Abstract
Recently, we discovered that bile acid, a main component of bile, is a host factor that regulates the composition of the cecal microbiota in rats. Because bile secretion increases on a high-fat diet and bile acids generally have strong antimicrobial activity, we speculated that bile acids would be a determinant of the gut microbiota in response to a high-fat diet. The observed changes in the rat cecal microbiota triggered by cholic acid (the most abundant bile acid in human biliary bile) administration resemble those found in animals fed high-fat diets. Here, we discuss the rationale for this hypothesis by evaluating reported diet-induced gut microbiota alterations based on the postulate that bile acids worked as an underlying determinant. The identification of host factors determining the gut microbiota greatly contributes to understanding the causal relationships between changes in the gut microbiota and disease development, which remain to be elucidated.
Introduction
Recent studies have shown that the gut microbiota plays important roles in maintaining host health and in disease development. Many studies have reported changes in the gut microbiota in obese animal models fed high-fat diets1-4 and in patients with type 2 diabetes mellitus,5 various inflammatory bowel diseases,6-11 and colorectal cancer.12 Current studies have focused on how diets or diseases reshape the gut microbiota, in many cases by seeking to identify biomarkers for diagnosing particular diseases or elucidating the etiology derived from dysbiosis (imbalanced composition of the gut microbiota as a result of reshaping). However, the driving force that reshapes the gut microbiota in response to high-fat diets and disease development is not clear, and the causal relationships between changes in the gut microbiota and disease development thus remain to be elucidated (Fig. 1).
Published online:
24 July 2012Figure 1. Relationship between a high-fat diet, imbalanced gut microbiota, and host pathophysiology.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/kgmi20/2012/kgmi20.v003.i05/gmic.21216/20141104/images/medium/kgmi_a_10921216_f0001.gif"})
Figure 1. Relationship between a high-fat diet, imbalanced gut microbiota, and host pathophysiology.
Host Factors Affecting the Composition of the Gut Microbiota
Diet clearly determines the composition of the gut microbiota. As a typical example, bifidobacteria directly assimilate prebiotic raffinose as a carbon source, enabling their proliferation in the colon.13,14 However, the organic acids produced by the fermentation of raffinose by bifidobacteria decrease luminal pH, inhibiting the growth of many microbiota populations while cross-feeding other groups of bacteria in the community. Therefore, the process is not straightforward, even in the case of prebiotics. In terms of host-derived factors in the human intestine, digestive liquors, immunoglobulin A antibody,15 and α-defensin16 have been implicated in affecting the gut microbiota composition. Genotype, sex and age have been suggested collectively as host factors. However, each factor must be connected to the molecules or environmental conditions directly responsible for the microbiota changes.
Postulated Role of Bile Acid in Modulating the Gut Microbiota In Vivo
Little is known about why a high-fat diet alters the gut microbiota, in part because researchers have examined a general “diet effect” rather than a specific “high-fat effect.” To adjust caloric composition, a high-fat diet normally differs from that of a standard diet not only in fat content, but also in sugar content or other parameters.1,2,17 We hypothesized that bile acids were the driving force reshaping the gut microbiota in a high-fat diet, although this has not been well characterized. Bile acids are amphipathic sterols that are secreted into the duodenum as the main component of bile and work to emulsify liposoluble dietary nutrients to facilitate their digestion and absorption. Another important feature of bile acids is their strong antimicrobial activity. Given their amphipathic properties, bile acids damage bacterial cell membranes by interacting with membrane phospholipids, which results in bactericidal activity.18 As bile secretion increases on starting a high-fat diet,19 we speculated that bile acids would exert strong selective pressure on the gut microbiota, especially when the host was fed a high-fat diet. The antimicrobial activity of bile (acid) was discovered early in the last century.20 Since then, many in vitro experiments have shown the bactericidal activity of various bile acids.21 In fact, we characterized the sensitivity/resistance of lactic acid bacteria and bifidobacteria to bile acids for many years to facilitate the utilization of probiotics in the dairy food industry,18,22 as bile is considered one of the main toxic challenges that probiotics must overcome to remain viable in the human gut. Strangely enough, no attempt has been made to clarify how the postulated selective pressure of bile acids affects the gut microbiota in vivo. During this period, bile acids have been studied from chemical, medical and pharmacological perspectives, more than from a microbiological one. At present, relatively few researchers work with bile acids, especially in microbiology.
The First Demonstration of Bile Acids as a Strong Host Factor Reshaping the Gut Microbiota In Vivo
Our recent article in Gastroenterology presented the first evaluation of the effect of bile acids on the gut microbiota in vivo.23 We fed rats a basal diet (control group) or diets supplemented with 1.25 or 5 mmol/kg cholic acid [CA; medium CA (M-CA) and high CA (H-CA) groups, respectively; Fig. 2], the most abundant biliary bile acid in humans, for 10 d. The cecal microbiota was analyzed by sequencing 16S rRNA gene clone libraries. Bile acid metabolism was also determined using fecal samples. The fecal bile acid composition revealed extensive conversion of CA in the diet into deoxycholic acid (DCA; Fig. 2) in both the M-CA and H-CA groups at estimated concentrations of 0.98 and 2.55 mM, respectively, in the cecal contents. DCA is a secondary bile acid arising from CA via a bacterial 7α-dehydroxylation reaction in the intestine, and almost 100% of CA flowed into large intestine is converted into DCA in the human colon.24 DCA has 10 times greater bactericidal activity than CA, and the inclusion of ~1 mM DCA in the culture medium severely inhibited the growth of many intestinal bacteria in vitro.18 Therefore, the DCA concentrations in the M-CA and H-CA groups seemed to exert great environmental stress on the cecal microbiota. By contrast, the DCA concentration in the control group was as low as 0.07 mM, with no apparent growth inhibition observed in vitro. As expected, CA feeding dramatically altered the gut microbiota. At the phylum level, the control group was dominated by Firmicutes (54.1%) and Bacteroidetes (30.7%), together with minority populations. This distribution is similar to those previously found in humans25 and mice.26 By contrast, Firmicutes increased significantly to 93.4% in the H-CA group and 98.6% in the M-CA group, at the expense of Bacteroidetes and minority groups (Fig. 3). The increase in Firmicutes resulted from expansion of the class Clostridia in particular, as well as the bacterial class Erysipelotrichi. At the genus level, Blautia (Clostridia) and Allobaculum (Erysipelotrichi) increased to account for approximately 60% and 15% of all clones, respectively. For Proteobacteria, expansion of the class Gammaproteobacteria was observed in the H-CA group, and all clones detected appeared to be Escherichia coli. The total cell counts per gram of cecal content remained at about 1010, but decreased with increasing CA concentrations down to about one-half that in the control group in the H-CA group, probably due to the antimicrobial activity of DCA. The phylum-level alteration in the proportions of Firmicutes and Bacteroidetes was also confirmed by fluorescence in situ hybridization analysis. An analysis of operational taxonomic units (OTUs) using 97% nucleotide identity as a cutoff value revealed that specific bacteria at the genus and species levels were concentrated in the M-CA and H-CA groups. The diversity of OTUs, expressed as Shannon indices, was lower in the M-CA (2.936) and H-CA (3.487) groups than in the control group (5.839). To substantiate the role played by DCA in controlling the gut microbiota, we isolated bacteria from the cecal contents and compared their sensitivities to DCA by determining the median inhibitory concentration (i.e., the IC50, the DCA concentration resulting in 50% growth inhibition) in vitro. Although not definitive given the small number of OTUs, the results supported the phylum-level population shift, with significantly higher values in Firmicutes (1.2–1.3 mM as determined using OTUs related to Clostridium innocuum and Blautia coccoides) than in Bacteroidetes (0.7–0.9 mM as determined using OTUs related to Bacteroides vulgatus and B. sartorii) and no growth inhibition detected in Gammaproteobacteria (> 2 mM as determined with E. coli). These results clearly demonstrated the hitherto unexplored role of bile acid as a host factor that controls the gut microbiota in vivo.
Published online:
24 July 2012Figure 2. Structures of cholic acid (CA) and deoxycholic acid (DCA), representative bile acids found in the human intestine. The bacterial 7α-dehydroxylation reaction eliminates the hydroxyl group at C-7 of CA to yield DCA.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/kgmi20/2012/kgmi20.v003.i05/gmic.21216/20141104/images/medium/kgmi_a_10921216_f0002.gif"})
Figure 2. Structures of cholic acid (CA) and deoxycholic acid (DCA), representative bile acids found in the human intestine. The bacterial 7α-dehydroxylation reaction eliminates the hydroxyl group at C-7 of CA to yield DCA.
Published online:
24 July 2012Figure 3. Phylum-level alterations in the cecal microbiota of rats fed different diets, as revealed by the sequencing of 16S rRNA gene clone libraries. Rats (n = 6) were fed either a control diet, medium cholic acid (M-CA) diet, or high cholic acid (H-CA) diet for 10 d. The mean percentage (%) of the total population is shown. The figure was modified from Islam et al.23 which contains the full data set and details of the experimental conditions.
Table
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/kgmi20/2012/kgmi20.v003.i05/gmic.21216/20141104/images/medium/kgmi_a_10921216_f0003.gif"})
Figure 3. Phylum-level alterations in the cecal microbiota of rats fed different diets, as revealed by the sequencing of 16S rRNA gene clone libraries. Rats (n = 6) were fed either a control diet, medium cholic acid (M-CA) diet, or high cholic acid (H-CA) diet for 10 d. The mean percentage (%) of the total population is shown. The figure was modified from Islam et al.23 which contains the full data set and details of the experimental conditions.
Table
In our study, we detected significant, but not very different, IC50 values for Firmicutes (1.2–1.3 mM) and Bacteroidetes (0.7–0.9 mM).23 We postulated that all bacteria residing in the intestine are equipped with defense mechanisms to combat bile acid attack at physiological concentrations,22 and that IC50 values reflected the magnitude of the effectiveness of the overall defense systems of each bacterium. In the intestine, where densely populated bacteria compete for a limited energy source, a small difference in sensitivity to DCA may be amplified into a drastic imbalance in a previously established equilibration, as represented by the observed shift in the Firmicutes/Bacteroidetes ratio. Bacteroides is the most abundant and variable genus across individuals,27,28 likely because it is more susceptible than Clostridia bacteria to fluctuations in intestinal DCA concentration. Our findings also demonstrated the importance of the physiological analysis of isolated bacteria together with a 16S rRNA gene-based community analysis to understand the population dynamics in a more comprehensive manner.
Is Bile Acid an Important Factor Modulating the Gut Microbiota on a High-Fat Diet?
As discussed in our article, the overall microbiota population shift brought about by CA administration resembles the observed alterations in the gut microbiota in animals fed high-fat diets: increased Firmicutes/Bacteroidetes ratio,1-4 expansion of class, phylogenetically overlapping bacteria (genus or species level) under both conditions,3,29 and reduced population diversity1,29 and cell densities30 (representative studies are summarized in Table 1 for comparison). In genetically obese ob/ob mice, even the administration of a standard diet increased the Firmicutes/Bacteroidetes ratio,31 probably because these mice have a mutation in the leptin gene and eat more than normal mice, resulting in the intake of more fat in the diet. In human studies, the Firmicutes/Bacteroidetes ratio did not change during carbohydrate-restricted dietary intervention,32 likely because carbohydrates do not affect bile acid excretion. The administration of a fat-restricted low-calorie diet for 1 y to obese people resulted in decreased Firmicutes/Bacteroidetes ratios,33 suggesting that the decreased excretion of bile reversed the ratio to the normal range.
However, these studies provided no information about bile acid concentrations in fecal or cecal samples or the response to dietary intervention. Therefore, for better understanding of the relationship between diet and gut microbiota, we strongly recommend inclusion of bile acid concentration analysis of feces or gut samples along with microbiota analysis itself. In particular, simultaneous monitoring of the gut microbiota composition and bile acid concentration in feces or gut samples and a comparison of these results among different dietary groups (control group, CA-fed group, high-fat group) will clarify the role of bile acids in controlling the gut microbiota on a high-fat diet. It seems also important to identify other host factors affecting the composition of the gut microbiota than bile acid.
Gut Microbiota Composition and Diet/Disease: Implication of a Bile Acid Effect
A recent study compared the fecal microbiota of children from rural Africa and urban Italy.34 The African children ate a traditional rural African diet that is low in fat and animal protein and rich in starch, fiber and plant polysaccharides. Conversely, the Italian children ate a typical Western diet. The study found significant enrichment of Bacteroidetes and depletion of Firmicutes in the African children with a unique abundance of bacteria from the genera Prevotella and Xylanibacter (both Bacteroidetes), which are capable of fermenting the cellulose and xylan that are abundant in the African diet. By contrast, the Italian children harbored a gut microbiota in the standard proportion (Firmicutes: Bacteroidetes ~3: 1). Furthermore, OTU analysis revealed greater microbial richness and biodiversity in the African children than in European children. These results also agree with the expected effect of bile acid, if we assume that the intestinal bile acid concentration was lower in African children than in European children due to diet. Needless to say, we consider the availability of carbon sources in the diet as the primary selective pressure in addition to bile acids. Interestingly, Prevotella has been found to be predominant in the fiber-associated community in the rumens of ruminants,35 in which bile acids are absent. It is also tempting to speculate that a putative concentration gradient of bile acids in the intestine across carnivores (high), omnivores (intermediate) and herbivores (low) created by dietary differences partly determines the phylogenetic (phylum- and genus-level) richness of the gastrointestinal microbiotas reported in each mammal group: carnivores (low), omnivores (intermediate) and herbivores (high).36
Recently, intensive sequencing analysis of human gut microbial communities identified three robust clusters referred to as “enterotypes,” each distinguished by the abundance of one of three genera: Prevotella, Bacteroides and Ruminococcus.27 Although this clustering differs from the results obtained with commonly used criteria such as the Firmicutes/Bacteroidetes ratio, the selective pressure of bile acid on gut microbiota composition must be considered among the factors involved in determining the enterotype, as enterotypes are strongly associated with long-term dietary habits: plant-based nutrition (Prevotella enterotype), animal protein and saturated fats (Bacteroidetes enterotype).37
In patients with inflammatory bowel disease, especially Crohn’s disease localized in the ileum (ICD), E. coli9,10 and Gammaproteobacteria closely related to E. coli11 have been reported to increase preferentially in fecal or biopsy samples in comparison with healthy controls. According to our results,23 E. coli can outgrow other species when the bile acid concentration increases sufficiently to kill the rest of the population, because E. coli is highly tolerant of bile acid attack. Therefore, bile acids are again thought to be involved in the observed gut microbiota changes associated with ICD, and thus in its etiology.
Conclusions
Our study clarified the postulated, but hitherto unproven, role of bile acids in the control of the gut microbiota in vivo and recalled the importance of bile acid as a factor interacting with the gut microbiota and affecting host pathophysiology.23 In this addendum, we have applied our findings to reinterpret reported changes in the gut microbiota. As described, the observed microbiota alterations in many cases can be explained much more rationally by the application of the “bile acid hypothesis” than otherwise. In this context, we have pointed out the importance of bile acid analysis of feces or gut samples along with microbiota analysis. Although we need to determine whether bile acids actually serve as an important determinant reshaping the gut microbiota, especially on a high-fat diet, these findings provide a new perspective for understanding the etiology of metabolic diseases (including obesity), inflammatory bowel disease and colorectal cancer in relation to dysbiosis.
| Table 1. Gut microbiota alterations on administration of cholic acid or high-fat diet |
| Experimental animal | Diet | F/Ba increase | Diversity decrease | Remarkable trait in the gut microbiota alteration; Increased relative abundance of | Reference | |
|---|---|---|---|---|---|---|
| Rat | Cholic acid-supplemented diet | √ | √ | Class Clostridia and Erysipelotrichi (genus Allobaculum and Clostridium innocuum) | 23) [Authors' work] | |
| Mouse | High-fat diet | √ | √ | Class Mollecutes | 1) Turnbaugh et al. | |
| Mouse | High-fat diet | √ | No description | Class Clostridia | 2) Hildebrandt et al. | |
| Humanized mouse | High-fat diet | √ | No description | Class Erysipelotrichi (closely related to Clostridium innocuum) | 3) Turnbaugh et al. | |
| Hamster | High-fat diet | No change (Origially high F/B) | √ | Class Erysipelotrichi (genus Allobaculum) | 29) Martínez et al. | |
a , ratio of Firmicutes to Bacteroidetes √: detected
Acknowledgments
The authors thank financial support from Mishima Kaiun Memorial Foundation to A.Y.
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