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ABSTRACT
ABSTRACT
Introduction
The role of the intestinal microbiota in host cardiometabolic health and disease has gained significant attention over recent decades. Previous studies have shown effects on metabolic health through gut microbiota modulation; this suggests diverse interaction pathways that constitute the communication between gut microbiota and host central nervous system, the so-called gut-brain axis.
Areas covered
This article provides an overview of the various mechanisms that may mediate the gut-brain axis. It places an emphasis on cardiometabolic health, including effects of short-chain fatty acids (SCFA), alterations in neurotransmitters and gut peptides and microbial effects on chronic inflammation and immune function. Moreover, this paper sheds light on whether these mechanisms afford therapeutic targets to promote metabolic health. To this end, a PubMed search with the terms ‘gut microbiota,’ ‘obesity’ and ‘insulin sensitivity’ was performed.
Expert opinion
Many properties of the human gut microbiome are associated with the central regulation of appetite and metabolic status. Some of these relationships are causal and there are positive effects from certain intervention methods. Microbial manipulation may offer a means to prevent or treat obesity and associated co-morbidities. However, to establish direct causal relations between altered gut microbiota and metabolic disease, clinical intervention studies are necessary.
1. Introduction
Obesity is a major public health problem. Despite professional efforts to promote cardiometabolic health, current approaches are not yet sufficient to prevent or treat obesity and related disorders. Cardiometabolic health encompasses cardiovascular and metabolic diseases and all cardiometabolic conditions share similar risk factors, of which overweight, obesity, and insulin resistance are the main contributors to impaired metabolic health. Insulin resistance can be considered a central problem from which subsequent metabolic problems such as type 2 diabetes, dyslipidaemia and cardiovascular disease can arise [1]. The central nervous system plays an important role in the development of obesity due to structural changes in the regulation of food intake [2–4].
The gut microbiota has been implicated to play a modulating role in human metabolism [5,6] and in the development of obesity and type 2 diabetes [3,7,8]. Obesity has been associated with alterations in composition of intestinal microbiota [9] and even co-twins discordant for obesity appear to show significant differences in microbiome composition [5,6,10]. Besides, transfer of gut microbiota from obese animals to non-obese animals has induced obesity in the recipients [9,11]. Conversely, transfer of microbiota from lean human donors to obese individuals has increased insulin sensitivity [12,13], whereas transfer of microbiota from obese donors to obese individuals worsened insulin sensitivity [14]. Mounting evidence suggests a prominent role for the gut microbiome in pathophysiological pathways that influence the central nervous system (CNS) regulation of food intake. However, to completely reveal the microbiome’s relevant potential for new therapeutic targets it is essential to establish causality between an altered microbiome and altered metabolic health in the host. In animal studies, some direct and significant impact of the gut microbiota on host metabolism has been established [15,16]. The mechanism of interaction between the human intestinal microbiome and appetite regulation is thought to be mediated via the so-called gut-brain axis. This axis represents a bidirectional signaling pathway that regulates body weight by balancing appetite, storage, and energy expenditure of an individual [15]. Recent animal studies have shown that the gut microbiota exert an influence on the regulation of food intake by affecting hormones and metabolites that influence metabolic function and areas in the brain associated with eating behavior [17,18]. This renders the gut microbiome a potential new therapeutic target for improving appetite regulation and cardiometabolic health.
Because of the complexity and diversity of cardiometabolic diseases and the numerous pathways involved in cardiometabolic health, various mechanisms via which microbiota influence the host metabolism have been suggested. This review will focus on the most presumable microbiota-derived pathways affecting host metabolism and appetite regulation involving the gut-brain-axis. These mechanisms include microbial production of short-chain fatty acids (SCFA), effects of microbiota on appetite-regulating hormones, microbial production of neural factors and the involvement of the microbiota in chronic inflammation and immunomodulation associated with obesity. Subsequently, the main potential intervention methods involving these mechanisms are discussed, including supplementation of SCFA, diet enrichment with pre- or probiotics and fecal transplantation. To this end, a PubMed search using the index terms ‘gut microbiota[Mesh] AND obesity[Mesh] AND insulin sensitivity’ was carried out, generating 253 results.
After thorough screening, 97 articles were selected and 53 articles were included via the snowball method. Ideally, managing metabolic health via the microbiome includes prevention methods by which obesity and related disorders are averted by modulating appetite and eating behavior, hereby maintaining healthy cardiovascular status, body lipid metabolism and glucose and insulin homeostasis. Comparable to the role of central nervous system (CNS) reward and satiety responses in drug addiction [2,19], obese individuals are characterized by excessive eating due to altered CNS reward and satiety responses to food [3,4,7,8]. In line with this, once an obese state has been reached, the probability of attaining normal body weight again is less than 1% [20]. Considering the therapeutic targets discussed in this review, we argue that both managing appetite and eating behavior by preventing obesity and insulin resistance is a keystone for improving cardiometabolic health. It has to be noted that not all effects on metabolic health exerted by the gut microbiota are mediated via the gut-brain axis. For instance, it has also been shown that altering the gut microbiota can result in altered body fat composition of the host via local alterations in intestinal lipid adsorption [21,22]. For the scope of this review, however, we will focus on interaction mechanisms between microbiota and host that arise via the gut-brain axis and are of importance for host cardiometabolic health.
2. Short-chain fatty acids involved in the gut-brain axis
Short-chain fatty acids (SCFA) are amongst the most frequently suggested mediators of the gut microbiota-host interaction. SCFA (acetate, butyrate, and propionate) are produced by gut bacterial strains in the process of colonic fermentation of dietary fiber [23,24]. The way in which SCFA mediate the communication between gut microbiota and their host is not yet fully defined. Researchers have suggested various mechanisms of action, of which a combination presumably enables the complex interaction between gut and host. SCFA act by binding to G-protein-coupled free fatty acid receptors 2 and 3 (FFAR2 and FFAR3, i.e. GPR43 and GPR41, respectively) on enteric cells via which intestinal innervation and gut peptide secretion are mediated [25], but also exert peripheral effects after being absorbed from the gut and binding to peripheral FFAR on adipocytes, pancreatic islets, and hepatocytes [26]. Finally, there is some evidence for SCFA entering the CNS to interact with satietogenic neurons and regulatory neuropeptides [27]. With respect to their use as an energy source, butyrate is highly used by colonocytes [28] and propionate is primarily used by hepatocytes [29]. As such, only acetate is thought to reach the peripheral circulation at relatively high amounts. Locally in the gut, SCFA are able to enhance the secretion of the anorexigenic hormones GLP-1 and PYY from L cells in the gastrointestinal tract into the circulation.
Several animal studies have shown beneficial effects of SCFA supplementation. SCFA supplementation of a high-fat diet (HFD) in male C57Bl/6J mice led to a switch from lipid synthesis to utilization, causing the mice to lose weight, increase energy expenditure, and have lower plasma insulin levels [30]. SCFA propionate and butyrate increase intestinal gluconeogenesis (IGN) in mice, resulting in lowered body weight and increased glucose tolerance and insulin sensitivity [31]. The two SCFA act via different mechanisms: the effect of butyrate is mediated via a cAMP-dependent mechanism, whereas propionate activates IGN gene expression by acting as an agonist of FFAR3 in the periportal afferent neural system and hereby activating a gut-brain neural circuit. Besides, dietary supplementation of SCFA can increase plasma levels of GLP-1 and protect against diet-induced obesity in mice [32,33]. SCFA have also been reported to exhibit potent immunomodulatory properties [34]. Finally, SCFA supplementation leads to alleviation of blood-brain barrier permeability and microglia immaturity in the CNS in GF mice [35]. It is important to note that several of these anti-inflammatory effects have also been demonstrated in mice with diet-induced obesity, illustrating the multifaceted role of SCFA in metabolic disease and appetite regulation [33,36].
SCFA supplementation also tends to result in a reduction in body weight in humans [37]. However, it has to be noted that causal relations concerning the effects of SCFA are hard to establish in most human studies since plasma SCFA are higher in obese people [38], people adhering to a HFD [39] and in people with a high alcohol consumption [40]. Additionally, plasma acetate levels are volatile because acetate is generally used in the citric acid cycle in the form of acetyl coenzyme A [41]. In addition, SCFA are interconverted by gut microbiota due to cross-feeding [42], which can cause alterations in one specific fatty acid to effectively increase the concentrations of other SCFA. Though many of the previously mentioned effects can be induced by all SCFA, there are distinct differences between the principal gut microbial-derived SCFA in the manner in which they affect the host’s metabolism.
2.1. Butyrate
The beneficial effects of butyrate on host metabolism have been repeatedly affirmed in animal studies, as dietary butyrate supplementation ameliorates body weight gain, triglycerides (TG) concentrations, oral glucose tolerance, and fasting insulin, as well as leptin in mice [32,33]. In addition, acute oral administration increases insulin, amylin, GLP-1, and PYY [32]. In dietary-obese mice, oral butyrate supplementation has also improved insulin sensitivity, increased energy expenditure [43], and prevented HFD-induced obesity and hepatic steatosis [44]. In humans, fecal microbiota transplantation (FMT) from lean donors has induced an improved peripheral insulin sensitivity in individuals with metabolic syndrome alongside an increase in abundance of the butyrate producers Roseburia intestinalis and Eubacterium hallii in the large and small intestine, respectively, suggesting these metabolic benefits of FMT are at least partially butyrate-mediated [12]. Indeed, oral butyrate administration has increased both peripheral and hepatic insulin sensitivity, although only in lean subjects [45]. Interestingly, the increase in fecal and plasma SCFA was not specifically driven by butyrate suggesting that SCFA conversion in the gut played a role in the established metabolic effects of oral butyrate supplementation. These results suggest that butyrate plays a role in the regulation of energy metabolism and glucose homeostasis, however, the effects of butyrate on the brain appear to be limited. The beneficial results of the abovementioned studies do imply a therapeutic role for butyrate in the promotion of cardiometabolic health, either via dietary supplementation or via the introduction of butyrogenic bacterial strains such as R. intestinalis or E. hallii, with the latter currently being tested in both animal [46] and human [47] models of insulin resistance.
2.2. Acetate
The metabolic effects of acetate have been investigated in various intervention studies, but results are controversial. It is already known that acetate travels to other organs, including the brain, for use as an energy substrate [48] and in fatty acid and cholesterol biosynthesis [49]. A study in HFD mice showed that acetate derived from the colon crosses the blood–brain barrier and is taken up by the brain [27]. Human studies have also shown that acetate can pass the blood–brain barrier [40,50]. In regard to the effects of acetate on host metabolism, dietary acetate supplementation in obese mice does not significantly affect cumulative food intake, but does ameliorate body weight gain, TG concentrations, fasting insulin, and leptin [33]. In addition, acute acetate injection decreases circulating concentrations of FFAs [51]. However, another study showed opposite results in HFD fed rats. In this study, increased colonic acetate levels induced activation of the parasympathetic nervous system, and consequently promoted an increase in glucose-stimulated insulin secretion (GSIS) and in ghrelin secretion [18]. This resulted in hyperphagia, hypertriglyceridemia, liver and muscle insulin resistance and ectopic lipid deposition in liver and skeletal muscle. Discrepancies in the effects of acetate may be due to the fact that the route of administration differs between studies. Additionally, the effects of SCFA appear to differ in diabetic conditions compared to the physiological situation [26,52]. Studies in humans have shown beneficial metabolic effects of rectal acetate administration on plasma peptide YY (PYY), GLP-1 [25], and plasma free fatty acid (FFA) levels [53]. However, these effects were only observed during the infusion period, rendering the therapeutic potential for rectal acetate administration a rather impractical method to improve metabolic health. Other human studies have shown metabolically beneficial effects of oral vinegar (acetic acid) administration on body weight and body fat composition [54] and postprandial glucose metabolism [55,56]. These findings suggest that acetate exerts both local and peripheral effects on glucose and insulin metabolism and appetite regulation. Some of these effects are metabolically beneficial whereas others operate in the opposite direction. Certain previous studies have shown beneficial results after oral acetate or acetic acid supplementation. However, results are still controversial and more research on the exact mechanisms of action exerted by acetate are needed to gain clearer insight into the role of acetate in managing cardiometabolic health.
2.3. Dietary enrichment with fermentable fiber
Beside administration of SCFA, dietary enrichment with fermentable fiber has also induced improvement of metabolic health. The effects of prebiotics (i.e. fermentable fibers promoting the growth of beneficial bacteria) are, at least in part, mediated through an increase in SCFA production. In both animal [57,58] and human studies [59,60], dietary supplementation with fermentable fiber has been shown to induce weight loss [61], improve glucose tolerance [62,63] and affect satietogenic gut peptide release [60]. None of these effects have been observed in germ-free or antibiotic-treated mice [64], suggesting that dietary fiber supplementation is mediated through increased fermentation by gut microbiota and the subsequent production of short-chain fatty acids and other metabolites. Several studies have shown that dietary inulin supplementation promotes colonic fermentation [60,65] and that this increased fermentation generates beneficial effects on satiety, satietogenic gut peptide production, and postprandial glucose responses [60]. Fermentation of prebiotics by gut microbiota has been shown to induce satiety, thereby decreasing total energy intake by about 10% [60,66]. Another human study showed that a 16-day dietary supplementation of inulin induced a stimulation of five specific strains of the genus Bifidobacterium and of the Faecalibacterium prausnitzii bacteria [67]. F. prausnitzii is a butyrate producer and it has been established in animal models that inulin functions as a butyrogenic agent [68]. Additionally, fiber consumption may also increase microbial diversity, which in turn has been implicated in a variety of chronic clinical conditions including metabolic disease [63], indicating that dietary fiber supplementation is also recommended as a preventive measure in healthy lean subjects, adhering to a western, low-fiber diet.
2.4. Conclusions: SCFA
Based on these previous results, increased intestinal levels of SCFA, especially butyrate, appear to be beneficial in metabolic health. Increased intestinal SCFA concentrations can be obtained by either dietary SCFA supplementation or SCFA administration via different routes (e.g. rectally or intravenously), though the latter is a less feasible therapeutic option to improve cardiometabolic health considering the perishing of the effects after administration is stopped [25,53]. Much is still unclear about the mechanisms in which gut microbiota-derived SCFA can influence host appetite and metabolism. In particular, the impact of SCFA in peripheral nervous system signaling remains largely understudied. Nonetheless, current evidence indicates that SCFA represent a potential therapeutic strategy for disease in relation to metabolism and appetite. The number of human studies on SCFA supplementation and SCFA producing novel probiotic strains is still too scarce to establish a definite causal relation between SCFA intake and improved metabolic health. In order to gain more insight into the complex dynamics of SCFA, there is a demand for more clinical intervention studies administering [12–13C]-labeled SCFA orally and rectally. This way, SCFA can be traced from the gastrointestinal tract and more insight can be gained into the proportion of intestinal SCFA traveling to peripheral tissues and exerting peripheral effects. Consequently, the metabolic effects of SCFA supplementation can be associated with SCFA concentrations in various tissues, thus assessing the relative contribution of peripheral effects of SCFA compared to local effects on human metabolism. Hereby, the ideal route of SCFA administration when targeting glucose metabolism and satiety can be established. The metabolic effects of fermentable fiber are, at least in part, mediated through the increased production of SCFA [62,63]. Though diet and exercise still make up the key principles for the treatment of obesity, adding inulin or oligofructose to the daily diet induces a feeling of satiety, which may improve insulin sensitivity and restore and maintain intestinal microbiota symbiosis.
3. Interplay between intestinal microbiota and gut peptides involved in appetite regulation
A second mechanism suggested to mediate the interaction between gut microbiota and host CNS consists of the microbial effects on gut-derived peptides such as GLP-1, PYY, GLP-2, and ghrelin. Histological and electrophysiological properties of the intestinal lining show that visceral afferent nerve endings in the intestine express a diverse array of mechanosensitive and chemical receptors [69,70]. These receptors are the targets of appetite and eating behavior regulatory peptides are known to improve glucose homeostasis and induce satiety [69]. Gut peptide secretion from enteroendocrine cells also contributes to this signaling from the gut to the brain via afferent nerve fibers as well as by direct secretion into the circulatory system. Some bacterial strains can modify gut hormone secretion, including GLP-1, PYY, leptin, and ghrelin, and thus affect appetite and satiety via hypothalamic neuroendocrine pathways. The interplay between microbial metabolites and satietogenic peptides can be used in various ways to promote host metabolic health. To this end, the two primary ways to modulate the gut microbiota are either by supplementing prebiotics or by the administration of metabolically beneficial bacterial strains in the form of probiotics.
3.1. Studies using prebiotics
As described above, the most promising intervention studies linking microbiota to the release of gut peptides have focused mainly on prebiotic treatment increasing colonic fermentation. Previous studies in rats have linked dietary prebiotic supplementation to a decrease in daily energy intake and plasma ghrelin levels, whilst increasing both cecal and plasma GLP-1 and PYY levels [71,72]. Moreover, dietary enrichment with oligofructose improved glucose homeostasis in streptozotocin (STZ)-treated diabetic rats [72]. In humans, oligofructose supplementation has induced a decrease in body weight, a lower AUC for ghrelin, a higher AUC for PYY and a reported reduction in caloric intake, as well as lower postprandial glucose and insulin levels [61]. Other human studies have also shown that prebiotic stimulation of gut fermentation induces satiety alongside alterations in plasma gut peptide levels [66,73]. In one study this increase in satiety was accompanied by a significant increase in postprandial plasma levels of PYY [73]. Another human study linked Orafti Synergy1 supplementation to increased microbiota fermentation by threefold and significantly lowered subjective hunger sensation as well as an increase in GLP-1 and PYY and a lower postprandial glucose response [60]. In the same study, the breath-hydrogen excretion (as a marker for microbial fermentation activity) correlated negatively to the glucose response area under the curve. These findings suggest that prebiotic fermentation in the gut plays a role in appetite regulation and glucose metabolism, presumably partially via affecting the release of appetite-regulatory hormones. Unfortunately, studies looking at dietary fiber supplementation in relation to altered metabolic health in combination with microbiome composition are scarce and therefore no definite conclusions can be drawn about the contribution of specific changes in gut microbiota composition with particular prebiotic interventions.
There have been a few studies that have looked at the influence of prebiotics on fecal microbiome composition. One study in humans showed that a 2-week treatment with Fn-type Chicory Inulin Hydrolyzate significantly increased fecal Bifidobacteria and this increase remained significant also after 5 weeks of inulin supplementation [74]. Another human study on dietary inulin-oligofructose supplementation showed a significant increase in Bifidobacteria proportion and a significant change in abundance of Faecalibacterium Prausnitzii [67]. However, in neither of those studies, appetite hormones or postprandial glucose response are reported, nor is any anthropometric information mentioned so no direct conclusions can be drawn about the mechanism linking the increased abundance of those bacteria to improved metabolic health.
3.2. Role for particular bacterial strains
Besides prebiotic treatment, microbiota enrichment with particular strains in animal studies has also been shown to alter gut peptide levels. When studied in mice, it has been found that colonization of the mouse colon with two prominent human gut microbes (saccharolytic bacterium Bacteroides thetaiotaomicron and methanogenic archaeon Methanobrevibacter smithii) increased plasma levels of PYY, accompanied by higher cecal levels of propionate and acetate compared to the gnotobiotic WT mice [75]. This effect was blunted by knocking out Gpr41. The finding that Gpr41 deficiency improves metabolic health is consistent with a recent study in Ffar2 and Ffar3 KO mice that demonstrated that a HFD induced higher insulin secretion and improvement of glucose tolerance compared to the effects of a HFD in WT mice [26]. This suggests that a Gpr41 activation inhibitor could induce less weight gain on a HFD, accompanied by a decrease in hepatic lipogenesis, thus providing a protective mechanism for maintaining cardiometabolic health, even when adhering to an unhealthy diet.
Besides modulating gut peptide levels, certain bacterial strains have been found to influence ghrelin receptor signaling [76]. An in vitro study showed that microbiota-derived metabolites (SCFA and lactate) and bacterial supernatants of Bifidobacterium and Lactobacillus attenuated ghrelin signaling via the ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] [77]. This finding suggests a novel route of communication between the gut microbiota and host, however more in vivo research is needed to study the significance of these effects on host physiology.
3.3. Conclusions: gut peptides
Modulation of the gut microbiome can lead to increased secretion of appetite-suppressing gut peptides alongside a decrease in appetite-stimulating peptide ghrelin, hereby altering host appetite and eating behavior. Promoting cardiometabolic health by intervening in the interaction between microbiota and gut peptides should consist of prebiotic treatment (e.g. oligofructose or inulin) or introduction of bacterial strains that influence gut peptide levels (e.g. B. thetaiotaomicron or M. Smithii).
4. Microbiota-derived neural factors involved in the gut-brain axis
It has also been suggested that the interaction between gut microbiota and host is partially modulated via microbiota-derived neural factors that affect the brain in a direct manner. The enteric microbiota communicate with the brain via epithelial cells, receptor-mediated signaling, and stimulation of cells in the lamina propria (see Figure 1). Changes in microbiota composition lead to changes in gastrointestinal and neuroendocrine signaling pathways. The mechanism of action of microbiota-produced neurotransmitters may be via stimulation of epithelial cells upon which they release molecules that modulate neural signaling within the enteric nervous system, or via direct stimulation of primary afferent axons [78]. So far, various results have indicated that microbiota are essential for maintaining sufficient levels of serotonin and dopamine [79,80]. It is known that certain bacterial species are capable of producing 5-hydroxytryptamine (a serotonin precursor) and dopamine [81,82]. Serotonin and dopamine are the most plausible neuroactive substances that are produced and influenced by microbiota and have been implicated in appetite-regulatory pathways [79,83]. See Table 1 for a complete overview of bacterial products involved in the gut-brain axis per producing species as discussed in this review.
Published online:
22 May 2020Figure 1. Schematic overview of relationship between intestinal microbiota, gut, and brain.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/iett20/2020/iett20.v024.i07/14728222.2020.1761958/20210507/images/medium/iett_a_1761958_f0001_oc.jpg"})
Figure 1. Schematic overview of relationship between intestinal microbiota, gut, and brain.
Table 1. Biogenic products involved in the gut-brain axis as discussed in the review per bacterial strain.
4.1. Serotonin
It has been established that indigenous spore-forming gut bacteria are able to modulate local and peripheral host serotonin production [96]. Multiple intestinal microbiota are capable of producing appetite-regulating neurotransmitter serotonin, including several Escherichia and Enterococcus species [81,82] as well as the species Lactococcus lactis, Lactobacillus plantarum, and Streptococcus thermophiles [82]. Plasma serotonin levels have been found to be up to threefold higher in mice with commensal microbiota compared to germ-free mice [80], whereas antibiotic-treated mice show substantial reductions in peripheral serotonin levels [96]. Additionally, a study on a 14-day oral administration of Bifidobacterium infantis in rats showed that B. infantis induced an increase in plasma concentrations of serotonin precursor tryptophan [83]. This indicates that circulating serotonin originates mainly from the gut microbiota.
Serotonin (5-hydroxytryptophan [5-HT]) has been shown to regulate glucose homeostasis [97] through effects on hepatocyte and adipocyte function [98] with circulating serotonin positively correlating to plasma glucose levels in humans [99]. Interestingly, serotonin does not increase anticipatory eating behavior in humans. Instead, serotonin released while consuming food activates 5-HT2C receptors on dopamine-producing cells [100,101]. This inhibits their dopamine-releasing activity and thereby decreases appetite, which is also why selective serotonin reuptake inhibitors (SSRIs) can induce weight gain. Drugs blocking or antagonizing 5-HT2C receptors make the body unable to recognize a feeling of satiety and are associated with weight gain [102]. However, in contrast with what would be expected, circulating 5-HT levels have been reported to be higher in obese humans [103], suggesting augmented release capacity for peripheral serotonin in obese individuals. In accordance with this finding, one study showed that serotonin suppression can improve glucose tolerance [104]. In this study, mice were given P533401 (a Tph1 inhibitor) which resulted in increased glucose tolerance. However, this increase was not accompanied by weight loss. In this same study, Tph1 -/- mice showed increased glucose clearance compared to Tph1 +/+ mice, with antibiotic treatment significantly improving glucose clearance in wild-type (WT) mice, but not in Tph1 -/- mice, suggesting that the gut microbiome mediates host glucose homeostasis via peripheral serotonin regulation [104]. All abovementioned findings suggest a role for the microbiota in maintaining host serotonin levels, thus implying a therapeutic potential for maintaining cardiometabolic health by altering tryptophan and serotonin levels via the gut microbiota. However, much research is still needed to identify how local elevations of serotonin in the gut can affect host metabolism and even brain function, if indeed they can.
4.2. Dopamine
Dopamine has been linked to appetite and eating behavior in various studies in animals and humans [19,105,106]. Obese individuals have fewer striatal D2 receptors than lean individuals and this lower count in obese subjects is associated with prefrontal metabolism [19,107]. Subsequent research showed a blunted striatal response to food consumption in obese individuals, the extent of which predicted the weight gain over the following 6–12 months [108,109]. These findings suggest that overeating in obese individuals may be caused by deficits in the dopaminergic system that individuals are trying to compensate. Previous studies comparing germ-free animals to conventional animals have demonstrated that commensal microbiota influence catecholamine levels in the gut lumen [79] and monoamine levels in specific brain regions of the host [108,110]. In germ-free mice, the majority of catecholamines in the gut lumen exist in a biologically inactive, conjugated form, and can be converted to catecholamines by incubation with bacterial β-glucuronidase (GUS) [111]. More recent experiments showed that gnotobiotic mice associated with either a combination of 46 Clostridia species or fecal flora from specific pathogen-free (SPF) mice (EX-GF) showed a drastic elevation of free norepinephrine and dopamine levels in the gut lumen, accompanied by an increase in cecal GUS activity, suggesting that catecholamines contained in the diet are digested and absorbed from the gut and that this process is facilitated by GUS activity [79]. These results suggest a role for the gut microbiota in maintaining sufficient dopamine levels as well as other catecholamines in the gut lumen. More elaborate research in humans is needed to gain clearer insight into the potential therapeutic applications of microbiota in maintaining cardiometabolic health via dopaminergic pathways.
4.3. Conclusions: neural factors
Gut microbiota are essential for maintaining adequate levels of plasma serotonin and dopamine. The most suitable therapies aimed at improving cardiometabolic health using the interaction between microbiota and bodily serotonin would involve TPH1 inhibition via P533401 supplementation. However, we are still at the very early stages of understanding the complex mechanisms of action of neural factors in the communication systems between gut bacteria and the brain. More clinical research is needed, since a serotonin suppressant could induce neuropsychiatric effects involving disturbance of mood and directly affecting CNS function [112], thereby causing the risks to outbalance the possible advantages. Broad-spectrum antibiotic treatment also appears to decrease microbiota-derived serotonin levels [96,109]; however, the benefit may not outweigh the potential harmful effects of antibiotics. A more suitable approach could be to apply narrow-spectrum antibiotics specifically targeting major serotonin-producing strains such as B. infantis, though more research is still needed to study the potency of the effect of such interventions on clinical outcomes as body composition and insulin resistance. Supplementation with bacterial GUS could increase peripheral and central dopamine levels, thus decreasing dopamine receptor availability and thereby decreasing motivational salience activity concerning food. However, more research will be needed to study the complex communication between gut bacteria and the human brain, before such therapies can be realized.
5. Gut microbiota involved in altered gut permeability and chronic inflammation in obesity and metabolic syndrome
Gut microbiota may also contribute to the chronic inflammatory state associated with obesity which may result in neuroinflammation and altered brain physiology. Low-level translocation of substances or microbes across the tight junctions of these luminal antigens is normal and shape a proper adaptive immune system [113]. Nonetheless, excessive intestinal permeability, often referred to as the ‘leaky gut’ phenomenon, is associated with a chronic state of low-grade inflammation and sepsis, in which inflammatory mediators are thought to exacerbate intestinal permeability [114]. When an individual reaches the obese state this is characterized by macrophage infiltration into various tissues such as muscle, liver and adipose tissue and this infiltration promotes the secretion of pro-inflammatory factors such as TNF-α, IL-1, IL-6, and MCP-1 [115,116]. Various studies have established associations between chronic inflammation parameters and specific microbial metabolites.
5.1. Microbial metabolites, metabolic endotoxemia, and chronic inflammation
Gastrointestinal barrier functionality and permeability are highly affected by the gut microbiota [117]. In the physiological situation, this barrier prevents toxic substances and pathogens from entering the circulation from the lumen. Obesity-associated increases in intestinal permeability can lead to an increased translocation of Gram-negative bacterial derived lipopolysaccharide (LPS) into the circulation, resulting in chronic low-grade systemic inflammation [118], in a condition called metabolic endotoxemia [119]. LPS is a major component of the outer membranes of gram-negative bacteria and, to date, is the best-known target of innate recognition and induces a robust inflammatory response in phagocytes [120]. LPS, via transcriptional activation of Toll-like receptor 2 (TLR2), TNF-α and MCP-1, induces increased expression of genes encoding cytokines, chemokines and receptors in adipose, hepatic, and cerebral tissue [121]. Absorption of LPS from the intestines into the peripheral circulation originates from physiological processes such as the transport of LPS from the gut toward target tissues by chylomicrons from intestinal cells in response to fat feeding [122,123]. One major factor contributing to the transition from the physiological situation to excessive absorption of LPS into the circulation is the disruption of tight-junction proteins involved in the gut barrier function. Previous studies have shown that a HFD contributes to the disruption of tight-junction proteins in the gut barrier [60,124]. This effect is abolished after antibiotic treatment, suggesting a direct involvement of the gut microbiota in gut barrier permeability. This hypothesis has been affirmed by the finding that prebiotic treatment with complex carbohydrates improves gut barrier integrity, lowers inflammation parameters and glucose tolerance and reduces metabolic endotoxemia [124–126]. Various studies have reproduced the beneficial effect of LPS receptor KO mice models on metabolic health [127,128], indicating that lowering plasma LPS levels could be a potential strategy to control cardiometabolic dysfunction. A 4-week HFD chronically increased plasma LPS levels two- to threefold in mice [119], as well as an alteration in cecal microbiota composition with a marked reduction in Bacteroides-related bacteria, Bifidobacterium spp. and Eubacterium rectale-Clostridium coccoides. LPS infusion induced endotoxemia and induced an increase in fasted glycemia and insulinemia to a similar extent as the HFD mice. Remarkably, this effect was drastically blunted in CD14 -/- mice [119]. These results suggest that metabolic endotoxemia dysregulates bodily inflammatory responses and triggers obesity and insulin resistance via CD14 stimulation.
Dietary intake may be considered a mediating factor in the low-grade inflammation process in obese individuals [119,129,130] and a study in 30 bariatric patients showed a time-dependent association between inflammatory parameters (hs-CRP, IL-6, and orosomucoid) and fecal levels of F. prausnitzii [131]. After bariatric surgery, plasma levels of inflammatory markers were reduced and this reduction was associated with an increase in F. prausnitzii, suggesting that F. prausnitzii plays a regulatory role in low-grade inflammation pathologies like obesity and diabetes.
5.2. Effects of chronic inflammation on brain physiology
Various studies have shown a relation between the obesity-associated inflammatory state and increased neuroinflammation and altered brain physiology. The neural effects of chronic inflammation in obese individuals appear to be, at least in part, mediated by microbial factors. For instance, peripherally administered LPS enhances the biosynthesis of noradrenaline in the locus ceruleus in mice [132]. Given the involvement of this nucleus in stress-induced sympathetic nervous system activation, LPS endotoxemia could function as a CD14-dependent stimulus for obesity-associated sympathetic overactivity. WT mice transplanted with HFD microbiota developed increased plasma levels of Toll-like receptor 4 (TLR4) and of the macrophage marker ionized calcium-binding adapter molecule 1, reflecting an altered immune function [11]. This change in immunological status was accompanied by changes in neuroinflammation and subsequent cognitive disruptions, indicating that HFD-induced changes in the gut microbiome are sufficient to disrupt brain physiology and function including the gut-brain axis. Central nervous inflammation can also contribute to reduced peripheral insulin sensitivity, especially in the liver, via a brain-liver neuronal signaling pathway [133]. TLR are also expressed in the brain and function as key players in the process of neurodegeneration [134]. Besides LPS, bacterial metabolite propionic acid, peptidoglycan (PGN) and lipoteichoic acid (LTA) have been shown to alter brain and plasma phospholipid molecular species and hereby inducing neuroinflammation and influencing cognitive development and behavior in rats [135,136]. PGN and LTA are derived from gram-positive bacteria (e.g. Staphylococcus aureus) and they can induce stimulation of the nuclear factor kappa B (NF-κB) [121]. Interestingly, PGN administration largely abolishes the effects of LPS on the expression of TLR2, MCP-1, and TNF-α in microglial cells across the brain parenchyma [137]. This suggests a therapeutic potential for PGN administration or introduction of gram-positive bacterial strains as a source for PGN to improve cardiometabolic health.
5.3. Conclusions: chronic inflammation
The gut microbiota contribute significantly to the chronic inflammatory state of the intestines and adipose tissue that accompanies obesity. The subsequent increase of plasma inflammatory markers and permeability of the gut result in neuroinflammation and altered brain physiology. The results discussed above suggest that various treatments improving gut microbiota health could be suitable potential therapeutic targets to reduce chronic low-grade inflammation in obese individuals. Based on abovementioned findings, the most valid therapeutic options are prebiotic treatment (e.g. oligofructose) and gut microbiota enrichment with F. prausnitzii.
6. Obesity-associated impairment of immune function mediated by gut microbiota
The increased intestinal permeability associated with obesity induces chronic exposure of the host to a variety of microbial metabolites. Some of these metabolites have a structure similar to the host’s own molecules that is divergent enough to be recognized as foreign by the host’s immune system, in a phenomenon known as molecular mimicry [139]. Long-term excessive exposure to these metabolites can modulate the host immune system. This process is mediated by TLR, specifically, TLR4 has been implicated in the recognition of LPS and TLR5 is involved in the recognition of bacterial flagellin [140]. This way, the innate immune system functions as a key modulator of the crosstalk between the host and the gut microbiota [141] and obesity and the accompanying chronic state of inflammation result in impairment of immune function, affecting both the innate and the adaptive immune system. In an obese state, gut microbial metabolites also reach the central nervous system in excessive amounts. The microbiota has been found to be one of the major factors contributing to the transition from the obesity-associated inflammatory state to impaired immune function and metabolic dysfunction.
6.1. From chronic inflammation to impairment of immune function
Obesity induces immune defects that cause attenuated host responses to infections [142–144]. Moreover, obese subjects are more prone to infections, for instance, the influenza A (H1N1) virus or nosocomial infections after surgery [145]. Innate immune receptors, such as Toll-like receptors (TLR) are known to be activated by specific microbial components [146]. This, in turn, causes T-cell differentiation into effector inflammatory T-cells and triggering signal transduction pathways such as JNK and IKKβ/NFκB hereby causing the release of inflammatory cytokines and chemokines. TLR are also activated by dietary lipids and upregulated in various tissues affected by chronic inflammatory disorders (e.g. liver, brain, and adipose tissue), contributing to the inflammation process that leads to insulin resistance [147]. Various animal models have linked obesity and metabolic dysfunction to alterations in the gut microbiota composition and to deficits in the bodily immune defense mechanisms [144,145]. For instance, ob/ob mice have shown increased susceptibility to different bacterial pathogens, caused by defective phagocytic activity [144]. The increased inflammatory markers from the inflamed periphery can enter the CNS via several pathways. Inflammation propagated to the brain can cause microglia to express inflammatory cytokines and to release reactive oxygen and nitrogen species [148,149]. Additionally, activated microglia may be a source of increased levels of central MCP-1, which recruits monocytes into the brain [150]. All these findings suggest a contributing role of the gut microbiota to the chronic inflammatory state that is associated with obesity, and the subsequent increase of inflammatory signaling molecules and immune cell activity in the central nervous system.
6.2. Therapeutic options restoring immune function
One previous study has shown that the specific Bifidobacterium strain B. pseudocatenulatum CECT 7765 can reduce obesity-associated inflammation by restoring lymphocyte-macrophage balance and gut microbiota structure in HFD mice thus improving immune function [151]. Additionally, supplementation with strain B. pseudocatenulatum CECT 7765 reduced hepatic steatosis, adipocyte hypertrophy and serum cholesterol, triglycerides, and glucose and significantly improved glucose tolerance and insulin sensitivity (measured by area under the curve of a GGT and ITT, respectively) in HFD mice [151]. HFD mice have showed higher levels of Enterobacteriaceae, which was reduced by administering B. pseudocatenulatum CECT 7765 and this reduction was paralleled by an amelioration in metabolic function [152]. Besides these mentioned metabolic changes, it has been shown that supplementation with this specific Bifidobacterium reduces total macrophage infiltration and the M1 polarization and increased Tregs in the livers of obese mice, an increase that was accompanied by reduced peripheral B cell and Tregs concentrations [151]. Additionally, the B. pseudocatenulatum CECT 7765 administration in HFD mice could partially restore microbiota composition of lean mice – a restoration that was most prominently visible for the Firmicutes phylotypes. Another study showed beneficial metabolic and immunological effects of the specific Bacteroides strain B. uniformis CECT 7771 after 7 weeks of oral administration in C57Bl-6 mice [152]. The mice showed decreased serum cholesterol, triglyceride, and glucose levels as well as improved insulin sensitivity and glucose tolerance.
In animal models of HFD-induced type 2 diabetes, a phenomenon called bacterial translocation has repeatedly been observed [153–155]. In a HFD diabetic mice model, administration of Bifidobacterium animalis subsp. lactis 420 has been shown to reverse metabolic bacteremia while simultaneously improving the animals’ overall inflammatory and metabolic status [134,156]. These findings suggest a modulating role for the gut ecosystem in immune cell infiltration and inflammation in the gut and periphery, parallel to improvements in metabolic dysfunction associated with obesity.
6.3. Conclusions: immune function
Obesity-associated impairment of immune function is at least in part mediated by gut microbiota. This mediation arises via activation of immune receptors such as TLR and NLR by microbial metabolites. Various animal studies have shown beneficial effects of microbiota alteration on immune function. Based on the abovementioned rodent studies, one potential new therapeutic target for improving metabolic health could consist of small intestine enrichment with the B. pseudocatenulatum CECT 7765, B. uniformis CECT 7771 strain or B. animalis subsp. lactis 420. However, the results from long-term, highly powered intervention studies in humans are awaited.
7. Conclusion
In recent years, it has become increasingly clear that the microbiota may be an active contributor to human metabolism and appetite regulation. In this review, we have emphasized the role of the microbiota in the so-called gut-brain axis. Initially, gut bacteria ferment dietary fiber and protein, thus producing SCFA. These SCFA interact with multiple bodily processes, affecting appetite regulation and glucose metabolism. This interaction involves local effects on the enteroendocrine L-cells, thus influencing the secretion or action of appetite-regulating hormones in the intestines, and peripheral effects of mainly acetate which is absorbed from the intestine and may act on pancreatic beta cell islets and appetite-regulating nuclei in the brainstem. In addition, the gut microbiota contributes to maintaining sufficient dopamine levels as well as other catecholamines in the gut lumen, and an altered microbiota composition can influence appetite regulation by deficiencies in dopaminergic circuits involved in CNS reward circuitry. Beside affecting and modulating various mechanisms of appetite regulation and glucose metabolism, the gut microbiota are an important contributing factor to the chronic inflammatory state of intestinal and adipose tissue that accompanies obesity. The subsequent increase of plasma inflammatory markers and permeability of the gut result in neuroinflammation and altered brain physiology. After a chronic state of obesity has been reached, the gut microbiota is one of the major factors contributing to the transition to impaired immune function and metabolic dysfunction via activation of immune receptors. The results discussed in this paper demonstrate that human cardiometabolic health can be promoted by the administration of short-chain fatty acids, fermentable fiber, metabolically beneficial bacterial strains in the form of novel, gut microbiota-based probiotics, or even fecal transplants. Despite the current progress that is being made in this field of research, the question remains whether there are sustainable methods to permanently shape the microbiota. Nevertheless, with a variety of options for the improvement of our intestinal microbiota composition and function, the foundation has been laid for new therapeutic strategies with which we can improve metabolic status, as well as food craving and insulin sensitivity.
8. Expert opinion
Over the past decades, the intestinal microbiota have intensively been studied regarding its role in the gut-brain axis in relation to host energy metabolism, appetite regulation and cardiometabolic health. Bidirectional communication between the gut and the brain has already been well established over the last couple of years [157–159]. Many recent studies have provided evidence for the fact that the relation between the gut microbiota and its human host consists of a mutualistic interaction, rather than a commensal relationship where the smaller organism benefits and the other organism is not significantly harmed or helped. Microbiota are beneficial in developing proper immunological defense mechanisms in animals and humans [160]. However, results on the gut microbial contribution to host energy metabolism and cardiometabolic health are less straightforward and show a higher inter-individual variation.
Obesity is associated with altered gut microbiota which is, in certain aspects, different from that of healthy individuals, including composition, diversity and functionality [161]. In addition, the fact that intestinal microbiome composition is associated to host metabolic health status is indisputable [5,6]. When the microbiome is studied in specific cohorts [162,163], functional profiles of complex microbial communities as well as specific microbial strains can more reliably be linked to humans phenotypes and diseases. These cohort studies are needed in order to establish more robust ‘healthy’ and ‘obese’ gut microbiota profiles despite the large inter-individual variability of the human microbiome. This variability is often much greater than the subtle differences caused by the presence or absence of disease [164,165] and remains, for the major part, still unexplained [166,167]. Possibly, a clearer definition of what constitutes an ‘obese’ microbiome will be established in the future, similar to the division between ‘junk’ DNA, which shows large inter-individual differences, and functional genes that are linked to diseases. However, these associations do not prove causality and causal inferences between complex microbiomes and other metabolic or inflammatory disorders in humans need to be made using large prospective cohort studies and intervention trials, which are not available at present [168]. This is partly due to the fact that both microbiota and host metabolic health are highly influenced by dietary intake, comorbidities, medication use, ethnicity and lifestyle [169,170] – all confounders that are really difficult to completely account for in observational clinical studies. With regard to diet and microbiota-gut-brain interactions, human brain imaging is a crucial tool to assess the microbiota-host interaction in this regard [171,172]. This approach will help to fathom how the microbiota influences brain function.
Thus far, causation has been nearly exclusively demonstrated in animal models. Recent studies involving microbiota-based interventions in small sample sizes in humans suggest that an altered microbiota may directly modulate host metabolism, but larger studies verifying that an altered microbiota precedes development of obesity and insulin resistance are still awaited. Thus far, it has been established that microbial metabolites affect host metabolism in a variety of ways, including direct effects in the gastrointestinal tract and in peripheral tissues. Currently, the field of human microbiome research is moving more toward functional metabolomic parsing of microbiota-host interactions [173]. To improve understanding of how the microbiota affects host metabolism, metagenomics, proteomics and metabolomics currently form key targets of both animal and clinical intervention studies. These data will form the foundation for animal studies and, eventually, pave the way for precision interventions in humans.
Arguably, the most persuasive experimental evidence for the causal role of the gut microbiota in human disease can be achieved by determining the therapeutic value of FMT. Currently, the only clinical application of FMT that is widely accepted is to treat recurrent C. difficile infections [174]. In order to broaden the clinical implications for FMT, there is a need for confirmation of causal host-microbiome relationships as well as identification of contributory mechanisms of the microbiota to metabolic health [175]. In order to correctly study the beneficial effects of FMT on metabolic outcomes, future clinical studies should be conducted following a strict design in which obese participants are transplanted with feces from lean, thoroughly screened donors. Durable weight loss cannot be expected from these donor FMT interventions, yet delaying new onset type 2 diabetes and autoimmune disease in humans would be a great asset in this regard. However, many other aspects concerning the effectiveness, donor feces handling, donor feces selection based on metabolic status of the donor [14], and optimal administration form have yet to be clarified before moving to a more specified method of restoring intestinal symbiosis. Thus, first the concept needs to be clear, then the field can move to more precise measures for treating intestinal dysbiosis. In order to gain more clear insight into the pathways via which the effects of FMT arise, there is a need for long-term intervention studies in humans following a rigid design.
Nevertheless, the general field of microbiota interventions will plausibly move toward precision strategies to promote intestinal symbiosis and improve microbial diversity, including administration of multi-strain probiotics. However, there are currently no clear clinical guidelines for their use and prescription as they are not currently considered pharmaceuticals, but rather as dietary supplements. In the future, clinical applications of pre- and probiotics will be subject to stricter guidelines as to which type and dosage should be applied for certain specific disorders or complaints. In this regard, it is important for researchers to establish more clearly which combinations of novel, gut microbiota-based probiotics can remedy metabolic complaints and diseases. In line with the development toward more specified therapeutic options, attention is increasing for other human gut-associated populations beyond the microbiota, including viruses and phages. Ample evidence already exists for specific and lasting changes in phageome composition in various conditions [176]. Additionally, co-transfer and stable engraftment of bacteriophages during FMT highlights their potential stabilizing role in the microbiome [177]. The gut phageome is already being used as a source of individual phages with effective therapeutic potential when treating recurrent C. difficile and other antibiotic-resistant bacterial infections [178]. Additionally, specific bacteriophages are associated to intestinal inflammatory disorders [179]. Future research will point out whether the applications of phage-based therapies also reach as far as the improvement of metabolic health or central appetite regulation. Finally, in recent years, the genetic engineering of bacterial strains in order to promote metabolically beneficial assets has garnered great interest as a novel therapeutic target. It has widely been confirmed that certain recombinant strains can be administered as an oral vector for mucosal delivery of bioactive substances [180]. In this regard, the L. lactis species has already been modified and successfully applied as an oral delivery system for recombinant Exd4 peptide in situ, which can enhance insulin secretion in pancreatic beta-cells [181]. Considering these promising results, the application of L. lactis producing recombinant Exd4 as a novel strategy for oral diabetes and obesity treatment is a therapeutic potential that is worth pursuing.
In conclusion, to use the intestinal microbiota as a novel diagnostic and therapeutic device, there currently is a demand for large prospective clinical studies in order to determine whether a change in gut microbiome composition precedes metabolic disease development, or whether the disease itself causes such modulations. Additionally, more clinical intervention studies in humans need to be conducted to clearly mark causality of communication processes in the human gut-brain axis. The identification of novel biomarkers for metabolic health needs to be structured around the fundamental framework of reproducible measurement, early detection of disease and consistent associations between currently known and newly discovered biomarkers. All in all, despite all challenges and complications in the search for causal evidence linking an altered gut microbiome to improved cardiometabolic health, we expect that the gut microbiota might be a novel component in the field of cardiometabolic health, which could have further impact on medicine in the near future.
| Bacterial genus or species | Effect/Production | Reference |
|---|---|---|
| SCFA | ||
| Clostridium, Roseburia, Faecalibacterium, Bacteroides | SCFA production | Guilloteau et al., [84] |
| Eubacterium | SCFA production | Westermann et al., [85] |
| Bifidobacterium | SCFA production | Cronin et al., [86] |
| Clostridium, Eubacterium, Faecalibacterium, Lactobacilli, Roseburia, Ruminococcus | SCFA production | Turnbaugh et al., [10]; Bäckhed et al., [87]; Yatsunenko et al., [88]; Ley et al., [89] |
| Roseburia intestinalis | Butyrate production | Muñoz-Tamayo et al., [90] |
| Eubacterium hallii | Butyrate production | Muñoz-Tamayo et al., [90] |
| Faecalibacterium prausnitzii | Butyrate production | Gibson et al., [68] |
| Akkermansia muciniphila | Butyrate production | Everard et al., [91] |
| Alistipes, Bacteroides, Parabacteroides, Prophyromonas, Prevotella | Butyrate production | Walters et al., [92]; Wu et al., [93]; Eckburg et al., [94] |
| Gut peptides | ||
| Bacteroides thetaiotaomicron, Methanobrevibacter smithii | Increased plasma levels of PYY | Samuel et al., [75] |
| Bifidobacterium, Lactobacillus | Supernatant attenuated ghrelin signaling via GHSR-1a | Torres-Fuentes et al., [77] |
| Neurotransmitters | ||
| Escherichia | Serotonin production | Shishov et al., [81] |
| Enterococcus | Serotonin production | Özogul, [82] |
| Lactococcus lactis, Lactobacillus plantarum, Streptococcus thermophiles | Serotonin production | Özogul, [82] |
| Bifidobacterium infantis | Increased plasma tryptophan levels | Desbonnet et al., [83] |
| Bacillus | Dopamine production | Özogul, [82] |
| Bacterial metabolites involved in chronic inflammaton | ||
| Escherichia coli | LPS production | Laflamme et al., [137] |
| Staphylococcus aureus | PGN production | Laflamme et al., [137] |
| Faecalibacterium prausnitzii | Anti-inflammatory effect and increase in survival rate | Sokol et al., [95] |
| Impaired immune function | ||
| Bifidobacterium pseudocatenulatum | Restoration of lymphocyte-macrophage balance and gut microbiota structure | Moya-Perez et al., [138] |
| Bifidobacterium pseudocatenulatum | Amelioration of metabolic function | Cano et al., [152] |
| Bacteroides uniformis | Improved lipidemia and insulin sensitivity | Cano et al., [152] |
| Bifidobacterium animalis subsp. lactis 420 | Reversing of metabolic bacteremia and improvement of inflammatory and metabolic status | Amar et al., [156] |
Acknowledgments
M. Wijdeveld is supported by the AMC MD/PhD fellowship 2017.
Article highlights
Many properties of the human gut microbiome are associated with metabolic health and glucose metabolism.
Increased levels of intestinal butyrate have been shown to be metabolically beneficial in both animal and human studies and dietary butyrate supplementation can improve peripheral insulin sensitivity.
Dietary enrichment with fermentable fiber induces satiety in humans and this effect is presumably mediated through the increased production of short-chain fatty acids (SCFA).
The gut microbiota might modulate host appetite by maintaining sufficient levels of dopamine and serotonin.
Microbiota-derived lipopolysaccharide (LPS) is one of the primary inducers of inflammation and metabolic diseases in obesity.
Specific Bifidobacterium pseudocatenulatum CECT 7765 has protected against impairment of immune function in animal obesity models.
Microbial manipulation may offer a means to prevent or treat obesity and associated co-morbidities, but further intervention research in humans is needed to establish a causal relation between intestinal microbiota and cardiometabolic health.
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose