatory bowel disease (IBD) is most common in the developed countries of Europe, the U.S.,
`and Scandinavia [24]. Reciprocal interaction between commensal gut bacteria and the host may induce
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`allergies and IBD. Overly aggressive Th-1 mediated cytokine response to commensal bacteria may be
`the pathogen of chronic intestinal inflammation [52]. In addition, disorders in bacterial recognition by
`macrophages are strongly related to pathogenesis of IBD. Furthermore, IBD could results from an abnormal
`immune response against the commensal microbiota in a genetically susceptible host. Jostins et al. [53]
`have identified 163 risk loci associated with IBD, and found that many loci were involved in the sensing
`and elimination of bacteria. A hypothesis is that the innate immune system in IBD patients could be
`deficient, which in turn leads to an uncontrolled adaptive response.
`Ulcerative colitis (UC) is one of the two major idiopathic IBDs [54]. In UC patients, the disease is
`limited to the colon. Numbers of lactobacilli were significantly lower during the active phase of the
`disease, and denaturing gradient gel electrophoresis analysis suggested that Lactobacillus salivarus,
`Lactobacillus manihotivorans and Pediococcus acidilactici were present in remission, but not during
`active inflammation [55]. Besides, the colonic bacterial communities from diseased mice were less
`complex, indicating less diversity of bacterial composition during acute inflammation. Bacteria of the
`Clostridiales group were more prominent in samples from the inflamed colon, indicating these bacteria
`might accumulate during colitis [56]. In a study of an animal colitis model, E. coli may have served
`as a biomarker for colitis severity. The development of colitis is associated with higher E. coli loads,
`and bacterial TLR2 ligands may contribute to colitis pathology. Bacterial products exacerbate
`acute
`inflammation via TLR2- and TLR4-signaling and potentially
`trigger TLR-dependent
`accumulation of neutrophiles and T-cells. IL-10−/− mice developed Th1-dominant colitis via IL-12
`and IL-23 hyperproduction through bacteria recognition by abnormally differentiated subsets of
`intestinal macrophages [57]. A recent study observed a reduction of Roseburia hominis and
`Faecalibacterium prausnitzii in fecal samples of UC patients, and both species showed an inverse
`correlation with disease activity [58]. UC patients had different gene expression profiles and lower
`levels of biodiversity than their healthy twins, as well as unusual aerobic bacteria. They also had lower
`percentages of potentially protective bacterial species (e.g., Lachnospiraceae and Ruminococcaceae
`families) than their healthy twins. The colonic microbiota appeared to interact with the transcriptional
`profile of the mucosa. This interaction appeared to be lost in the colon of UC patients. Bacterial
`functions, such as butyrate production, might affect mucosal gene expression [59]. It has been suggested
`that prebiotic combination (a combination of chicory-derived long-chain inulin and oligofructose)
`reduced colitis in HLA-B27 transgenic rats, associating with alterations to the gut bacteria, decreased
`proinflammatory cytokines, and increased immunomodulatory molecules [52].
`Crohn’s disease (CD) is another type of IBDs. It has been thought to be an autoimmune disease,
`in which the body’s immune system attacks the gastrointestinal tract and causes inflammation [60].
`Seksik et al. [61] found that the fecal microflora in patients with both inactive and active colonic
`CD contained significantly more enterobacteria than in healthy subjects. In addition, about 30% of
`the dominant bacteria did not belong to the usual dominant phylogenetic groups. Another study
`found that five bacterial species characterised dysbiosis in CD patients, which were a decrease in
`Dialister invisus, an uncharacterised species of Clostridium cluster XIVa, Faecalibacterium prausnitzii
`and Bifidobacterium adolescentis, and an increase in Ruminococcus gnavus. There was a different
`composition of gut microbiota in unaffected relatives of patients with CD compared with healthy
`controls. This dysbiosis was not characterized by lack of butyrate producing-bacteria as observed in
`CD but suggested mucin-degradation capacity of microorganisms [62]. In addition, an increased
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`including Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and
`in bacteria
`abundance
`Fusobacteriaceae and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales,
`correlated strongly with disease status in a large pediatric CD cohort study. The study also indicated that
`antibiotic use amplified the microbial dysbiosis associated with CD. It suggested as well that assessing
`the rectal mucosal-associated microbiome offered unique potential for convenient and early diagnosis of
`CD at this early stage of disease [63]. Exclusive enteral nutrition treatment significantly changed gut
`bacterial composition, and the changes of gut Bacteroides species were associated with reduced
`inflammation in CD patients [64]. However, resident Bifidobacteria and Lactobacilli did not suppress
`the growth of disease-inducing Bacteroides species or clostridia to mediate protective action.
`Furthermore, several studies showed that prebiotic and probiotic use has an effect on the induction of
`remission in IBD patients [65]. In general, gut bacteria take a critical role in the development of IBD
`through the regulation of inflammation in the gut.
`
`3.2. Gut Bacteria and Obesity
`
`Normal gut bacteria play an important role in diet-induced obesity, because germ-free mice have been
`reported to be thinner and did not become adipose when subjected to high-fat diet [66]. The high-fat diet
`altered the composition of bacteria to display higher levels of luminal Firmicutes and Proteobacteria
`and lower levels of Bacteroidetes [67], indicating that obesity may be associated with decreased
`diversity and changes in composition of the gut bacteria. Gut bacteria is an important determinant of
`susceptibility to obesity and related metabolic diseases. The ratio of Firmicutes to Bacteroides has been
`found to be correlated to body weight, with the ratio being higher in obese people [68]. Gut bacteria
`could also affect obesity by promoting chronic inflammatory status [69]. In addition, Clostridium difficile
`infections may be another possibility of causing obesity [70]. Gut bacteria may affect obesity through
`regulation of the microbiota-brain-gut axis by its metabolites. Overweight individuals have more faecal
`SCFAs than lean individuals, with significantly increased levels of propionate. Butyrate and propionate
`were reported to protect against diet-induced obesity and regulate gut hormones via free fatty acid
`receptor 3(FFAR3)-independent mechanisms in mice [71]. SCFAs (propionate and butyrate) activated
`intestinal gluconeogenesis (IGN) by complementary mechanisms. Butyrate directly activated IGN gene
`expression via an increase in cAMP in enterocytes. Propionate, acting as a FFAR3 agonist in the
`periportal afferent neural system, induced IGN via the microbiota-gut-brain axis. A portal vein glucose
`sensor detected glucose produced by IGN and communicated to the brain by the peripheral nervous
`system to promote beneficial effects on food intake and glucose metabolism [72].
`Conjugated linoleic acid (CLA) has anti-obesity effect. Some rumen bacteria have the ability to form
`CLA from diets, such as food products from beef, milk fat, natural, and processed cheeses, yogurt, and
`plant oil. The amount of CLA in human adipose tissue is thought to be directly related to dietary intake.
`It was found that six strains (four Bifidobacterium breve strains, a Bifidobacterium bifidum strain and a
`Bifidobacterium pseudolongum strain) were able to produce different CLA and conjugated α-linolenic
`acid isomers from free linoleic acid and α-linolenic acid [73]. Lactobacillus rhamnosus PL60 is a human
`originated bacterium that produces t10, c12-CLA. A study showed that after eight weeks of feeding,
`L. rhamnosus PL60 reduced the body weight of diet-induced obese mice without reducing energy intake,
`and caused a significant, specific reduction of white adipose tissue, including epididymal and perirenal [74].
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`There was no observation of liver steatosis, a well known side effect of CLA by L. rhamnosus PL60
`treatment. Furthermore, oral Lactobacillus reuteri therapy alone prevented the pathology of abdominal
`obesity and age-associated weight gain in mice regardless of their baseline diet, and changed the
`pro-inflammatory immune cell profile, which was particularly dependent on CD4+ T cells and the
`presence of anti-inflammatory IL-10 [75]. In addition, an epidemiological study showed that eating
`yogurt surprisingly preven