Dietary Influences on Gut Microbiota with a Focus on Metabolic Syndrome

Abstract

There is a clear correlation between gut microbiota, diet, and metabolic outcomes. A diet high in fiber has been shown to decrease inflammation, increase insulin sensitivity, and reduce dyslipidemias whereas a diet high in fat and sugar leads to dyslipidemia, insulin resistance, and low-grade inflammation. There is recent evidence suggesting that the human gut microbiota has a significant role in the development or the resolution of metabolic syndrome (MetS) and associated conditions. Leading a stressful, sedentary lifestyle with limited or no physical activity and consuming an unhealthy diet high in saturated fat, simple carbohydrates, and sodium and low in dietary fiber and in high-quality protein are some of the contributing factors. Unhealthy diets have been shown to induce alterations in the gut microbiota and contribute to the pathogenesis of MetS by altering microbiota composition and disrupting the intestinal barrier, which leads to low-grade systemic inflammation. In contrast, healthy diets can lead to changes in microbiota that increase gut barrier function and increase the production of anti-inflammatory biomarkers. This review aims at providing a more in-depth discussion of diet-induced dysbiosis of the gut microbiota and its effect on MetS. Here, we discuss the possible mechanisms involved in the development of the metabolic biomarkers that define MetS, with an emphasis on the role of sugar and dietary fiber in microbiome-mediated changes in low-grade systemic inflammation and metabolic dysfunction.

Introduction

Metabolic syndrome (MetS) is defined by a combination of interdependent physiological, biochemical, and metabolic factors, which raises the risk for the development of cardiovascular diseases and type 2 diabetes (T2D). It is identified by a hallmark of clinical manifestations, including central obesity, high blood pressure, elevated concentration of blood sugar, and dyslipidemia (high serum triglycerides [TGs] and low high-density lipoprotein cholesterol [HDL-C]).

The worldwide prevalence of MetS varies from <10% to 84% depending on the geographic region as well as the definition criteria applied.¹ The MetS can be described as a phenotype generated by the complex interaction of host intrinsic factors, such as genetics, the endocrine system, the immune system, oxidative stress, and the gut microbiome, and extrinsic factors such as diet, medication, obesity, and lifestyle. Recent evidence suggests a role of the gut microbiota as a pathogenic factor affecting the host's normal metabolism.

Individuals with MetS often have changes in the composition of the gut microbiota, which may result in metabolic imbalance in the host. This is caused by a low-grade inflammatory response in the body that weakens the gut barrier and causes insulin resistance, forming a chain of events that promotes the progress of MetS.² This review was aimed at summarizing the results of recent studies.

Gut Microbiota

The major population of microorganisms in the human body resides in the gastrointestinal (GI) tract and is collectively termed the gut microbiota, with up to 100 trillion (10¹⁴) microbes inhabiting the colon (10¹¹ cells/mL).³ The gut microbiota affects human physiology and pathology by modulating host nutrition and energy harvest. These modulatory functions include the production of vitamins and amino acids; fermentation of indigestible substrates such as dietary fiber and endogenous intestinal mucus; production of short-chain fatty acids (SCFA); metabolism of dietary toxins and carcinogens; conversion of cholesterol and bile acids, intestinal epithelial homeostasis, maturation of the immune system, and protection against pathogens.^4
–6

The gut microbiota derives their nutrients from the host's dietary components, as is the case of fiber, as well as from the host tissue, such as the mucus layer and the shedding of epithelial cells in the GI tract. The gut microbiota is considered an organ by itself with an impressive metabolic capability and functional flexibility.⁷ Maintaining a healthy human metabolism depends on the mutualistic and symbiotic relationship between the gut and the residing microbiota.

In a healthy gut microbiome, there is greater microbial diversity with an abundance of various species involved. Gut microbiome diversity correlates with health outcomes.⁸ A shift toward higher species diversity or richness in gut microbiota is deemed healthy. Several factors can disrupt the gut microbiome and the homeostasis of the microbial ecosystem to an alternative state, dysbiosis, with characteristic pathophysiological traits in microbiota and host. Dysbiosis inferred from 16S rRNA gene sequencing data is associated with host metabolic dysfunction, contributing to the pathogenesis and progression of multiple diseases as mentioned earlier.

Humans lack the digestive enzymes to degrade the bulk of dietary fiber. Hence, dietary fiber passes through the small intestine unaffected, and its fermentation is facilitated by the anaerobic microbes in the cecum and colon, maximizing the energy provided by the diet. Fermentation produces several metabolites, of which SCFA are the major group, as well as carbon dioxide, hydrogen, and methane.⁹ The most abundant SCFA are acetate, propionate, and butyrate in the approximate ratio of 3:1:1, where 95% of the SCFA produced are readily absorbed by the colonocytes and 5% are excreted in the feces.

The SCFA are an important fuel for intestinal epithelial cells contributing to gut barrier function as well as growth and maintenance of microbiota in the anaerobic gut environment. Although butyrate is a prime energy source for colonocytes and maintains intestinal homeostasis through anti-inflammatory actions, acetate and propionate are essential for the interconnected pathways of macronutrient metabolism.¹⁰ Even though the mechanism is unclear, recent studies speculate the key role of SCFA in neuro-immunoendocrine regulation through microbiota-gut-brain crosstalk.^11,12

Further, the gut microbiota produces essential amino acids and several vitamins for the host such as folate, vitamin K, biotin, riboflavin (B2), and cobalamin (B12).¹³ The interaction of the gut microbes influences the host's physiologic responses such as GI motility, secretion, and sensation contributing to overall health. Moreover, it is suggested that the microbiota intensifies intestinal immunity by regulating the expression of Toll-like receptor (TLR),¹⁴ as well as that of the antigen-presenting and the differentiated T cells.

It also regulates lymphoid follicles and affects systemic immunity by increasing splenic CD4+ T cells. A radical modification in diet, such as consuming strictly animal-based or plant-based foods, alters microbial composition within just 24 hr of introduction, with a return to baseline within 48 hr of stopping the diet.¹⁵

The gut microbiota is involved in the catabolism of several xenobiotics such as drugs and environmental toxins.^16,17 The modification of choline, L-carnitine, betaine, and other choline-containing compounds into trimethylamine (TMA), which later forms trimethylamine N-oxide (TMAO) by the liver, is another pathway of importance. The TMAO is considered as a proatherogenic metabolite. There are conflicting results about the role of TMAO in the development of atherosclerosis based on the differences in diet.^14,16,18

The Western diet has been shown to increase plasma TMAO in human and animal studies,^19

–22 whereas the Mediterranean diet showed beneficial effects.^23,24 Gut bacteria and their metabolites also regulate GI physiology by increasing serotonin production from the enterochromaffin cells in the GI tract. As this neurotransmitter is a paracrine messenger derived from the GI tract with effects on other tissues, it contributes to health and disease.²⁵

Associations Between Microbial Taxa and Host Metabolic Effects

Microbial composition and diversity differ vastly along the intestine.^26,27 Accumulating evidence suggests that the human gut microbiota is dominated by Firmicutes and Bacteroidetes and to a lesser extent by Actinobacteria and Proteobacteria.^4,15 The Firmicutes/Bacteroidetes (F/B) ratio appears to be related to normal intestinal homeostasis and is dependent on environmental factors, including mode of birth delivery, breastfeeding, lifestyle modifications, such as diet,^15,28 medications especially antibiotics use, personal hygiene, the presence of toxins, genetic factors,^6,29,30 and exercise.³¹

Elevated or decreased F/B ratio is considered dysbiosis, whereby the former identifies with obesity,²⁶ and the latter with inflammatory bowel disease. When compared with normal individuals, T2D patients differ by decreased levels of Firmicutes, and Clostridia, and decreased F/B ratio and the phyla. The F/B ratios are negatively and significantly correlated with plasma glucose concentration.^32,33 Although some studies demonstrate that obese patients with MetS have a higher F/B ratio compared with “healthy obese” individuals,^34,35 it is not conclusive and needs to be investigated further.

The key members of Firmicutes include the genera Lactobacillus, Clostridium, and Ruminococcus, as well as the butyrate producers Fecalibacterium, Eubacterium, and Roseburia. Members of Bacteroidetes, including the genera Bacteroides, Prevotella, and Xylanibacter, are efficient degraders of dietary fiber. The Bacteroides enterotype relates to diets enriched in protein and lipids, whereas the Prevotella enterotype is linked to diets rich in carbohydrates and sugar. Bifidobacterium is a key genus in Actinobacteria, and several taxa are known to have probiotic effects when consumed from food or supplements. Proteobacteria include Escherichia and Desulfovibrio, whereas Verrucomicrobia principally includes the mucus-degrading genus Akkermansia.

Influence of Diet on Gut Microbiota

The gut microbiota influences the host's response to diet, whereas simultaneously, the host can influence the gut microbiota by alterations in dietary patterns.³⁶ Diet influences and reshapes gut microbiota composition, diversity, and species richness in a time-dependent manner. In mice, switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar diet changed the microbiota in a day.³⁷

Human studies have depicted noticeable changes in gut microbiota within 24 hr of shifting from a high-fat/low-fiber diet to a low-fat/high-fiber diet.²⁸ Diet also corresponds with enterotypes by tracing clusters of bacterial communities with a similar composition in people with common traits.³⁸ People on a diet high in animal fat have a Bacteroides-dominated enterotype, whereas those on a carbohydrate-rich diet have a Prevotella-dominated enterotype.²⁸ In addition to interpersonal variability, a spectrum of environmental factors modulate the effect of diet, which determines gut microbiome composition.

Thus, a poor diet results in reduced microbial diversity,⁸ a lowering of the metabolites that protect intestinal permeability, and destruction of the mucus layer leading to inflammation and metabolic diseases.³⁹ In contrast, a healthy diet increases gut barrier function and mucus secretion, decreases the luminal pH, and reduces microbial translocation,⁴⁰ leading to increased insulin sensitivity and increases in anti-inflammatory markers.^39,41 A comparison of the metabolic changes induced by microbiota between a healthy, fiber-rich diet versus an unhealthy high-fat, high-sugar diet is summarized in Fig. 1.

FIG. 1.

The impact of high-fat, high-sugar diet on gut microbiota composition and consequent effects on MetS characteristics. (A) Fiber-rich diet promotes eubiosis: Dietary fiber intake results in increased fermentation metabolizing SCFA, while increasing mucus production, decreasing pH, and thus improving gut barrier function. The increase on SCFA is implicated in the release of anorectic gut hormones, the PYY and GLP-1, which have an important impact on satiety, hunger, energy expenditure, insulin sensitivity, and lipolysis. SCFA inhibit TGs and cholesterol synthesis. The increased gut barrier function may reduce the bacterial translocation and blood LPS, with a consequent reduction of inflammation. The metabolites and hormones produced by the microbiota modulated by the diet have a possible impact on the host, by reducing low-grade systemic inflammation, which can consequently affect some MetS parameters, such as reduction of body weight, waist circumference, hypertension, and dyslipidemia. (B) High-fat, high-sugar diet promotes dysbiosis: The consumption of an unhealthy diet rich in fat and sugar may promote gut dysbiosis. With fewer substrates for fermentation available, SCFA production is reduced along with mucus production. The resulting luminal pH disrupts the gut barrier, causing gut permeability, triggering increased bacterial translocation and LPS, and causing metabolic endotoxemia, which sequentially triggers expression of inflammatory markers. The LPS plays a role in the development of low-grade inflammation and decreases insulin sensitivity, which triggers the various characteristic features of MetS. GLP-1, glucagon-like peptide-1; LPS, lipopolysaccharides; MetS, metabolic syndrome; PYY, peptide tyrosine-tyrosine; SCFA, short-chain fatty acid; TGs, triglycerides.

High Intake of Simple Carbohydrates Is Associated with Gut Dysbiosis and MetS

A diet rich in sucrose is associated with an increased risk for the development of metabolic diseases, mainly due to the disruption of the modulating responses of insulin and glucagon. However, its impact in the human gut is still controversial.⁴² In mice, dietary glucose and fructose when taken in high amounts have been shown to regulate the gut microbiota by increasing intestinal permeability, which led to the development of metabolic endotoxemia, inflammation, and lipid accumulation and culminated in hepatic steatosis and obesity.⁴³

Human subjects fed with elevated levels of natural sugars such as glucose, fructose, and sucrose in the form of date fruits exhibited an increase in the relative abundance of Bifidobacteria, with reduced Bacteroides.⁴⁴ Correspondingly, the addition of lactose to the diet replicated similar bacterial shifts while also decreasing Clostridia spp.^45,46

In addition to the natural sugars, dietary sweeteners are ever present in the U.S. diets in the form of ultra-processed foods that have added sugars and non-nutritive sweeteners.⁴⁶ When fed in high doses, some non-caloric artificial sweeteners (NAS) (saccharin, sucralose, and aspartame) alter the composition and function of the gut microbiota, leading to the development of glucose intolerance. Saccharin-fed mice were noted to have intestinal dysbiosis with an increased relative abundance of Bacteroides and reduced Lactobacillus reuteri. ⁴⁷

Treatment with antibiotics to deplete the microbiota eliminated this effect, supporting the involvement of gut microbes in the metabolism of NAS. Further, the fecal transfer of NAS-treated microbiota into germ free (GF) mice generated similar effects. This fact highlights the harmful potential of NAS in inducing glucose intolerance through the gut microbiota when consumed in high amounts.⁴⁸

The overconsumption of sugar negatively affects the gut microbiome community, disrupting the host's overall gut health. The effects include slower bowel transit times,⁴⁹ gut dysbiosis, and increased production of endotoxins.^50,51 Gut dysbiosis alters the gut mucosa, which plays a critical role in the gut barrier function,⁵² resulting in increased gut permeability. Disruption of the fine balance between gut bacteria and the host's immune system leads to the intestinal translocation of bacterial fragments and promotes the development of metabolic endotoxemia, further leading to low-grade systemic inflammation and insulin resistance.^53,54

The Enterobacter cloacae B29, an endotoxin-producing bacterium isolated from the morbidly obese human gut, was shown to induce obesity and insulin resistance in GF-mice while increasing circulating endotoxin.⁵³ The elevation of this bacterium represents a cause rather than a result of the host's metabolic endotoxemia.^53,55 Thus, lowering metabolic endotoxemia could represent a potential treatment strategy for metabolic disease.^53,54

Over time, this may lead to issues rooted in chronic inflammation, resulting in increased weight, cardiovascular disease, T2D, obesity, MetS, hepatic steatosis, irritable bowel syndrome, and even dental caries.⁵⁶ Moreover, foods rich in added sugars being a source of empty calories displace more nutrient-dense foods, thus leading to simultaneously overfed and undernourished people.⁵⁷

Dysbiosis of the gut microbiome also plays a role in the pathogenesis of T2D.⁵⁸ Human cross-sectional studies report compositional and functional differences in the gut microbiota of subjects with T2D or prediabetes versus normal glucose tolerance.^58
–60 Fecal transplants from mice with glucose intolerance into healthy GF mice induce glucose intolerance,⁴⁸ supporting a causal role of gut microbiota on T2D. In a human fecal microbiota transplant study, the transfer of fecal material from lean donors into individuals with MetS resulted in an increase in gut microbial diversity and improved insulin sensitivity.⁶¹

These details support the hypothesis that dysbiosis of the gut microbiome contributes to metabolic dysfunctions. However, the composition and functional characteristic of gut microbiota and the mechanisms that affect host glucose homeostasis is unclear. There is a knowledge deficit in this area, with contradicting data regarding gut and metabolic health.⁶²

Fiber and the Role of SCFA in Gut Eubiosis

The definition of dietary fiber is broad according to several parameters, including its primary food source, chemical structure, fermentability, water solubility, and viscosity. With subtle differences, dietary fiber is defined by several associations^63,64 as a group of carbohydrate polymers and oligomers that escapes digestion by enzymes in the small intestine to be metabolized in the cecum and colon by partial or complete fermentation yielding metabolites such as SCFA.⁶⁵ Dietary fiber aids in creating the optimal gut environment, allowing beneficial bacteria to thrive (eubiosis), thus promoting favorable physiological effects, including decreases in plasma cholesterol and glucose.⁶³

After dietary fiber intake, several SCFA-producers significantly increased, including Lachnospira, Akkermannsia, Bifidobacterium, Lactobacillus, Ruminococcus, Roseburia, Clostridium, Faecalibacterium, and Dorea.^6,7,9 The SCFA alter the intestinal environment and modify metabolic regulation in humans through selective stimulation of the growth and/or activity of certain microorganisms.⁶⁶ A high intake of complex carbohydrates increase microbiota gene richness in obese humans.⁶⁷ Some studies suggests that non-digestible carbohydrates increase intestinal bifidobacteria as well as lactic acid bacteria.⁶⁸

These effects may be related to an increased production of SCFA, to alterations in microbiota diversity, and to the Prevotella/Bacteroides ratio. Increases in SCFA in both plasma and stool have also been related to changes in metabolism, such as in insulin sensitivity or in total cholesterol,^14,69 The effect on glycosylated hemoglobin is more prominent, where fiber-promoted SCFA-producers are present in greater diversity and abundance.⁷⁰

Further, the cholesterol-lowering effect observed after beta-glucan intake is associated with higher abundances of specific SCFA-producing species such as Bifidobacterium and Akkermansia muciniphila. Diets rich in dietary fiber are associated with a richer and more diverse microbiome when compared with a high-energy, high-fat Western-type diet, as depicted in Fig. 1.

Improved gut barrier function reduces the penetration of microbes and microbial endotoxins into the vascular system, thereby reducing the immune responses associated with metabolic diseases.⁷¹ The stool of subjects consuming a high-fiber diet has a decreased pH compared with that of those on a low-fiber diet, which is correlated with a higher production of SCFA, improved bacterial community, and decreased growth of pathogenic bacteria.⁷² Metabolic regulation is modulated by several microbial-produced metabolites. For instance, the products of the microbial conversion of dietary tryptophan and lignin, such as indole and enterolactone, correlate with increased fiber intake and a lower risk of T2D.⁵⁹

Bacteroides thetaiotaomicron, an acetate and propionate producer, promotes differentiation of goblet cells and expression of mucin-related genes. In contrast, Faecalibacterium prausnitzii, an acetate consumer as well as a butyrate producer, decreases the effect of acetate on mucus and prevents overproduction of mucus, thus supporting a suitable structure and composition of the gut epithelium.⁷³ Further, dietary fiber can also mechanically stimulate the intestinal epithelium to secrete mucus.⁷⁴

Prolonged insufficiency of dietary fiber damages the mucus barrier, resulting in an increased abundance of mucin-degrading bacteria such as A. muciniphila. ⁵² Through mucin degradation, A. muciniphila produces various fermentation metabolites, including SCFA, which serve as energy substrates for other gut microbes.⁷⁵ Further, when the diet is devoid of dietary fibers, some gut bacteria switch their metabolism to using mucin glycans by inducing gene expression of mucin-degrading enzymes.⁷⁶

Consistent with this, mice fed a Western diet with low fiber present an increase in the penetrability of the inner mucus layer, making the mucus penetrable, thus increasing the susceptibility to infections.⁷⁷ An altered gut microbiota resulting from a diet low in fiber leads to a severe deterioration of the mucus layer, enhancing the susceptibility to infections and the development of chronic inflammatory diseases.

Tremblay et al. highlight the importance of dietary fiber as the main predictor of health outcomes, with significant reductions in body weight and waist circumference with adequate dietary fiber while on a plant-based diet.⁷⁸ Dietary fiber produces noticeable shifts in metabolic as well as immune markers, for instance, reductions in interleukin-6 (IL-6), insulin resistance, and peak postprandial glucose with the intake of non-digestible carbohydrates present in whole grains.^79,80

Butylated high amylose maize starch consumption increases the plasma level of anti-inflammatory cytokine IL-10.⁸¹ The prebiotic effect of dietary fiber on metabolic and immune functions in the gut involves not only increased production of SCFA but also strengthening of GI-associated lymphoid tissue from fiber fermentation. Hence, a healthy gut microbiota contributes to the maturation and the development of the immune system as well.⁸²

The SCFA influence host metabolism by acting locally on receptors expressed by the intestinal enteroendocrine L-type cells (i.e., G protein coupled receptors [GPR]-41, GPR-43) or distally, after entering the circulation and being transported to other organs (liver, adipose tissue, brain, and muscle). Importantly, SCFA are sensed by the gut bacteria themselves and regulate pathogenic colonization, depending on their concentration.⁸³ The SCFA also affect energy homeostasis through the regulation of GI hormones that regulate appetite, such as cholecystokinin, glucagon-like peptide 1, peptide tyrosine-tyrosine, and leptin, and therefore play a role in obesity.^84,85

A prospective study on non-obese individuals demonstrated that long-term weight gain is inversely correlated with the intake of dietary fiber,⁸⁶ whereas high fiber intake was found to be correlated with a lower long-term weight gain.⁸⁷ A recent intervention study with oligofructose-enriched inulin for 16 weeks in overweight and obese children reduced their fat mass, suggesting that increased intake of fermentable fiber may have beneficial effects on obesity.⁸⁸

Obesity is associated with MetS and T2D. T2D is also correlated with lower concentrations of fiber-degrading bacteria.^59,89 Consequently, diets high in digestible starch and low in fiber are linked with an increased risk for T2D.⁹⁰ When soluble fiber was provided in the form of oligofructose and long-chain inulin, a number of benefits were observed, including reductions in body weight gain and inflammation as well as improved glucose metabolism.⁴⁰

Barley kernel-based bread, rich in β-glucans in healthy human volunteers, improved glucose metabolism.⁹⁰ Thus, we could speculate that the reductions in bacterial obesity associated with obesity are due to reduced fiber intake. In contrast, the lack of these fiber-degrading bacteria may predispose to T2D.

The underlying mechanisms or pathways that link diet, gut microbiota, and the development of MetS are partially elucidated. Multiple mechanisms have been proposed, including increased energy harvested from the diet, increased systemic lipopolysaccharides (LPS), altered energy homeostasis and metabolic processes, altered production of SCFA, alterations in gut hormone secretion, altered gut microbiota-induced metabolic endotoxemia, systemic low-grade inflammation, oxidative stress, modulation of signaling pathways, and the immune system as indicated in Fig. 1.

Depending on the nature of the onset of several factors triggering the development of MetS, the relative contribution of each factor varies in importance. It is reasonable to assume that there may be other factors or mediators yet to be explored that participate in the pathogenesis of MetS and its characteristics.

Influence of Gut Microbiota on the Characteristic of MetS

Insulin resistance

Cani et al. demonstrated that mice fed a high-fat diet for 4 weeks developed obesity and insulin resistance.⁹¹ These changes were accompanied by elevated levels of LPS and increased pro-inflammatory markers.^40,83 The LPS is a component of the cell membrane of Gram-negative bacteria found in human and mouse gut microbiota and is produced by the constant breakdown of these bacteria and translocation from the intestine to other metabolic tissues. When bound to the TLR 4, LPS triggers a pro-inflammatory response, thus establishing a connection, between diet, microbiota, and metabolic diseases.^37,40

A metagenome-wide association study showed the presence of microbial abnormalities in prediabetic subjects.⁵⁹ These authors reported a decrease in the abundance of butyrate-producing bacteria and an increase in several adaptable pathogens. In agreement with these findings, the anti-inflammatory effects associated strain F. prausnitzii were reduced, whereas LPS-producing bacteria were enriched. These results provide an explanation regarding the metabolic changes in diabetic subjects associated with impaired barrier function and higher circulating LPS.⁵⁹ Other observations related to this topic are that the colonic level of A. muciniphila is decreased in obese subjects.⁹²

Increased LPS in plasma correlates with low-grade inflammation.⁴⁰ Excessive levels of pro-inflammatory factors, such as LPS, lead to an inhibition of insulin signaling, resulting in insulin resistance in a chronic condition. The strain Enterobacter cloacae (B29) has been shown to be highly abundant in morbidly obese subject (35%) with MetS features. Following a rigorous program of weight loss, E. cloacae was no longer detectable.⁵³ Further studies need to be conducted to establish the presence of Proteobacteria and its potential role in obesity and diabetes. In contrast, the relative abundance of Bifidobacterium is increased in healthy gut microbiota. This is why obese⁹³ and diabetic subjects⁵⁹ have lower levels of Bifidobacterium.

Obesity

Evidence suggests that the gut microbiota may play a role in obesity by increasing the host's energy-harvesting efficiency.⁹⁴ Studies have shown that in genetically obese ob/ob mice, in diet-induced obesity mice, as well as in obese and overweight humans, the prevalence of phylum Firmicutes is high when compared with Bacteroidetes^93,95,96 and a reversed profile in people after 1-year diet therapy⁹⁶ and intestinal bypass.⁹⁷ The same tendency is observed in weight-reduction diets,⁹⁸ although a study with human twins showed that in obese individuals, the decrease in Bacteroidetes was accompanied by an increase in Actinobacteria rather than in Firmicutes.⁹⁹

The observed shift in the relative abundances of these phyla results in low-grade inflammation as well as an improved capacity for harvesting energy from food.⁹⁹ Consequently, the ratio of Firmicutes to Bacteroidetes relative abundance (the F/B ratio) was a biomarker indicative of obesity susceptibility. Remarkably, the energy harvest phenotype is transmissible simply by transplanting the obese microbiota into healthy, lean donors.^37,98

At the family level, Prevotellaceae^97,100 and Enterobacteriaceae¹⁰¹ are enriched in obesity. Among bacterial genera, the endotoxin-producing Enterobacter ¹⁰⁰ was excessive in morbidly obese patients, and it suggestively induced obesity. Lactobacillus increased after a weight-loss program in adolescents¹⁰² but was abundant in obese and overweight children.¹⁰³ When obese subjects consumed more indigestible polysaccharides, an increase in the butyrate-producing Roseburia genus was observed.¹⁰⁴

In overweight/obese adults on a 6-week calorie-restricted (CR) diet followed by a 6-week weight stabilization diet, subjects with a higher gene richness and abundance of A. muciniphila, the mucus-degrading, SCFA-producing bacteria, exhibited the healthiest metabolic status as well as improved insulin sensitivity and metabolic markers after CR diet.¹⁰⁵ Oral supplementation, of A. muciniphila in obese subjects with MetS reduced the levels of relevant blood markers of liver dysfunction and inflammation without affecting the overall gut microbiome structure.¹⁰⁶

Obesity results in a chronic state of low-level inflammation that is very distinct from classical inflammation.¹⁰⁷ The pattern portrays moderate induction of inflammatory cytokines such as tumor necrosis factor-α, IL-1β, and C-C Motif Chemokine Ligand 2, as well as an increase in mast cells, T cells, and macrophages.¹⁰⁷ An increase in Bifidobacterium spp. modulates inflammation in obese mice by increasing the production of glucagon-like peptide-2, which reduces intestinal permeability and thus reduces the translocation of LPS.⁴⁰

These studies suggest that gut microbiota is an important environmental factor involved in the regulation of fat storage in the host, which affects the incidence of obesity. The adherence of a high protein diet for 6 months reduced body weight in MetS subjects when compared with a standard protein diet; however, the gut microbiome needs to be explored further in this type of studies.¹⁰⁸

Inflammation

Two major problems exist in MetS: chronic low-grade inflammation and a predominance of insulin resistance. Obesity and insulin resistance are inherent with low-grade chronic systemic inflammation.^40,107 The gut microbiota has been implicated in the regulation of inflammation by influencing several metabolic pathways, including differentiation of inflammatory cell types, cytokine production, and hematopoiesis. The leakage of endotoxins into the circulation promotes systemic inflammation and the development of obesity and related metabolic diseases.

Atherosclerosis also demonstrates an altered human gut metagenome, and bacterial DNA has been detected in atherosclerotic plaques.¹⁰⁹ Further, an increased blood concentration of the choline metabolite, TMAO, which is modified by microbiota, is linked to an increased risk of atherosclerosis, indicating that gut microbiota has a prominent role in atherogenesis.¹¹⁰

Humans colonized by bacteria and archaea of the genera Faecalibacterium, Bifidobacterium, Lactobacillus, Coprococcus, and Methanobrevibacter have a relatively less tendency to develop inflammation and metabolic disturbances and, sequentially, T2D and ischemic cardiovascular disorders.^26,27 A study in MetS subjects demonstrated a reduction in inflammatory biomarkers (IL-6 and soluble vascular cell adhesion molecule 1) while slightly modifying the gut microbiome after the supplementation of Lactobacillus reuteri v3401 when following a healthy hypocaloric diet as well as physical activity for 12 weeks.¹¹¹

Dyslipidemia

The diagnostic criteria for MetS define dyslipidemia as the elevation in circulating TGs and/or a reduction in circulating HDL-C. In vitro as well as in vivo experiments have established that dyslipidemia can lead to gut microbiota imbalance, and the consequent dysbiosis can further aggravate lipid metabolic disorders.¹¹² Dyslipidemia and the resulting atherosclerotic plaques remain major risk factors for cardiovascular disease and are often intricately linked with impaired glucose metabolism and obesity. Further, diseases linked to dyslipidemia, such as non-alcoholic fatty liver disease and atherosclerosis, display changes in the gut microbiota profile.¹⁰⁹ The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as SCFA, secondary bile acids, and TMA and by pro-inflammatory bacteria-derived factors such as LPS.

Significant alterations of gut microbiota of C57BL/6J mice fed a high-glucose (HGD) or high-fructose (HFrD) diet are confirmed by 16S rRNA analysis. With unchanged body weights, both the HGD and HFrD groups had increased hepatic lipid accumulation with a reduction in gut microbiota diversity. Interestingly, in the HGD and HFrD groups, the proportion of Proteobacteria was elevated compared with Bacteroidetes.⁴³ Separately, the LifeLines-DEEP Dutch study cohort reported by Wang et al.¹¹³ estimated that the gut microbiome explains 4.5% of the variation in body mass index, 6.0% in TGs, and 4% in HDL-C.¹¹⁴

The gut microbiome in subjects with dyslipidemia is characterized by low microbial diversity, with a high abundance of some taxa from the phylum Actinobacteria, and a lower abundance of many taxa from the phyla Proteobacteria and Bacteroidetes. These studies offer evidence for an association between blood lipids and the gut microbiome.

Hypertension

Hypertension is one of the components of MetS and is the primary risk factor for cardiovascular and cerebrovascular diseases. Studies in animals and humans support an association between high blood pressure and gut dysbiosis. Chronic low-grade inflammation can be a cause or consequence of hypertension.¹¹⁵ Low-grade inflammation can be the result of a reduction in microbial gene richness.⁶⁷ Yang et al. reported that in addition to increases in the F/B ratio, reductions in microbial diversity were observed due to inflammation in spontaneously hypertensive rats.¹¹⁶

These changes were accompanied by a reduction of acetic acid and butyrate production. In addition, hypertensive patients also display a pattern of dysbiosis due to the lack of diversity in their gut microbiota. Compared with healthy controls, these pre-hypertensive and hypertensive population showed a significant decrease in microbiota bundance.¹¹⁷ Harmful bacteria such as Prevotella and Klebsiell are present in both pre-hypertensive and hypertensive populations.

In addition, by transplanting feces from hypertensive human donors into sterile mice, a transfer of elevated blood pressure through the microbiota was observed, confirming the direct effect of the gut microbiota on host blood pressure. A 10-hr time-restricted diet reduced weight as well as improved all facets of MetS when added to standard medical practice to treat MetS, demonstrating the importance of the circadian system.¹¹⁸ The disruption of the circadian system can also alter microbiome communities, disturbing host metabolism, energy homeostasis, and inflammatory pathways, causing MetS.¹¹⁹

A summary of the reviewed studies in both humans and animal models on the interactions between diet and microbiota and how they affect the biomarkers of MetS is presented in Table 1.

Table 1.

Effects of Diet and Related Bacteria on the Biomarkers of Metabolic Syndrome

Dietary treatment and duration	Humans/animal studies	Outcomes	Bacteria involved	References
High fat, carbohydrate free diet, 4 weeks	Male C57BL6/J mice (n = 9)	Increased plasma LPS, metabolic endotoxemia Increased liver cytokines TNF-α, IL-1, IL-6 Insulin resistance	↓ Bacteroides-related bacteria ↓ Eu. rectale-Cl. Coccoides	41
HGD or HFrD diet, 12 weeks	Male C57BL/6J mice (n = 9)	Increased gut permeability, metabolic endotoxemia, inflammatory cytokines TNF-α and IL-1β Observed fewer OTU and lower Shannon indices in the HGD and HFrD groups than in an ND group	↓ Muribaculum intestinale (phylum, Bacteroidetes) ↓ Desulfovibrio vulgaris (phylum, Proteobacteria) ↑ Akkermansia muciniphila	112
CR diet, 6 weeks	Overweight/obese adults (n = 49)	Improvements in glucose homoeostasis, blood lipids, and body composition after CR	↑ A. muciniphila	104
A. muciniphila supplementation (10¹⁰ bacteria per day), 3 months	Overweight/obese adults with MetS (n = 32)	Improved insulin sensitivity and plasma total cholesterol	Overall gut microbiome unaffected ↑ Fecal A. muciniphila	105
Lactobacillus reuteri V3401 supplementation, with healthy lifestyle (hypocaloric diet and physical activity, 12 weeks)	Adults with MetS (n = 53)	↓ IL-6 and sVCAM No characteristic biochemical or metabolic differences observed	↑ Verrucomicrobia	110
Prebiotic OI (8 g/day) once daily for 16 weeks	Overweight/obese children (n = 22)	Reduced body weight z-score, percent body fat, percent trunk fat, and serum level of IL-6	↑ Bifidobacterium sp ↓ Bacteroides vulgates	87
High-protein diet, 6 months	Adults with MetS (n = 118)	Significant weight loss when compared with standard-protein diet	—	107
10 hr TRE, 12 weeks	Adults with MetS receiving standard medical care, including high rates of statin and anti-hypertensive use (n = 19)	Reduces waist circumference, percent body fat, and visceral fat Blood pressure, atherogenic lipids, and glycated hemoglobin	—	118

CR, calorie restriction; HFrD, high-fructose; HGD, high-glucose; IL, interleukin; LPS, lipopolysaccharides; MetS, metabolic syndrome; ND, normal diet; OI, oligofructose-enriched inulin; OTU, operational taxonomic units; sVCAM, soluble vascular cell adhesion molecule; TNF, tumor necrosis factor; TRE, time-restricted eating.

Conclusion

The effects of specific dietary patterns, including dietary fiber and high sugar diets, on gut microbiota and their relevance to the health or dysbiosis of the host have been extensively studied. The microbiota signature in MetS is heterogeneous and although diet and lifestyle results in a specific pattern, the development and intensity of metabolic criteria also depend on the microbiota associated with gut dysbiosis.

The translocation of microbial populations and the resulting events causing metabolic endotoxemia induce low-grade systemic inflammation, which results in insulin resistance through metabolites affecting host metabolism and hormone release, forming a vicious cycle that promotes the continuous progress of MetS. Consequently, diet modulation of gut microbiota may be a potential target for the treatment of MetS and related disorders.

Consumption of the typical westernized diet containing high fat/high sugar fuels the progression and development of MetS. Sweeteners and processed foods cause gut dysbiosis and metabolic endotoxemia, leading to low-grade inflammation, insulin resistance, dyslipidemia, obesity, and metabolic disorders. In contrast, dietary fiber is a crucial dietary component that preserves gut health by regulating macronutrients and host physiology.

Dietary fiber improves insulin sensitivity, aids in weight regulation, and reduces inflammation with increases in gut-derived SCFA, all of which may reduce the risk of developing metabolic diseases. However, findings from intervention trials are often inconsistent. Much of the evidence linking SCFA to metabolic regulation comes from animal studies and it is unclear whether these effects translate directly to human conditions.

Controlled human trials supporting the proposition of SCFAs as key regulatory factors in human metabolism need to be conducted. Prospective studies detailing taxonomic and functional information on the microbial communities, with a greater focus on the standardization of protocols and quality controls would provide a clearer understanding of gut microbiota and host metabolic regulation.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

No funding was received for this article.

References

Saklayen

. The global epidemic of the metabolic syndrome. Curr Hypertens Rep, 2018; 20:12.

Wang

, Deng

, Zhang

, et al. Gut microbiota and metabolic syndrome. Chin Med J, 2020; 133:808–816.

Whitman

, Coleman

, Wiebe

. Prokaryotes: The unseen majority. Proc Natl Acad Sci USA, 1998; 95:6578–6583.

Qin

, Li

, Raes

, et al. Europe PMC Funders Group Europe PMC Funders Author Manuscripts A human gut microbial gene catalog established by metagenomic sequencing. Nature, 2010; 464:59–65.

Ley

, Peterson

, Gordon

. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 2006; 124:837–848.

Jandhyala

, Talukdar

, Subramanyam

, et al. Role of the normal gut microbiota. World J Gastroenterol, 2015; 21:8836–8847.

Sonnenburg

, Bäckhed

. Diet-microbiota interactions as moderators of human metabolism. Nature, 2016; 535:56–64.

Manor

, Dai

, Kornilov

, et al. Health and disease markers correlate with gut microbiome composition across thousands of people. Nat Commun, 2020; 11:5206.

Topping

, Clifton

. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol Rev, 2001; 81:1031–1064.

10.

Tremaroli

, Bäckhed

. Functional interactions between the gut microbiota and host metabolism. Nature, 2012; 489:242–249.

11.

, Tian

, Mao

, et al. Associations between disordered gut microbiota and changes of neurotransmitters and short-chain fatty acids in depressed mice. Transl Psychiatry, 2020; 10:350.

12.

Silva

, Bernardi

, Frozza

. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol, 2020; 11:25.

13.

Bäckhed

, Ley

, Sonnenburg

, et al. Host-bacterial mutualism in the human intestine. Science, 2005; 307:1915–1920.

14.

Lundin

, Bok

, Aronsson

, et al. Gut flora, Toll-like receptors and nuclear receptors: A tripartite communication that tunes innate immunity in large intestine. Cell Microbiol, 2008; 10:1093–1103.

15.

David

, Maurice

, Carmody

, et al. Diet rapidly alters the human gut microbiota. Nature, 2014; 505:559–563.

16.

Spanogiannopoulos

, Bess

, Carmody

, et al. The microbial pharmacists within us: A metagenomic view of xenobiotic metabolism. Nat Rev Microbiol, 2016; 14:273–287.

17.

Maurice

, Haiser

, Turnbaugh

. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell, 2013; 152:39–50.

18.

Thomas

, Fernandez

. Trimethylamine N-Oxide (TMAO), diet and cardiovascular disease. Curr Atheroscler Rep, 2021; 23:12.

19.

Boutagy

, Neilson

, Osterberg

, et al. Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. Nutrit Res, 2015; 35:858–864.

20.

Boutagy

, Neilson

, Osterberg

, et al. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity, 2015; 23:2357–2363.

21.

Boutagy

, Neilson

, Osterberg

, et al. Trimethylamine-N-oxide and its biological variations in vegetarians. Nutrients, 2019; 10:1–12.

22.

Chen

, Zheng

, Feng

, et al. Gut microbiota-dependent metabolite Trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice. Front Physiol, 2017; 8:139.

23.

de Filippis

, Pellegrini

, Vannini

, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut, 2016; 65:1812–1821.

24.

Pignanelli

, Just

, Bogiatzi

, et al. Mediterranean diet score: Associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function. Nutrients, 2018; 10:779.

25.

Reigstad

, Salmonson

, Rainey

, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J, 2015; 29:1395–1403.

26.

Liou

, Paziuk

, Luevano

, et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med, 2013; 5:178ra41.

27.

Rajilić-Stojanović

, de Vos

. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev, 2014; 38:996–1047.

28.

, Chen

, Hoffmann

, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science, 2011; 334:105–108.

29.

Costello

, Lauber

, Hamady

, et al. Bacterial community variation in human body habitats across space and time. Science, 2009; 326:1694–1697.

30.

Semenkovich

, Danska

, Darsow

, et al. American diabetes association and JDRF research symposium: Diabetes and the microbiome. Diabetes, 2015; 64:3967–3977.

31.

Petriz

, Castro

, Almeida

, et al. Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats. BMC Genom, 2014; 15:1–13.

32.

Larsen

, Vogensen

, van den Berg

FWJ

, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One, 2010; 5:e9085.

33.

Mukhuty

, Fouzder

, Das

, et al. An insight into the changing scenario of gut microbiome during type 2 diabetes. Accessed at www.intechopen.com on October 30, 2021.

34.

Cortés-martín

, Iglesias-aguirre

, Meoro

, et al. There is no distinctive gut microbiota signature in the metabolic syndrome: Contribution of cardiovascular disease risk factors and associated medication. Microorganisms, 2020; 8:416.

35.

Louis

, Tappu

, Damms-Machado

, et al. Characterization of the gut microbial community of obese patients following a weight-loss intervention using whole metagenome shotgun sequencing. PLoS One, 2016; 11:e0149564.

36.

Wegh

CAM

, Schoterman

MHC

, Vaughan

, et al. The effect of fiber and prebiotics on children's gastrointestinal disorders and microbiome. Expert Rev Gastroenterol Hepatol, 2017; 11:1031–1045.

37.

Turnbaugh

, Ridaura

, Faith

, et al. Metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med, 2009; 1:1–19.

38.

Cheng

, Ning

. Stereotypes about enterotype: The old and new ideas. Genomics Proteomics Bioinformatics, 2019; 17:4–12.

39.

Chakaroun

, Massier

, Kovacs

. Gut microbiome, intestinal permeability, and tissue bacteria in metabolic disease: Perpetrators or bystanders?. Nutrients, 2020; 12:1082.

40.

Cani

, Amar

, Iglesias

, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 2007; 56:1761–1772.

41.

Ghosh

, Wang

, Yannie

, et al. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocr Soc, 2020; 4:bvz039.

42.

Stanhope

. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit Rev Clin Lab Sci, 2016; 53:52–67.

43.

, Lee

, Oh

, et al. High-glucose or-fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change. Nutrients, 2018; 10:761.

44.

Eid

, Enani

, Walton

, et al. The impact of date palm fruits and their component polyphenols, on gut microbial ecology, bacterial metabolites and colon cancer cell proliferation. J Nutrit Sci, 2014; 3:1–9.

45.

Jeffery

, O'Toole

. Diet-microbiota interactions and their implications for healthy living. Nutrients, 2013; 5:234–252.

46.

Francavilla

, Calasso

, Calace

, et al. Effect of lactose on gut microbiota and metabolome of infants with cow's milk allergy. Pediatr Allergy Immunol, 2012; 23:420–427.

47.

Steele

, Baraldi

, da Costa Louzada

, et al. Ultra-processed foods and added sugars in the US diet: Evidence from a nationally representative cross-sectional study. BMJ Open, 2016; 6:e009892.

48.

Suez

, Korem

, Zeevi

, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 2014; 514:181–186.

49.

Parthasarathy

, Chen

, et al. Relationship between microbiota of the colonic mucosa vs feces and symptoms, colonic transit, and methane production in female patients with chronic constipation. Gastroenterology, 2016; 150:367.e1–379.e1.

50.

Hyland

, Quigley

EMM

, Brint

. Microbiota-host interactions in irritable bowel syndrome: Epithelial barrier, immune regulation and brain-gut interactions. World J Gastroenterol, 2014; 20:8859–8866.

51.

Groschwitz

, Hogan

. Intestinal barrier function: Molecular regulation and disease pathogenesis. J Allergy Clin Immunol, 2009; 124:3–20.

52.

Desai

, Seekatz

, Koropatkin

, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell, 2016; 167:1339.e21–1353.e21.

53.

Fei

, Zhao

. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J, 2013; 7:880–884.

54.

Amar

, Chabo

, Waget

, et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms and probiotic treatment. EMBO Mol Med, 2011; 3:559–572.

55.

de La Serre

, Ellis

, Lee

, et al. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol, 2010; 299:G440.

56.

Dietary guidelines advisory committee reports. Nutrit Today 1985;20:8–15.

57.

Murphy

, Johnson

. The scientific basis of recent US guidance on sugars intake. Am J Clin Nutrit, 2003; 78:827S–833S.

58.

Vrieze

, Holleman

, Zoetendal

, et al. The environment within: How gut microbiota may influence metabolism and body composition. Diabetologia, 2010; 53:606–613.

59.

Wang

, Qin

, Li

, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature, 2012; 490:55–60.

60.

Zhang

, Shen

, Fang

, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One, 2013; 8:e71108.

61.

Vrieze

, van Nood

, Holleman

, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 2012; 143:913.e7–916.e7.

62.

Utzschneider

, Kratz

, Damman

, et al. Mechanisms linking the gut microbiome and glucose metabolism. J Clin Endocrinol Metab, 2016; 101:1445–1454.

63.

Fernandez

. Soluble fiber and nondigestible carbohydrate effects on plasma lipids and cardiovascular risk. Curr Opin Lipidol, 2001; 12:35–40.

64.

Mann

, Cummings

. Possible implications for health of the different definitions of dietary fibre. Nutrit Metab Cardiovasc Dis, 2009; 19:226–229.

65.

Cummings

, Pomare

, Branch

HWJ

, et al. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut, 1987; 28:1221–1227.

66.

Pandey

, Naik

, Vakil

. Probiotics, prebiotics and synbiotics—A review. J Food Sci Technol, 2015; 52:7577–7587.

67.

Cotillard

, Kennedy

, Kong

, et al. Dietary intervention impact on gut microbial gene richness. Nature, 2013; 500:585–588.

68.

Costabile

, Klinder

, Fava

, et al. Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: A double-blind, placebo-controlled, crossover study. Br J Nutrit, 2008; 99:110–120.

69.

Vanegas

, Meydani

, Barnett

, et al. Substituting whole grains for refined grains in a 6-wk randomized trial has a modest effect on gut microbiota and immune and inflammatory markers of healthy adults. Am J Clin Nutrit, 2017; 105:635–650.

70.

Zhao

, Zhang

, Ding

, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science, 2018; 359:1151–1156.

71.

Knudsen

KEB

, Lærke

, Hedemann

, et al. Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients, 2018; 10:1499.

72.

Walker

, Duncan

, Carol McWilliam Leitch

, et al. pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Appl Environ Microbiol, 2005; 71:3692–3700.

73.

Wrzosek

, Miquel

, Noordine

, et al. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent. BMC Biol, 2013; 11:61.

74.

McRorie

, McKeown

. Understanding the physics of functional fibers in the gastrointestinal tract: An evidence-based approach to resolving enduring misconceptions about insoluble and soluble fiber. J Acad Nutrit Dietet, 2017; 117:251–264.

75.

Khan

, Nieuwdorp

, Bäckhed

. Microbial modulation of insulin sensitivity. Cell Metab, 2014; 20:753–760.

76.

Sonnenburg

, Xu

, Leip

, et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science, 2005; 307:1955–1959.

77.

Schroeder

, Birchenough

GMH

, Ståhlman

, et al. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe, 2018; 23:27.e7–40.e7.

78.

Tremblay

, Clinchamps

, Pereira

, et al. Dietary fibres and the management of obesity and metabolic syndrome: The resolve study. Nutrients, 2020; 12:1–20.

79.

Keim

, Martin

. Dietary whole Grain-Microbiota interactions: Insights into mechanisms for human health. Adv Nutrit, 2014; 5:556–557.

80.

Martínez

, Lattimer

, Hubach

, et al. Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME J, 2013; 7:269–280.

81.

West

, Christophersen

, Pyne

, et al. Butyrylated starch increases colonic butyrate concentration but has limited effects on immunity in healthy physically active individuals. Exercise Immunol Review, 2013; 19:102–119.

82.

Rescigno

. Intestinal microbiota and its effects on the immune system. Cell Microbiol, 2014; 16:1004–1013.

83.

Rastelli

, Knauf

, Cani

. Gut microbes and health: A focus on the mechanisms linking microbes, obesity, and related disorders. Obesity, 2018; 26:792–800.

84.

Reimer

, Maurer

, Eller

, et al. Satiety hormone and metabolomic response to an intermittent high energy diet differs in rats consuming long-term diets high in protein or prebiotic fiber. J Proteome Res, 2012; 11:4065–4074.

85.

Keenan

, Zhou

, McCutcheon

, et al. Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat. Obesity, 2006; 14:1523–1534.

86.

Mozaffarian

, Hao

, Rimm

, et al. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med, 2011; 364:2392–2404.

87.

Menni

, Jackson

, Pallister

, et al. Gut microbiome diversity and high-fibre intake are related to lower long-term weight gain. Int J Obes, 2017; 41:1099–1105.

88.

Nicolucci

, Hume

, Martínez

, et al. Prebiotics reduce body fat and alter intestinal microbiota in children who are overweight or with obesity. Gastroenterology, 2017; 153:711–722.

89.

Karlsson

, Tremaroli

, Nookaew

, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature, 2013; 498:99–103.

90.

Sluijs

, Forouhi

, Beulens

, et al. The amount and type of dairy product intake and incident type 2 diabetes: Results from the EPIC-InterAct Study. Am J Clin Nutrit, 2012; 96:382–390.

91.

Cani

, Bibiloni

, Knauf

, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 2008; 57:1470–1481.

92.

Belzer

, de Vos

. Microbes insidefrom diversity to function: The case of Akkermansia. ISME J, 2012; 6:1449–1458.

93.

Schwiertz

, Taras

, Schäfer

, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity, 2010; 18:190–195.

94.

Jumpertz

, Le

, Turnbaugh

, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutrit, 2011; 94:58–65.

95.

Carvalho

, Guadagnini

, Tsukumo

DML

, et al. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia, 2012; 55:2823–2834.

96.

Ley

, Bäckhed

, Turnbaugh

, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA, 2005; 102:11070–11075.

97.

Zhang

, DiBaise

, Zuccolo

, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA, 2009; 106:2365–2370.

98.

Ley

, Turnbaugh

, Klein

, et al. Microbial ecology: Human gut microbes associated with obesity. Nature, 2006; 444:1022–1023.

99.

Turnbaugh

, Hamady

, Yatsunenko

, et al. A core gut microbiome between lean and obesity twins. Nature, 2009; 457:480–484.

100.

Chen

, Wang

, Kuo

, et al. Metabolome analysis for investigating host-gut microbiota interactions. J Formos Med Assoc, 2019; 118(Suppl. 1):S10–S22.

101.

Santacruz

, Collado

, García-Valdés

, et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutrit, 2010; 104:83–92.

102.

Santacruz

, Marcos

, Wärnberg

, et al. Interplay between weight loss and gut microbiota composition in overweight adolescents. Obesity, 2009; 17:1906–1915.

103.

Ignacio

, Fernandes

, Rodrigues

VAA

, et al. Correlation between body mass index and faecal microbiota from children. Clin Microbiol Infect, 2016; 22:258.e1–258.e8.

104.

Duncan

, Belenguer

, Holtrop

, et al. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microbiol, 2007; 73:1073–1078.

105.

Dao

, Everard

, Aron-Wisnewsky

, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: Relationship with gut microbiome richness and ecology. Gut, 2016; 65:426–436.

106.

Depommier

, Everard

, Druart

, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: A proof-of-concept exploratory study. Nat Med, 2019; 25:1096–1103.

107.

Gregor

, Hotamisligil

. Inflammatory mechanisms in obesity. Annu Rev Immunol, 2011; 29:415–445.

108.

Campos-Nonato

, Hernandez

, Barquera

. Effect of a high-protein diet versus standard-protein diet on weight loss and biomarkers of metabolic syndrome: A randomized clinical trial. Obes Facts, 2017; 10:238–251.

109.

Koren

, Spor

, Felin

, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci USA, 2011; 108(Suppl. 1):4592–4598.

110.

Brandsma

, Kloosterhuis

, Koster

, et al. A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ Res, 2019; 124:94–100.

111.

Tenorio-Jiménez

, Martínez-Ramírez

, del Castillo-Codes

, et al. Lactobacillus reuteri v3401 reduces inflammatory biomarkers and modifies the gastrointestinal microbiome in adults with metabolic syndrome: The PROSIR study. Nutrients, 2019; 11:1761.

112.

, You

. The potential role of gut microbiota in the prevention and treatment of lipid metabolism disorders. Int J Endocrinol, 2020; 2020:8601796.

113.

Wang

, Koonen

, Hofker

, et al. Gut microbiome and lipid metabolism: From associations to mechanisms. Curr Opin Lipidol, 2016; 27:216–224.

114.

, Bonder

, Cenit

, et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res, 2015; 117:817–824.

115.

Schiffrin

. Immune mechanisms in hypertension and vascular injury. Clin Sci, 2014; 126:267–274.

116.

Yang

, Santisteban

, Rodriguez

, et al. Gut dysbiosis is linked to hypertension. Hypertension, 2015; 65:1331–1340.

117.

, Zhao

, Wang

, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome, 2017; 5:14.

118.

Wilkinson

, Manoogian

ENC

, Zadourian

, et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab, 2020; 31:92.e5–104.e5.

119.

Kaczmarek

, Thompson

, Holscher

. Complex interactions of circadian rhythms, eating behaviors, and the gastrointestinal microbiota and their potential impact on health. Nutrit Rev, 2017; 75:673–682.