Altered Gut Microbiota: A Link Between Diet and the Metabolic Syndrome

Abstract

Diet with increased intake of energy-rich foods has long been implicated in the etiology of metabolic syndrome. In recent years, an increasing body of evidence has emerged that suggests that the intestinal microbial flora or “gut microbiota” may play a crucial role in the development of metabolic syndrome and associated disorders. Studies on animals and humans have shown that diet-induced changes in gut microbiota may be causally involved in the pathogenesis of metabolic syndrome. This article reviews the available evidence from studies on animal models and humans with or without metabolic syndrome that have investigated the impact of diet on intestinal microbial composition and activity on the metabolic syndrome. The underlying mechanisms or pathways that link diet and altered gut microbiota to the development of metabolic syndrome are discussed with special emphasis on gut microbiota-induced changes in intestinal short-chain fatty acids, metabolic endotoxemia, low-grade systemic inflammation, and innate immune system activation and their inter-relationships to metabolic syndrome.

Introduction

Metabolic syndrome represents a cluster of metabolic disturbances that include obesity, glucose intolerance, insulin resistance, dyslipidemia, and hypertension.¹ Over the past decade, the prevalence of metabolic syndrome has increased in epidemic proportions,^2

–5 and has become a global public health concern because of its strong association with type-2 diabetes mellitus, cardiovascular disease, chronic kidney disease, and overall mortality.^6

–11

Diet with increased intake of energy-rich foods has long been considered as a factor in the etiology of metabolic syndrome and related diseases. Several studies on animals and humans have demonstrated that consumption of diets high in fat and sugars induces obesity, dyslipidemia, and insulin resistance,^12

–15 the three major components of metabolic syndrome. However, the mechanisms by which these diets contribute to the pathogenesis of metabolic syndrome are incompletely understood. In recent years, increasing evidence has emerged that suggests that the intestinal microbial flora may play a crucial role in the development of obesity, insulin resistance, and other abnormalities of metabolic syndrome.

Composition of the Human Gut Microbiota

The human intestinal tract constitutes a nutrient-rich environment inhabited by a highly diverse microbial community, collectively referred to as “gut microbiota.” It has been estimated that the gut microbiota makes up to 100 trillion (10¹⁴) microbes, which comprises ∼10-fold the number of human cells, and encodes 150-fold more genes than our own genome.^16,17 A recent estimate of the relative abundance of bacterial cells and human cells in the human body has been revised, and it was shown that the total number of bacteria in a 70-kg “reference man” is 3.8¹³ and the total number of human cells is 3.0.^13,18

Metagenomic studies indicate that most of the microbes residing in the human intestinal tract are dominated by members of two bacterial divisions, namely Firmicutes and Bacteroidetes, which comprise >90% of the known phylogenetic categories.¹⁹ Other bacterial phyla found in human gut include Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia.¹⁹ Studies on healthy adults have revealed substantial diversity in their gut microbial composition and differences between and within individuals,^16,19 which may contribute to variations in normal physiology and metabolism. Despite this interindividual diversity of intestinal microbial composition, a host–bacterial relationship exists that is mutually beneficial and essential in maintaining physiological homeostasis and metabolism in the host.²⁰ One important manifestation of this symbiotic relationship is the maintenance of energy balance in response to changes in the diet, where the gut microbes, on the one hand, act to harvest energy from the diet, and the host, on the other hand, absorbs and extracts or deposits energy in host fat depots. Such a relationship between gut microbiota and host may be disrupted by dietary indiscretions which may predispose the individual to metabolic syndrome and related diseases.²¹

Diet and Gut Microbiota

A number of studies on animal models and humans have shown that changes in diet are associated with alterations in the composition and diversity of the gut microbial community.^22

–28

Animal Studies

In a series of studies on mice, Turnbaugh et al.²² have demonstrated that changing from a low-fat, plant polysaccharide-rich diet to a high-fat (HF), high-sugar “Western” diet altered gut microbiota composition in a rapid and reproducible fashion, and altered microbial gene expression.

Consumption of the Western diet resulted in a relative increase in the abundance of the Erysipelotrichi class of bacteria within the Firmicutes phylum, which were most closely related to Clostridium innocuum, Eubacterium dolichum, and Catenibacterium mitsuokai. There was also a significant increase in the relative abundance of the Bacilli (mainly Enterococcus) and a significant decrease in the abundance of members of the Bacteroidetes. In addition, the “Western” diet resulted in increased adiposity that can be transmitted to germ-free (GF) mice via transplantation of the gut microbiota from Western diet-fed donor mice. Similarly, Hildebrand et al.,²³ using another mouse strain prone to diet-induced obesity, showed a shift in the gut microbiota composition in mice when their diet was changed from a standard chow to a high-fat diet (HFD). HFD resulted in a decrease in Bacteroidetes and an increase in Firmicutes and Proteobacteria, effects that were independent of obesity.²³

High-energy diets containing refined sugars, such as sucrose or fructose, have also been reported to alter gut bacterial composition.^24,25 Parks et al.²⁴ examined the changes in gut microbiota composition in response to a HF/high-sucrose (HF/HS) diet in >100 inbred strains of mice with differing obesity traits, and observed that the percentage of body fat (a measure of adiposity) varied widely among the strains both before and after HF/HS feeding. Notably, there were significant changes in the gut microbiota composition at the phylum level after HF/HS feeding. Specifically, HF/HS-fed mice, as compared with mice fed a chow diet, showed a greater abundance of several genera classified to order Clostridales in Phyla Firmicutes and lower abundance of Bacteroidetes, classified to family Porphyromonadaceae. A total of 17 genera were observed whose abundance was significantly changed by the HF/HS diet. Another notable finding in this study is the genome-wide association studies (GWAS) analysis which identified 11 genome-wide significant loci that correlated with body fat. There was also a strong relationship between genotype and gut microbiota composition after HF/HS feeding, suggesting that gut microbiota composition is determined in part by genetic factors.

Consumption of fructose, a major component of the Western-style diet, has also been reported to alter gut microbiota composition. In a study of adult Sprague Dawley rats, Di Luccia et al.²⁵ showed that fructose feeding for 8 weeks induced several markers of the metabolic syndrome, inflammation, and oxidative stress. These effects were associated with altered the composition of the gut microbiota typified by increased number of two bacterial genera: Coprococcus and Ruminococcus. The fructose-rich diet also resulted in increased plasma levels of nonesterified fatty acid, plasma lipopolysaccharide (LPS), and tumor necrosis factor (TNF-α). Moreover, these biochemical and inflammatory markers were reversed by treatment with antibiotic treatment, or by transplantation of fecal samples of control rats under standard diet, suggesting that abundance of these microorganisms may be contributing to the development of metabolic syndrome.

Human Studies

Only a few studies have investigated the effect of diet on gut microbiota composition in humans.

In a cross-sectional study of 98 healthy human subjects, Wu et al.,²⁶ using diet inventories and 16S rDNA sequencing methods, examined the association of long-term dietary patterns with gut microbiota, and found that specific nutrients were associated with different gut microbial populations. For example, long-term Western-style diets rich in protein and animal fat are associated with gut microbial taxa typified by a Bacteroides enterotype, whereas diets rich in carbohydrates and simple sugars are associated with a Prevotella enterotype. Additionally, a controlled-feeding study of healthy subjects showed that microbiota composition changed within 24 hr of initiating a HF/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, the effect of long-term dietary patterns is associated with microbial enterotypes, whereas the effect of short-term dietary variations appears to be rapid and of modest magnitude but not sufficient to induce a significant change in enterotypes.

In another study on humans, David et al.²⁷ evaluated the effects of two different diets on gut microbial composition: an animal-based diet which consists of foods rich in meat, poultry, and cheese, and a plant-based diet which consists of foods derived from grains, lentils, fruits, and vegetables. Consumption of the animal-based diet for 5 days produced significant changes in gut microbiota with an increase in the abundance of three bacterial clusters Alistipes, Bilophila, and Bacteroides, and a decrease in the abundance of phylum Firmicutes comprising Roseburia, Eubacterium rectale, and Ruminococcus bromii. The plant-based diet also altered gut microbiota composition, but the changes in abundance of bacterial clusters were much less compared with the animal-based diet. Additionally, both diets significantly altered microbial metabolic activity as reflected by changes in fecal concentrations of short-chain fatty acids (SCFAs). The animal-based diet as compared with plant-based diet was associated with lower levels of acetate and butyrate (the products of carbohydrate fermentation), and higher levels of isovalerate and isobutyrate (the products of amino acid fermentation). Taken together, these data indicate that diet can rapidly alter human gut microbiota composition, which may result in significant shifts in carbohydrate and protein fermentation in the gut.

The quality and quantity of dietary fat and carbohydrate have also been reported to alter gut microbiota composition. Fava et al.²⁸ evaluated the effect of different types of diets that varied in the amount and type of fat and carbohydrate in 88 human subjects at risk of metabolic syndrome. Subjects were fed a high saturated fat diet for 4 weeks, and then randomized into one of the five experimental diets for 24 weeks: (1) HS; (2) high monounsaturated fat (MUFA)/high glycemic index (GI; HM/HGI); (3) high MUFA/low GI (HM/LGI); (4) high carbohydrate (HC)/high GI (HC/HGI); and (5) high HC/low GI (HC/LGI). The HC diets increased both fecal Bifidobacterium and Bacteroides but the effect of the types of diet differed, in that the HC/HGI increased fecal Bacteroides, whereas HC/LGI and HS increased Faecalibacterium prausnitzii. Of note, this increase in Bacteroides after HC diets was associated with decrease in body weight. In contrast, the HFDs (HS, HM/HGI, HM/LGI) decreased the numbers of total bacteria but had no significant effects on fecal concentrations of SCFAs except for HS diet, which increased SCFA levels. Altogether, these findings suggest that both the quantity and the type of dietary fat and carbohydrate can modify gut microbiota composition in humans at risk of metabolic syndrome.

Accumulated data from several observational and epidemiological studies indicate that high-fructose consumption is an important contributory factor in the development and rising incidence of obesity and metabolic syndrome.^29

–33 To date, however, there has been lack of data regarding the effects of diets rich in fructose or sucrose on gut microbiota composition in humans. More clinical studies are required to determine whether high-fructose diet can alter gut microbiota composition and its metabolic activity in human subjects.

Gut Microbiota and Metabolic Syndrome

Data from studies on animals and humans suggest a link between the composition of gut microbiota and components of the metabolic syndrome. In seminal studies of mouse models, Turnbaugh et al.³⁴ demonstrated that gnotobiotic or GF mice when colonized with gut microbiota from obese mice rapidly developed obesity, manifested by accelerated body weight gain and increased fat mass. The increased body fat was associated with an increase in the relative abundance of Firmicutes/Bacteroidetes phyla. As a result of colonization of gut microbiota from obese mice, recipient mice subsequently acquired a gut microbiota similar to their obese donor, indicating that the obesity trait-associated gut microbiome is transmissible.

Altered gut microbiota has also been demonstrated in a unique mouse model resembling human metabolic syndrome. In studies of mice lacking in Toll-like receptor 5 (TLR5) or T5KO mice, Vijay-Kumar et al.³⁵ found that these mice when fed a HFD develop characteristic features of metabolic syndrome, including adiposity, insulin resistance, hyperlipidemia, and hypertension. In T5KO mice, there was altered abundance of gut microbiota composition similar to that reported in other studies (Firmicutes, 54%; Bacteroidetes, 39.8%; Proteobacteria, 1.1%; Tenericutes, Actinobacteria, TM7, and Verrucomicrobia, <0.2% of the sequences) that correlated with the metabolic features of metabolic syndrome. Transplanting the gut microbiota from TK5O mice to wild-type GF mice conferred many characteristics of metabolic syndrome to the recipient mice. HFD exacerbated metabolic syndrome and hepatic steatosis with concomitant increases in hyperglycemia, insulin resistance, and serum triglycerides. However, food restriction in TK5O mice prevented the development of obesity but not insulin resistance.

Evidence for a direct connection between gut microbiota and the metabolic syndrome has been provided by the studies of Di Luccia et al. in rats with fructose-induced metabolic syndrome, showing that altered gut microbiota composition induced by high-fructose diet was directly correlated with markers of the metabolic syndrome.²⁵ Moreover, many of the metabolic alterations induced by fructose were reversed by antibiotic treatment or fecal transplantation. Recently, Haro et al.³⁶ evaluated the gut microbiota composition in patients with metabolic syndrome, and found differences in the abundance of several bacterial groups or genera. Specifically, a higher abundance of Bacteroides, Eubacterium, and Lactobacillus genera but a lower abundance in Bacteroides fragilis group, Parabacteroides distasonis, Bacteroides thetaiotaomicron, Faecalibacterium prausnitzii, Fusobacterium nucleatum, Bifidobacterium longum, Bifidobacterium adolescentis, Ruminococcus flavefaciens subgroup, and Eubacterium rectale was observed in patients with metabolic syndrome compared with healthy control subjects. Interestingly, the changes in gut microbiota in metabolic syndrome patients were modified by long-term consumption of a Mediterranean diet with partial restoration of the Bacteroides fragilis group. However, more studies on humans with metabolic syndrome are needed to further confirm these changes in gut microbiota composition.

Mechanisms Linking Diet, Altered Gut Microbiota, and the Metabolic Syndrome

The underlying mechanisms or pathways that link diet, gut microbiota, and the development of metabolic syndrome are incompletely understood. Several mechanisms have been proposed, including increased energy harvest from the diet, altered energy homeostasis and metabolic processes, increased production of SCFAs, gut microbiota-induced metabolic endotoxemia, systemic low-grade inflammation, oxidative stress, modulation of signaling pathways and the immune system (Fig. 1). The relative contribution of these factors may vary in importance, and depend on the nature or timing of the inciting stimulus during the evolution of metabolic syndrome. It is also possible that there may be other mediators or pathways yet to be identified that participate in pathogenesis of metabolic syndrome and associated disorders.

FIG. 1.

Proposed mechanisms linking diet, altered gut microbiota, and metabolic syndrome.

Increased Energy Harvest

Studies on mouse models and humans have demonstrated the inter-relationships between diet, gut microbiota composition, and energy equilibrium, and suggested that the gut microbiota has the ability to alter energy balance in the host by modulating extraction of calories from the diet.^34,37
–39 In their studies of normal and GF mice, Bäckhed et al.³⁷ demonstrated that transplantation of gut microbiota from normal mice into GF mice produced a marked and rapid increase in body fat. The increase in body fat was observed even though the food intake in the recipient mice was reduced. This finding indicated that the gut microbiota by virtue of its capacity to harvest energy from the diet was responsible for increased fat storage in the host. Further direct biochemical evidence on the role of gut microbiota in energy harvesting is the observation that the presence of the microbiota promotes increased monosaccharide uptake from the gut lumen to the liver resulting in induction of de novo hepatic triglyceride production. This effect is mediated by transactivation of hepatic lipogenic enzymes and carbohydrate response element binding protein (ChREBP) and sterol response element binding protein 1 (SREBP-1), two transcription factors known to mediate hepatocyte lipogenic responses to insulin and glucose.³⁷ The microbiota was also shown to promote storage of triglycerides in adipocytes through suppression of fasting-induced adipocyte factor (Fiaf), a circulating lipoprotein lipase (LPL) inhibitor, resulting in increased LPL activity in adipocytes.³⁷

The relationship between gut microbiota composition, dietary caloric load, and nutrient absorption has also been investigated in humans. In studies of obese individuals who were placed on two different low-calorie diets for 12 months, Ley et al.³⁸ showed an increase in the Firmicutes and a decrease in the Bacteroidetes phyla in the feces of obese subjects that was associated with adiposity. This change in fecal microbiota composition was reversed with weight loss on the two types of low-calorie diet, suggesting that the gut microbiota in obese humans is responsive to changes in caloric intake. Additionally, in energy-balance studies, Jumpertz et al.³⁹ also found close relationships between fecal bacterial composition, nutrient load, and stool energy loss in lean and obese subjects. Using bomb calorimetry to measure stool calories as an indirect measure of nutrient absorption, these investigators estimated that a 20% increase in Firmicutes was associated with an increase in nutrient absorption of ≈150 kcal, whereas a 20% increase in Bacteroidetes was associated with a decrease in absorption of ≈150 kcal.³⁹

Role of Short-Chain Fatty Acids

Another mechanism that links gut microbiota to metabolic syndrome involves metabolites, such as the SCFAs, produced by colonic microbiota through anaerobic fermentation of dietary fat and carbohydrate.^40,41 SCFAs, namely acetate, propionate, and butyrate, enter the systemic circulation, and act as metabolic precursors for glucose and lipid metabolism in the host. For example, acetate is utilized for lipogenesis in the liver. Propionate is also largely taken up by the liver, and is used as a substrate for hepatic gluconeogenesis. Butyrate is the major fuel source for colonocytes. SCFAs also act as signaling molecules and ligands for at least two G protein-coupled free fatty acid receptors, FFAR2 (GPR43) and FFAR3 (GPR41), which are expressed in the distal small intestine, colon, and adipocytes.^42,43

Besides serving as a source of energy, SCFAs have multiple physiological actions in various tissues which can have positive or negative effects on glucose metabolism and energy homeostasis. For example, butyrate has been shown to improve insulin sensitivity and reduce adiposity in mice with diet-induced obesity.⁴⁴ The SCFAs butyrate and propionate have also been shown to suppress food intake and prevent HFD-induced weight gain in mice.⁴⁵ The inhibition of food intake and body weight was mediated in part through stimulation of the gut hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide by butyrate and propionate.⁴⁵ It was further shown that SCFAs stimulate the release of the gut-derived peptides, GLP-1 and peptide YY (PYY) through activation of G-protein-coupled receptor FFAR2 (GPR43) in the intestine to modulate nutrient absorption from the gut, intestinal motility, and appetite.^46,47 Along similar lines, gut microbiota-derived SCFAs butyrate and propionate were shown to increase intestinal glucose production through activation of intestinal gluconeogenic (IGN) genes.⁴⁸ The increased IGN gene expression induced by butyrate appears to be mediated by an increase in intracellular cyclic adenosine monophosphate (AMP), whereas IGN activation by propionate involves a gut–brain neural axis mechanism.⁴⁸

In vitro and in vivo studies have shown that SCFAs increase the secretion and circulating levels of the adipocyte-derived hormone leptin.⁴⁹ The stimulatory effect of SCFAs on leptin secretion appears to be mediated through activation of G-protein-coupled receptor GPR41.⁴⁹ As leptin is well known to suppress food intake,^50,51 it is possible that SCFAs can exert a negative impact on energy balance by stimulating leptin production.

On the contrary, SCFA acetate has also been shown to exert direct effects on adipocytes. For example, exposure of cultured brown adipocytes in vitro with acetate promoted adipogenesis and increased mitochondrial mass.⁵² These effects were mediated through activation of GPR43 receptor in adipocytes.⁵² Chronic acetate treatment was also shown to upregulate the expression of beige adipogenesis-related genes in 3T3–L1 cells in vitro and visceral white adipose tissue (WAT) of KK-Ay mice in vivo.⁵³ The physiological significance of these effects of acetate on brown adipocytes and WAT to the overall regulation of energy balance is unclear, and needs further investigation.

Activation of the sympathetic nervous system (SNS) has been proposed as one of the mechanisms implicated in diet-induced obesity and the metabolic syndrome.^54,55 Excessive caloric intake stimulates the activity of SNS through β-adrenergic receptor action on target tissues, which then activates thermogenesis, as a means of the body's defense against diet-induced obesity.⁵⁶ There is also evidence that SCFAs contribute to energy homeostasis by regulating SNS activity. Kimura et al.⁵⁷ have shown that SCFA propionate directly stimulates SNS via activation of GPR41 receptor located at the sympathetic ganglion. By contrast, β-hydroxybutyrate, the major ketone body produced during starvation or diabetes, had opposite effects and inhibited SNS activity by inactivating GPR41signaling.⁵⁷ More recently, in a series of studies performed on rats, Perry et al.⁵⁸ demonstrated that plasma levels of acetate and whole-body acetate turnover were increased in rats fed a HFD. In addition, chronic intragastric infusions of acetate in chow-fed rats increased body weight gain and induced insulin resistance, which were accompanied by increases in glucose-stimulated insulin secretion (GSIS) as well plasma concentrations of gastrin (a marker of parasympathetic nerve activity). Furthermore, these effects of acetate were prevented by vagotomy or treatment with the parasympathetic blocker atropine, indicating the involvement of para-SNS activity in mediating acetate's effect in promoting GSIS and metabolic syndrome.

Metabolic Endotoxemia

It has been proposed that alterations in gut microbiota induced by HFD may increase intestinal permeability leading to translocation or passage of bacteria or their products into the systemic circulation.^59

–62 Cani et al.⁵⁹ first reported and identified bacterial LPS, a major glycolipid constituent of the cell wall of gram-negative bacteria, as a triggering factor in initiating obesity and insulin resistance. These investigators demonstrated a marked increase in circulating levels of LPS, termed as “metabolic endotoxemia,” in mice fed a HFD. In addition, HFD-fed rats had altered the intestinal bacterial composition with an increase in the proportion of an LPS-containing microbiota in the cecum of HFD-fed mice.⁵⁹ Moreover, chronic subcutaneous infusion of exogenous LPS induced obesity in association with increased fasting plasma glucose and insulin levels and liver insulin resistance. Both HFD and LPS infusion were also associated with increased gene expression of inflammatory cytokines [(TNF-α, IL-1, IL-6, and plasminogen activator inhibitor (PAI-1)]. These findings indicate that endotoxemia induced by endogenous LPS or by exogenous infusion of LPS may be causally involved in the induction of obesity and insulin resistance associated with HF feeding.

Recent studies on humans have also linked circulating endotoxemia with metabolic disorders and nutrient intake. For example, in a large Finnish-population-based study, Pussinen et al.⁶³ have shown for the first time that fasting serum endotoxin or LPS activity (measured by kinetic Limulus Amebocyte Lysate test) was significantly associated with increased risk of clinically incident diabetes. This association persisted even after excluding known diabetic risk factors, such as body mass index (BMI) and serum levels of glucose, lipids, and C-reactive protein. In a subsequent study of Finnish subjects, it was shown that serum LPS activity correlated strongly with components of metabolic syndrome.⁶⁴ High LPS activity was noted to be more common in subjects who had high BMI, dyslipidemia, and insulin resistance. Serum LPS or endotoxin levels were also shown to be directly associated with energy intake⁶⁵ and exacerbated by HF intake.⁶⁶ Altogether, the results of these studies support findings in animal models that metabolic endotoxemia as determined by serum LPS activity, induced by high energy or HF intake, is strongly associated with metabolic disorders.

Low-Grade Systemic Inflammation

Chronic low-grade inflammation has been considered as a crucial event in the development of obesity-related insulin resistance, metabolic syndrome, and type-2 diabetes mellitus.^67
–69 The inflammatory response associated with these conditions is thought to be mediated by infiltration of macrophages in metabolic tissues, especially adipose tissue and liver, leading to increased adipocyte production of several proinflammatory cytokines, including TNF-α, IL-1, IL-6, and other chemokines.^68,70 The molecular mechanisms mediating the inflammatory response to insulin resistance appear to involve activation of transcription factor NF-kappa B and Jun amino-terminal kinase pathways.⁷¹

Increasing evidence indicates that the gut bacteria participate in metabolic endotoxemia, and low-grade inflammation associated with obesity and diabetes.^60,72,73 Cani et al.⁶⁰ provided experimental evidence from studies on mouse models by showing that antibiotic treatment in mice with diet-induced obesity improved glucose tolerance and insulin resistance, and reduced the gene expression of inflammatory markers and concentration of lipid peroxides (a marker of oxidative stress) in visceral adipose tissue. In addition, antibiotic treatment in another mouse model of obesity, ob/ob mice, produced similar improvements in glucose tolerance, and reductions in inflammatory and oxidative stress markers. Furthermore, studies on mutant ob/ob CD14^−/−mice that lack LPS receptor CD14 reproduced the effects of antibiotic treatment, suggesting a role of this receptor in the metabolic endotoxemia-induced inflammatory response.⁵⁹ Along similar lines, Luche et al.⁷³ in their studies of wild-type and CD14-knockout (KO) mice demonstrated that metabolic endotoxemia induced by LPS infusion in wild-type mice directly increases the number of adipocyte precursor cells but reduced triglyceride accumulation during adipocyte differentiation. LPS infusion also increased the number of macrophages as well as the mRNA concentrations of inflammatory markers in CD14-positive cells in adipose tissue. These effects of LPS were not observed in CD14KO mice. These data suggest that adipose tissue inflammation induced by metabolic endotoxemia is mediated through a CD14-dependent mechanism.

Recent experimental studies by Fujisaka et al.⁷⁴ in three inbred mouse strains, for example, B6J, 129T, and 129J mice, showed significant interactions between gut microbiota composition, host genetics, metabolic phenotypes, and inflammatory response. On a HFD, the three mouse strains displayed different responses in the development of metabolic abnormalities (hyperglycemia, hyperinsulinemia, and insulin resistance). This difference was due, in part, to differences in gut microbiota composition. Antibiotic treatment altered the composition of gut microbiota in HFD-fed mice, and this effect also depended on the mouse genetic background. Both HFD and antibiotic treatment also induced significant effects on plasma bile acid metabolites that were correlated with gene expression of inflammatory markers. In particular, HFD in 6BJ mice increased the plasma levels of cholic acid (CA) and deoxycholic acid (DCA), and decreased the levels of chenodeoxycholic acid (CDCA), whereas antibiotic treatment reduced DCA and taurodeoxycholic acid (TDCA) levels. These effects of antibiotic treatment on inflammatory markers and DCA/TDCA levels suggest a link between bile acid metabolites and the inflammatory response associated with metabolic syndrome.

Innate Immunity Dysfunction

An interaction of gut microbiota with the innate immune system has also been implicated in the development of metabolic syndrome.^35,75 Evidence for such an interaction is derived from a previous study, showing that mice lacking the innate immune TLR5 (TLR5KO) had altered gut microbial composition which led to the development of metabolic syndrome.³⁵ TLR5KO mice exhibited increased food intake and developed abnormalities characteristic of the metabolic syndrome, namely hyperlipidemia, hypertension, insulin resistance, and obesity. Of note, these metabolic abnormalities correlated with changes in gut microbial composition. Furthermore, transplantation of the gut microbiota from TLR5KO mice to wild-type GF mice produced many abnormalities characteristic of metabolic syndrome to the recipient mice. These data indicate that alterations in gut microbiota composition resulting from malfunction of the innate immune system may contribute to the development of metabolic syndrome.³⁵ Recently, it was shown that altered gut microbiota in T5KO mice increased de novo lipogenesis in the liver mediated by hepatic lipogenic enzyme, stearoyl CoA desaturase (SCD1), leading to elevated oleate-enriched neutral lipids and insulin resistance.⁷⁶ These findings provide a molecular mechanism involving elevated hepatic neutral lipids underlying the development of metabolic syndrome in T5KO mice.

The other TLR of the innate immune system, TLR4, the receptor for bacterial LPS, has also been shown to be involved in mediating the inflammatory reaction associated with obesity and metabolic syndrome.⁷⁷ For example, in vitro and in vivo studies have shown that activation of TLR4 by FFAs increases the gene expression of inflammatory cytokines, such as TNF-α and IL-6, in macrophages and adipocytes.⁷⁷ These effects were attenuated or prevented in the absence of TLR4 expression in adipocytes and in TLR4 KO mice.⁷⁶ These results are in line with those obtained from another study of wild-type and TLR4 KO mice fed a HFD,⁷⁸ in which increases in plasma levels of endotoxin (LPS) and inflammatory markers (TNF-α, IL-1B, and IL-6) induced by HFD were associated with altered gut microbiota composition and increased macrophage infiltration in adipose tissue. Furthermore, the effects of HFD on obesity, plasma endotoxin, and inflammatory cytokines were blunted in TLR4 KO mice. Taken together, these data suggest that TLR4 signaling is another mechanistic pathway that links diet, gut microbiota, host immune system, and metabolic syndrome.

Summary

In summary, an increasing body of evidence from studies on animals and humans indicates that changes in the diet have a significant effect on the composition and function of the gut microbiota, which can contribute to the development of metabolic syndrome. In several experimental studies on rodents (mice and rats), consumption of diets high in fat and sugars (fructose), such as Western-style diet, was shown to alter the composition and diversity of gut microbiota. Few studies on humans also suggest that diets rich in animal fat and protein can modify human gut microbiota composition. The mechanisms whereby altered gut microbiota composition and function may lead to the development of metabolic syndrome and obesity are not completely clear. Several potential mechanisms have been discussed, and include increased energy harvest from diet by gut microbiota, alterations in metabolism of carbohydrate, lipid, and bile acid metabolism, metabolic endotoxemia, low-grade inflammation, and activation of the innate immune system. It is possible that there may be other factors or mediators yet to be discovered that link gut microbiota to metabolic syndrome. More research is needed to elucidate the metabolic, cellular, and molecular mechanisms underlying diet–gut microbiota–host relationships that determine the development of metabolic syndrome. A better understanding of these interactions might prove useful in designing novel nutritional therapies in patients with metabolic syndrome and associated diseases.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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