Microbial regulation of organismal energy homeostasis


The gut microbiome has emerged as a key regulator of host metabolism. Here we review the various mechanisms through which the gut microbiome influences the energy metabolism of its host, highlighting the complex interactions between gut microbes, their metabolites and host cells. Among the most important bacterial metabolites are short-chain fatty acids, which serve as a direct energy source for host cells, stimulate the production of gut hormones and act in the brain to regulate food intake. Other microbial metabolites affect systemic energy expenditure by influencing thermogenesis and adipose tissue browning. Both direct and indirect mechanisms of action are known for specific metabolites, such as bile acids, branched chain amino acids, indole propionic acid and endocannabinoids. We also discuss the roles of specific bacteria in the production of specific metabolites and explore how external factors, such as antibiotics and exercise, affect the microbiome and thereby energy homeostasis. Collectively, we present a large body of evidence supporting the concept that gut microbiota-based therapies can be used to modulate host metabolism, and we expect to see such approaches moving from bench to bedside in the near future.

Facts and figures on the gut microbiota

The term microbiota refers to all the microorganisms present in the various ecosystems in the human body. Diverse communities of microorganisms are located throughout the human body, including the gut, lungs, vaginal and urinary tracts and skin. The microbiota is composed of several types of microbes: bacteria, archaea, viruses, phages, yeast and fungi1.

Humans have constantly coevolved in the presence of these microorganisms, thereby establishing symbiotic relationships. Several lines of evidence suggest that in addition to bacteria, other types of microbes, such as fungi, protozoa and viruses, also have important interactions with the human in which they reside, referred to as the host in this review2,3. Nevertheless, interactions between bacteria and human cells have been studied the most and will be the focus of this review.

The human body carries approximately 3.9 × 1013 bacterial cells, with the largest amount residing in the large intestine: 1011 bacteria cells g–1 of wet stool4. At the most recent estimation, almost 10 million non-redundant microbial genes have been identified in the human gut5. This number is 150-fold higher than the number of genes in the human genome6. Therefore, the metabolic capacity of the gut microbiota greatly exceeds the metabolic capacity of human cells.

Diversity and richness in the gut microbiome

Importantly, in addition to analysing gut microbiota composition, investigating bacterial genes (referred to as the microbiome) that are present in the host generates complementary information regarding the metabolic potential of the gut microbiota. In that context, it appears that the number of gut microbial genes (that is, the gene count) positively correlates with a healthy metabolic status. For example, individuals with low bacterial gene richness have increased adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype7,8,9. Similarly, it was recently proposed that the key microbiome signal associated with diseases such as Crohn’s disease is more of an overall modification of microbial cell counts rather than an alteration of the proportions of various microbes10.

Therefore, study of the metabolic potential of the gut microbiota may elucidate potential interactions with the host. Of particular interest is the production of various gut microbiota compounds, such as metabolites. In this Review, we will focus on various gut microbial metabolites that are capable of interacting with the host via direct or indirect mechanisms and thereby influence host metabolism.

The theory of energy harvest

Pioneering studies linking SCFAs and energy harvest

The complex and dynamic ecosystem of the gut microbiota contributes to the metabolism of various compounds, thereby leading to the production of numerous metabolites. In the early 2000s, pioneering studies from Gordon and colleagues11 linked the production of specific metabolites, such as short-chain fatty acids (SCFAs), to host energy homeostasis (Table 1). Bäckhed et al.12 demonstrated the role of the gut microbiota in host energy metabolism and growth by showing that germ-free mice gained less body weight and fat mass than conventionalised mice (that is, those harbouring a gut microbiota). This difference was observed despite increased food intake in germ-free mice. The same group of researchers found that the microbiota of genetic obese mice (ob/ob) harvests more energy than their lean ob/+ counterparts. In addition, this phenotype was transferred in germ-free mice transplanted with the microbiota from the obese donors11. Initially, the hypothesis was that this shift provided more SCFAs (acetate, propionate, butyrate and lactate) that could be used as metabolic substrates by the host (Fig. 1). In addition, it was suggested that the gut microbiota contributed to energy metabolism through a direct interaction with the digestive tract. Indeed, the germ-free mice exhibit a lower level of caecal SCFAs than conventionalised mice, thereby suggesting that gut bacteria directly contribute to energy absorption by providing energy substrates to the host13.

Table 1 SCFAs involved in energy metabolism
Fig. 1: Energy harvest and metabolism.

The composition of the gut microbiota is a key factor that influences the capacity of the bacteria to ferment specific non-digestible carbohydrates and fibres. Despite intake of the same diet (in terms of quantity and composition of fibre), the subjects’ differing gut microbiota lead to differing non-digestible carbohydrate fermentation profiles and differing amounts of SCFAs. These different microbiota may thereby contribute to more or less energy harvest from the diet.

Short-chain fatty acids in humans

The link between microbiota and the presence of SCFAs in the gut has been corroborated by additional studies performed on obese mice and humans and by metagenomic analysis of the microbiota, revealing an increased capacity for the degradation (fermentation) of various carbohydrates, thereby suggesting increased SCFA production12,14,15. Nevertheless, other studies have not fully linked the intestinal abundance of SCFAs to obesity and related metabolic disorders16,17,18,19. Therefore, although it is compelling to use the theory of energy harvest to explain the potential link between specific gut microbes and the development of metabolic disorders, this theory is more complex than a simple variation of the quantity of SCFAs in faeces. Indeed, the quantity and relative percentage of each SCFA likely contribute to the regulation of host homeostasis (Fig. 1). Moreover, the proportion of SCFAs that enters the blood and reaches specific organs is probably even more important than intestinal SCFAs20. Thus, SCFAs are used as energy sources and may contribute to several metabolic pathways, including gluconeogenesis21,22 and lipogenesis23, thus contributing to whole-body energy homeostasis (Fig. 1 and Table 1).

Molecular mechanisms linking specific bacteria, SCFAs and metabolism

It has also been shown that gut microbes regulate the somatotropic axis, since insulin-like growth factor 1 (IGF-1) and its downstream effectors IGF-1-binding protein 3 and protein kinase B (also known as Akt) have been shown to be altered in germ-free mice24. In fact, these components of the somatotropic axis are all involved in the postnatal growth and are decreased in germ-free mice, thereby contributing to the decreased body weight gain observed in the absence of gut microbes24. In addition, it has been shown that colonisation of germ-free mice with strains of Lactobacillus plantarum partially compensated these defects through activation of the somatotropic axis, thereby directly linking specific bacteria with energy harvest and growth24. This finding is of interest because it demonstrates that SCFAs may have roles in opposing situations, that is, during positive energy balance, such as obesity, but also in conditions such as malnutrition in children. Indeed, undernutrition is a persistent challenge that is often difficult to remedy by only improving diet. Along this line, the first indication of an association between gut microbes and undernutrition was published in 195825; the association was uncovered in a cohort of children suffering from kwashiorkor who were treated with a combination of antibiotics and yoghurt containing Lactobacillus delbrueckii bulgaricus. This treatment led to a dramatic reduction of mortality (9% treated versus 45% non-treated)25. More recently, data have shown that the overall gut microbiota is altered in undernourished as compared with healthy children. Several studies have highlighted an increased abundance of Proteobacteria in undernourished children (for example, Helicobacter, Campylobacter, Klebsiella and Escherichia) together with a decrease in both diversity and amount of Firmicutes26,27,28. It is worth noting that it is very difficult to provide a list of common bacteria changed in such a situation since a signature of more than 200 taxa whose abundance is modified during malnutrition has been identified29.

Interestingly, as detailed above, although the direct impact of SCFAs and specific bacteria during overnutrition is currently under discussion, De Filippo et al.30 elegantly demonstrated that the contribution of the microbiota to the regulation of energy homeostasis is not only dependent on the bacteria present in the intestine but also strongly associated with the source of nutrients provided by the diet. In a specific population (children from a village in Burkina Faso), the authors discovered that children from one rural village displayed significantly more SCFAs in their guts, as well as a unique abundance of bacteria from the genera Prevotella and Xylanibacter (known for their capacity to degrade cellulose and xylan). Strikingly, these bacteria were completely lacking in the European children30. The other notable finding was that the total energy intake of African children was lower than that of European children by several hundred kilocalories per day despite the fact that these children exhibited similar growth rates; this result suggests that the microbiota can maximize metabolic energy extraction from ingested plant polysaccharides (Fig. 1).

The previous examples of using SCFAs as a hallmark family of microbial metabolites clearly demonstrates that SCFAs may not be simply and directly linked with the onset of obesity and altered energy homeostasis since the levels of SCFAs are highly dependent on the composition of the host’s diet (Fig. 1).

Short-chain fatty acids and specific GPRs

In addition to their impact on lipogenesis or gluconeogenesis, several other specific roles have been attributed to SCFAs. Their effects range from stimulation of gut peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), involved in the control of energy homeostasis (see below; Figs. 2 and 3) to the regulation of immunity, adipogenesis, inflammation and cancer (for review, see ref. 1). It is worth noting that most of these metabolic effects are mediated via the activation of both specific G-protein-coupled receptors (GPR-41, GPR-43 and GPR109A) and the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) in colonocytes, which in turn regulates the expression of genes involved in β-oxidation31,32. Taken together, these data strongly suggest that gut bacteria are acting on host energy homeostasis and eventually body composition and growth.

Fig. 2: The gut microbiota modulates energy intake via the gut–brain axis.

SCFAs mainly influence food intake in a gut hormone-dependent manner: SCFAs link GPR-41 and GPR-43 receptors on enteroendocrine L cells, thus stimulating the release of GLP-1 and PYY. GLP-1 and PYY, in turn, modulate the activity of brain feeding centres acting on gut hormone receptors expressed in the ARC and in the NTS or on the vagal intestinal terminations. A recent study21 suggests that SCFAs can also modulate energy intake in a gut hormone-independent manner, acting via the vagus nerve or directly entering the brain. Microbial components, such as ClpB, also play a role in the host’s appetite control. Besides directly producing neurotransmitters, the gut microbiota modulates host synthesis and release of neurotransmitters both at the intestinal and the central level. Whether the gut microbiota influences the dopaminergic circuit involved in the hedonic regulation of feeding is currently being investigated.

Regulation of food intake

The brain area controlling food intake

Appetite and energy intake are primarily regulated in the hypothalamus and nucleus of the solitary tract (NTS). Those two areas of the brain receive and integrate nervous and endocrine signals related to the nutritional status33. Given its close proximity to the median eminence (ME, a circumventricular organ outside the blood–brain barrier) and to the third ventricle, the hypothalamus senses nutrients and hormones from the blood and cerebrospinal fluid (CSF). Within the hypothalamus, the arcuate nucleus (ARC) fine-tunes feeding behaviour by secreting neuropeptides with opposing actions: neurons co-expressing pro-opiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART) release anorexigenic (appetite-suppressing) peptides, while neurons co-expressing Agouti-related protein (AgRP) and neuropeptide Y (NPY) release orexigenic (appetite-stimulating) peptides (Fig. 2). ARC and NTS express receptors for gut hormones (GLP-1, PYY, ghrelin and CCK) and adipokines (leptin and insulin) (for extensive review, see refs. 34,35). On the other hand, in addition to sensing endocrine signals, the NTS also receives neuronal signals transmitted by vagal afferents from the periphery (for example, the gastrointestinal tract) (Fig. 2).

In summary, the reciprocally interconnected hypothalamus and the NTS respond to various sets of stimuli and co-operate to orchestrate adaptive responses to maintain energy homeostasis.

Short-chain fatty acids can control appetite

As mentioned above, SCFAs can trigger the secretion of several gut peptides involved in the regulation of appetite (for example, GLP-1 and PYY). It was initially thought that the anorexigenic activity of dietary fibres was primarily due to bulking effects (that is, water retention). However, an initial series of manuscripts published between 2004 and 2007 by Cani and colleagues36,37,38,39 demonstrated microbial fermentation of specific dietary fibres leading to substantial SCFA production as well as decreased energy intake in rodents and humans. The authors attributed the reduced energy intake to increased levels of gut peptides involved in regulation of food intake and energy homeostasis (for example, GLP-1, PYY and ghrelin). In more detail, rodents fed a normal diet or a high-fat diet (HFD) enriched with fermentable dietary fibres exhibited reduced food intake, increased colonic expression of proglucagon, a higher content of GLP-1 and lower ghrelin levels in the fasted condition36,38. The PYY levels were also increased by supplementation with dietary fibers37. Further investigation revealed that the anorexigenic effect of dietary fibre was associated with the increased differentiation of L cells in the proximal colon40. Interestingly, L cells selectively express the SCFA receptors GPR-41 and GPR-43 (refs. 41,42,43) and secrete PYY and GLP-1 once activated44,45 (Fig. 2). On the other hand, while it is not clear how colonic SCFAs modulate gastric ghrelin production, some lines of evidence suggest that GLP-1 and ghrelin mutually influence each other’s levels and activity 46,47. PYY, GLP-1 and ghrelin modulate appetite through both endocrine action (reaching the brain through the circulation)48,49,50 and paracrine action (signalling to the brain through the vagus nerve) by directly activating vagal afferents lying in the lamina propria of the gut (for review, see refs. 51,52; Fig. 2). Several studies have confirmed the appetite-suppressive effect of SCFAs by direct administration of these compounds in rodents or humans53,54,55. Moreover, the role of vagal afferents in mediating the anorexigenic action of SCFAs was recently highlighted55,56.

To date, only one experimental study has suggested that SCFAs may also exert an appetite-suppressive action independently of the secretion of gut peptides. In this work, Frost et al.57 showed that peripherally (that is, intraperitoneally) administered acetate entered the brain, where it increased neuronal activation in the ARC—observed by in vivo functional imaging—and increased POMC and reduced AgRP expression, thus supporting the central-mediated anorectic role of acetate.

Microbial components dialoguing with the brain

In addition to being affected by microbiota-derived compounds, food intake could be modulated by microbial components themselves, including the chaperone protein ClpB, which is found in several commensal and pathogenic bacteria58. ClpB mimics the anorexigenic POMC-derived α-melanocyte-stimulating hormone (α-MSH), which is known to play a role in host appetite control58,59. In fact, mice treated with the wild-type strain of Escherichia coli had different feeding behaviour than animals administered E. coli deficient in ClpB58,59. Further studies are necessary in order to better clarify how ClpB exerts its action and, potentially, to identify the existence of other molecules of bacterial origin that modulate appetite (Fig. 2).

Importantly, in addition to the elements detailed above, other important factors, including neurotransmitters, play a role in the gut-to-brain axis. Gut bacteria can regulate the levels of neurotransmitters either directly or via modulation of host biosynthetic pathways of these compounds. This phenomenon has been shown in the intestine as well as in other organs located away from the gut. Gut bacteria are able to produce and metabolize numerous neurotransmitters (for review, see ref. 60). Specific gut microbes also partially stimulate neurotransmitter production by the host in the intestine61 and modulate neurotransmitter levels in the blood and brain61,62. These effects of the gut microbiota have been suggested to influence several pathologies in humans related to the central nervous system, including depression63,64, anxiety65, Parkinson’s disease66, Alzheimer’s disease67, multiple sclerosis68 and symptomologies of autism spectrum disorder69. Even if the causality of the gut microbiota in disease is not always directly demonstrated, targeting the microbiota has been proposed as an intriguing approach for modulating intestinal and peripheral neurotransmitters and for treating central nervous system-related diseases. Among the various neurotransmitters, some are involved in the complex regulation of food intake. Dopamine is a key neurotransmitter involved in food reward (Fig. 2). In addition to the homeostatic control of food intake described in the previous paragraph, rewards associated with food intake also play a major role in regulation of energy metabolism70. Therefore, we speculate that gut microbes might also modulate the gut-to-brain axis, controlling hedonic and reward responses to food intake in physiological conditions and in the pathology of obesity.

A particularly noteworthy neurotransmitter is nitric oxide (NO), a gaseous molecule produced by enteric neurons (ENs) following activation of the GLP-1 receptor (GLP-1r)71,72. Recent work suggests that GLP-1-mediated NO production is modulated by the microbiota. Grasset et al.73 demonstrated that ileum dysbiosis observed in two different murine models of type 2 diabetes induces GLP-1 unresponsiveness by hampering NO production. Conventionalization of germ-free mice with the ileum microbiota of diabetic mice reproduced the GLP-1 resistance, supporting the causal role of the gut microbiota in this context.

An existing relationship among the gut microbiota, NO and host metabolism has also been suggested by Catry et al.74. They demonstrated that prebiotic (for example, inulin-type fructans) supplementation reverses endothelial dysfunction through activation of the host’s NO synthase–NO pathway and via a blooming of NO-synthetizing bacteria. However, the mechanisms responsible for microbiota-induced regulation of endogenous NO levels are not yet completely understood.

Regulation of energy expenditure

Proper regulation of energy expenditure is essential for a healthy metabolic state (that is, normal body weight and fat mass levels). An imbalance between energy intake and energy expenditure, for example due to a dysregulation of energy expenditure, can lead to the development of metabolic disorders. Among the various drivers modulating energy expenditure, thermogenesis is an important component that appears to be regulated by the gut microbiota through different mediators and is under influence of both exogenous and endogenous factors (Fig. 3).

Fig. 3: Crosstalk between the gut microbiota and the host and its regulation of metabolism.

Endogenous and exogenous factors affect the gut microbiota, which in turn influences the functions of several organs via the production of various mediators. These mediators include bile acids, SCFAs, the ECS, TMAO, BCAAs, IPA, endotoxins and microbial components, gut hormones and neurotransmitters. The host metabolism is ultimately dependent on various components regulating glucose homeostasis, inflammatory tone, thermoregulation, redox balance and energy homeostasis.

Bile acids

Emerging evidence has demonstrated an important impact of the gut–liver axis in the regulation of host homeostasis and immunity75,76,77,78. As a matter of fact, bile acids can influence both gut microbiota diversity and proliferation. In turn, specific intestinal bacteria, such as Acetatifactor and Bacteroides, are able to transform primary bile acids (for example, cholic acid (CA) and chenodeoxycholic acid (CDCA)) into secondary bile acids (for example, deoxycholic acid (DCA) and lithocholic acid (LCA))75,79. Besides this, it has also been reported that the abundance of primary versus secondary bile acids resulting from this crosstalk contributes to the modulation of both the metabolism and innate immune system of the host80. Although bile acids are well known for their role in lipid absorption, they also act as bioactive lipids and signalling molecules by activating receptors, such as the farnesoid X receptor (FXR) and TGR5, a G-protein-coupled receptor81 (Fig. 4). TGR5 stimulation leads to intracellular cyclic adenosine monophosphate (cAMP) accumulation, which activates protein kinase A (PKA). Consequently, PKA phosphorylates the co-activator cAMP response element-binding protein (CREB), which induces the transcription of Dio2 in thermogenically competent tissues, such as brown adipose tissue (BAT) and white adipose tissue (WAT). The product of this gene is the enzyme 2-iodothyronine deiodinase (D2). D2 generation triggers the conversion of inactive thyroxine (T4) into 3,3′,5-triiodothryonine (T3), the active form of thyroid hormone, thus increasing thermogenesis82. Emphasizing the connection between the gut microbiota, bile acids and thermogenesis, a recent paper has reported that polyphenol-rich camu camu extract can prevent obesity in diet-induced obese mice in a gut microbiota-dependent manner through increasing BAT thermogenesis via changes in the levels and composition of circulating bile acids83. In addition, bile acids also influence the gut microbiota to promote browning. Recently, it has been demonstrated that activation of intestinal FXR shapes the gut microbiota to increase LCA production79. LCA is the TGR5 agonist with the highest affinity and therefore stimulates browning in WAT and BAT79 (Fig. 4). Taken together, these findings suggest that the gut microbiota can modulate thermogenesis via bile acid metabolism.

Fig. 4: The gut microbiota and its derived metabolites influence host energy homeostasis.

SCFAs are by-products of microbiota fermentation. In mice, data suggest a role played by the SCFAs on energy homeostasis. Butyrate has been shown to induce lipolysis, fatty acid oxidation and thermogenesis, while acetate exerts an anti-lipolysis action and enhances beiging in WAT. In liver, acetate limits fat accumulation and stimulates mitochondrial activity. The gut microbiota and bile acids influence each other; the latter are bioactive lipids capable of modulating energy expenditure by inducing both BAT and WAT thermogenesis through TGR5 signalling. When the A. muciniphila population is increased, an enhanced beiging is often observed in WAT.

Thermogenesis and beiging

Specific situations that promote thermogenesis, such as cold exposure, can induce a marked change in gut microbiota composition84. Several papers provide proof-of concept evidence that this compositional shift occurs as an adaptive response to a cold environment85,86. For instance, depletion of the gut microbiota in mice exposed to cold leads to weight loss, decreased blood glucose and high faecal caloric content85. In addition, faecal transplantation is sufficient to reproduce a lean and pro-thermogenic phenotype of cold-exposed donor mice in recipient mice85,86. In a cold environment, certain mammalian species display huddling. A recent paper hypothesized that this social thermoregulatory behaviour may imply reshaping of the gut microbiota as a mean driver for potentiating energy conservation87. Indeed, huddling voles exhibited lower resting metabolic rates and less non-shivering thermogenesis than their separated counterparts. The two groups displayed distinct microbial communities, and the ‘energy-saving’ phenotype could be conferred by microbiota transfer. This study illustrates how the gut microbiota can reshape energy metabolism according to environmental stress.

Reviewing the link between cold exposure and microbiota prompts us to highlight one specific bacterial strain, Akkermansia muciniphila, whose presence or absence appears to modulate energy efficiency depending on the nutritional status of the host or the ambient temperature, therefore acting as an energy sensor. This Gram-negative bacterium resides in the mucosal layer of the intestine and represents 1–5% of the microbial community88. Health-promoting effects of the bacterium have gained considerable attention, as reduced amounts of A. muciniphila have been correlated with obesity, diabetes, insulin resistance and other cardiometabolic disorders in rodents and in humans9,89,90 (for review, see refs. 1,91). In the context of high energy availability, administration of A. muciniphila delays the development of diet-induced obesity and insulin resistance in mice, notably via the modulation of energy homeostasis and reinforcement of the gut barrier function89,92 (Figs. 3 and 4). Two recent murine studies observed an important and rapid reduction in A. muciniphila abundance under the condition of cold exposure, regardless of the nutritional status86. Chevalier et al.85 suggest that this depletion aims to potentiate the intestinal energy uptake required upon cold environment. This increased caloric uptake was characterized by increased intestinal surface area together with increased expression of glucose transporters. Notably, this increased intestinal absorptive capacity was transferable by microbiota transplantation, but was abolished by A. muciniphila supplementation85. These data therefore support the previously mentioned theory of energy harvest and suggest that the presence of specific bacteria may stimulate or conversely abrogate microbiota-induced energy harvest. Intriguingly, A. muciniphila supplementation in cold-exposed mice did not reverse either the cold-induced thermogenesis or the improved insulin sensitivity seen in this experiment85. This non-deleterious effect is not inconsistent with recent experiments showing that the abundance of A. muciniphila positively correlated with markers of beiging, such as uncoupling protein-1 (UCP-1)89,90,9395 . Among those, one study showed that A. muciniphila administration in HFD-fed mice led to reduced energy efficiency and enhanced WAT browning94 (Fig. 4). Similarly, a recent study performed under standard conditions found a positive correlation between the higher abundance of A. muciniphila, lipid oxidation and browning processes in HFD-fed mice supplemented with tea or coffee extracts94,95. The same association was reported in a bile diversion mouse model in which mice exhibited increased circulating primary bile acids and improved metabolic phenotypes93.

Recent literature strongly suggests that A. muciniphila in a controlled-temperature environment (22–24 °C) promotes browning. This phenomenon likely involves mechanisms of action different from those initiated by acute or chronic cold stress since those conditions induce depletion of this strain to optimize caloric uptake through modification of host intestinal morphology.

The data discussed here and above focus on the mechanisms by which the gut microbiota influences the adaptive response under a cold stimulus to affect peripheral tissue. Nevertheless, it is worth noting that host metabolism can also trigger a shift in the gut microbiota as a strategy to improve adaptation to low temperatures. For example, it has been shown that the hepatic conversion of cholesterol into bile acids following cold exposure results in an important increase in faecal bile acids, ultimately reshaping the gut microbiota96.

In addition to cold exposure, periodic fasting can also lead to beiging97. Intermittent fasting is a condition associated with well-known health benefits and has been characterized by marked microbiome variation98,99,100. The subsequent increases in circulating acetate and lactate have been suggested to be the molecular mediators of specifically observed WAT browning, notably via the upregulation of monocarboxylate transporter 1 (MCT-1) expression in beige fat cells100. Several studies have shown that prolonged fasting is associated with increased A. muciniphila populations in animals and humans101,102,103. This observation was later proposed to be an adaptive response to a lack of food-derived nutrients104.

Short-chain fatty acids

In terms of their molecular mechanisms, SCFAs are particularly interesting. Several studies have suggested that SCFAs act as mediators of gut–adipose tissue crosstalk105,106,107 (for review, see ref. 108; Figs. 14). For example, bile diversion procedures that induce energy expenditure by thermogenesis were associated with a higher abundance of SCFAs in the caecal content93 (Fig. 4). In addition, in mice, oral butyrate administration led to the induction of thermogenesis, enhanced mitochondrial efficiency and fatty acid β-oxidation55,106,107. In obese diabetic mice, it has been proposed that acetate initiates beige adipogenesis on the basis of changes in adipocyte morphology and gene expression (Fig. 4), which would imply a potential direct effect since in vitro data have shown enhanced beige fat differentiation in 3T3-L1 cells incubated with acetate109. These data are consistent with observations reported in another study that uncovered a distinct peripheral mode of action for acetate in terms of fat mobilization, regulating whole-body adiposity. In the liver, acetate inhibited lipid uptake and enhanced mitochondrial activity, while in adipose tissue, it suppressed lipolysis and enhanced beiging110 (Fig. 4).

In humans, the distinct relation between SCFAs and the browning processes is less consistent. While some studies have highlighted beneficial effects of SCFA administration in terms of resting energy expenditure, fat oxidation or whole-body lipolysis, others have suggested that the beneficial effects depended on the basal fitness of individuals; some have even reported positive correlations between colonic SCFA levels and adiposity111,112,113,114,115. These conflicting results have yielded some potential deleterious effect of SCFAs. For instance, Singh et al.23 demonstrated that the gut-derived increased in SCFA levels, observed in a TLR5-KO mouse model, participate in the pro-obesogenic phenotype by promoting the hepatic production of oleate, a substrate for detrimental lipogenesis.


Another mechanism by which the thermogenic function of adipose tissue is regulated is the modulation of the endocannabinoid system (ECS). The ECS consists of cannabinoid receptors, their endogenous lipid ligands and ligand-metabolizing enzymes (reviewed in ref. 116). In a study by Geurts et al.117, the adipose tissue-specific deletion of Napepld (a gene encoding an endocannabinoid synthesizing enzyme) in mice resulted in a higher body fat mass than in wild-type mice despite equal food intake. The mice had an obese-like phenotype that was linked to reduced beiging of adipose tissue. Interestingly, a profound shift in the composition of the gut microbiota was also observed. Transferring this modified microbiota into germ-free recipient mice replicated the phenotype, suggesting that endocannabinoid-related compounds derived from adipocytes contribute to changes in the gut microbiota, which can in turn affect adipose tissue functions and metabolism (Fig. 3).

The ECS is considered a key player in energy homeostasis because it regulates appetite, energy distribution and energy expenditure, and it is also involved in adipose tissue expansion, glucose homeostasis and regulation of inflammation118,119,120,121. Because the ECS is such a versatile and ubiquitous system, it is not surprising that it also has the power to modulate the microbiota122. This relationship was discovered to be reciprocal, as the gut microbiota can influence the ECS as well121. For example, the presence of the bacterial strain Lactobacillus acidophilus induced the expression of cannabinoid receptors in intestinal cells123, thereby inducing changes in gut permeability121,124 (Fig. 3).

Unfortunately, data remain predominantly based on animal studies. In humans, a direct relationship between changes in the gut microbiota and the endocannabinoid system tone has yet to be conclusively demonstrated.


It is well-established that food choices affect the gut microbiota. Nevertheless, other factors exist that may influence microbial communities in humans. The most obvious example is the use of antibiotics (Fig. 3).

Since their discovery in the early 20th century, antibiotics have become essential drugs used in human and animal medicine. However, their (over)usage has dangerous consequences beyond the development of antibiotic resistance. Epidemiological studies have linked antibiotic use to several chronic conditions, including obesity and diabetes (reviewed in ref. 125). Although more relevant in infants, in whom the gut microbiota has not yet been fully established, antibiotic use may also have negative effects on the microbiome and host health if used later in life126.

The observational designs used in epidemiological studies did not allow the inference of causality because too many confounding factors were involved. Nevertheless, since host-associated microbes perform several important functions, it is not unlikely that reshaping the microbial community via antibiotics could have fundamental functional consequences on metabolic parameters. This hypothesis is supported by numerous studies using germ-free, diet-induced obese mice and even healthy mice127,128,129,130. Whether these findings could be extrapolated to humans is not clear, and there is a lack of consensus as to whether antibiotics can truly affect host metabolism125,131. For example, in two studies, one in obese men132 and another in healthy young males125, a shift in the microbiota was found but no effect on host metabolism was observed.

Many important questions about the health effects of antibiotics remain unanswered. Studies using healthy mice or germ-free mice treated with antibiotics or colonized with antibiotic-modified microbiota could help to elucidate some of the mechanisms through which antibiotics affect the microbiome and, in turn, host health. However, since mouse models (especially germ-free mouse models) have limitations133, only a real randomized placebo-controlled clinical trial to reveal the short- and long-term effects of commonly used antibiotics in adult humans free of infection will end the debate.

Notably, antibiotics could also prove to be allies in the treatment of some metabolism-related diseases. For example, they have been used successfully to increase growth rates in malnourished children134,135. However, additional data on this subject must be collected, as some previous studies have reported no benefits136 or even adverse effects137 of antibiotics. Another key factor to bear in mind is the selectivity of specific antibiotics, which, in theory at least, should make reshaping the gut microbiota composition for beneficial effects feasible by using the correct combination of antibiotics. For example, Fecalibacterium prausnitzii, an anti-inflammatory probiotic whose effects on metabolism are only beginning to be understood138, increases following ampicillin treatment but decreases in response to other antibiotics such as ciprofloxacin or tetracycline139.

Humans are constantly exposed to a plethora of xenobiotics other than antibiotics, ranging from environmental pollutants and pesticides to food additives and drugs. It is more and more evident that the gut microbiome plays a role in the metabolism of xenobiotics by changing their toxicity and bioavailability140. This interaction is bi-directional, as the gut microbiota also adapts to such exogenous influences, resulting in a modified microbial metabolic activity139.

Several recent studies have demonstrated that many commonly used medications, such as proton pump inhibitors, antidepressants and statins, alter the gut microbiota signatures141,142,143. These changes could have far-reaching consequences for the host, as they may change host metabolism and even predisposition to certain diseases144,145,146.

Most of the effects of drugs on the gut microbiota have been found to be deleterious to human health. Statins, for example, have been associated with profound remodelling of the gut microbiota and an increased risk of new-onset diabetes147. Other drugs, such as metformin, tip the balance in favour of health. Metformin use has been positively associated with an increase in Akkermansia muciniphila and several butyrate-producing bacteria148. These observations challenge the current view that metformin acts solely through improving insulin sensitivity in the liver and suggest that the gut microbiota may actively participate in the improvement of glucose metabolism. This observation is clinically important, as it implies that metformin could be used in prediabetic patients or could even provide benefits in the treatment of non-diabetic diseases149.

Taken together, determining the interactions between the gut microbiota and xenobiotics has high clinical relevance. Understanding which members of the gut microbiota are metabolically active may be crucial for predicting individualized responses to drugs and for personalized medicine139,150.


According to recent studies in both mice and humans, another important factor that modulates gut microbial composition and diversity in both the short-151 and long-term is exercise152,153. Currently, the mechanisms by which exercise causes changes in the microbiota are not fully understood, but there are probably several factors and pathways involved154 (Fig. 3). Drawing firm conclusions from many of these (human) studies is challenging because of important confounding factors, including diet and lifestyle. A recent crossover study by Allen et al.155 partially overcame this problem and provided evidence that 6 weeks of exercise altered the gut microbiota in previously sedentary lean and obese adults without any changes in dietary patterns. These effects were largely reversed once exercise training ceased. The consequences of exercise in the long term nevertheless remain unanswered.

Whether the gut microbiome can contribute to an individual’s exercise performance remains under investigation. One study comparing specific pathogen-free (SPF), germ-free (GF) and Bacteroides fragilis gnotobiotic (BF) mice found that endurance swimming times were longer for SPF and BF mice than for GF mice, and this result was associated with lower serum and hepatic glutathione peroxidase activity in GF than SPF and BF mice156. The authors concluded that the gut microbial status and its subsequent antioxidant capacity could be crucial for exercise performance. Another putative contribution of the gut microbiota might be the production of SCFAs155,157, which among other things (see above), were found to activate the 5′ AMP-activated protein kinase (AMPK) pathway, which controls various factors implicated in the metabolism of lipids and glucose in the muscle158. In addition to the AMPK genes, the microbiome has also been shown to regulate key transcriptional co-activators, transcription factors and enzymes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and SIRT1 (ref. 159). Data such as these support the hypothesis that adaptation to exercise might be influenced by the gut microbiota and that modifying its composition could be a useful therapeutic tool to improve athletic performance and general health159.

Direct effects of microbial metabolites on metabolic processes

As shown by the examples discussed in this Review, various microbial metabolites may contribute to the regulation of metabolism. Nevertheless, the first strong links between some amino acids and metabolic disorders were discovered via the use of specific methods, including metabolomic profiling of apparently healthy individuals versus individuals with disease. Indeed, pioneering work from Newgard et al.160 highlighted a positive correlation between branched-chain amino acid (BCAA)-related metabolites and insulin resistance. To decipher the molecular mechanisms, the researchers exposed rats to a HFD supplemented with BCAAs. They found that increased levels of BCAAs in skeletal muscle led to the activation of mammalian target of rapamycin (mTOR) and phosphorylation of insulin receptor substrate-1 (IRS1), resulting in impaired insulin sensitivity160. Subsequently, several studies reported a significant relationship between a higher proportion of BCAAs in the serum and the gut microbiota161,162,163. Another recent example is the link between BCAAs and Prevotella copri or Bacteroides vulgatus. It has been suggested that the presence of these specific species enhanced BCAA synthesis. Interestingly, both bacteria were also found to be enriched in insulin-resistant humans161. In addition to BCAAs, glutamate was also associated with metabolic complications. Indeed, a serum metabolomic study has indicated that obese individuals exhibited an increased glutamate level compared to lean individuals. This was correlated with a lower abundance of Bacteroides thetaiotaomicron, a gut bacterium which ferments glutamate. To prove the causality, Liu and colleagues163 force-fed mice with B. thetaiotaomicron and found that these mice were protected from diet-induced obesity and displayed a decreased plasmatic concentration of glutamate, strengthening the fact that elevation of this amino acid is negatively correlated with beneficial health. However, it is also worth noting that γ-aminobutyric acid (GABA), which is synthesized from glutamate by glutamic acid decarboxylase (GAD), might be a new potential therapeutic molecule to treat diabetes. Indeed, a long-term administration of GABA in vivo induced α cell to β-like cell conversion in the pancreas, increasing insulin secretion164. This evidence suggests that even though an elevation of glutamate is associated with negative health effects, inhibiting its production could be deleterious. For the future, it may be of interest to find a way to enhance GAD activity in β cells in the pancreas in the context of diabetes.

Gut microbiota metabolites, such as SCFAs, propionate, butyrate and succinate, also have a major role in the regulation of blood glucose level and glucose homeostasis through the regulation of intestinal gluconeogenesis21,165,166. However, it is important to point out that succinate-producing bacteria such as Prevotella copri have not only been associated with metabolic benefits but also with chronic inflammation under specific circumstances161,167,168.

Trimethylamine N-oxide (TMAO) is a bacterial-derived metabolite that has been strongly associated with cardiovascular risks in both human and animal studies162,169,170,171. Choline and l-carnitine are the major precursors of TMAO, and they are highly abundant in the Western diet, which is rich in red meat, dairy products, eggs and fish (Fig. 3). These molecules are transformed by gut microorganisms into γ-butyrobetaine (γBB) and trimethylamine (TMA), respectively. Once TMA reaches the liver, it is converted into TMAO by flavin-containing enzyme monooxygenase-3 (FMO3)172. Increasing evidence suggests that increased levels of TMAO or its precursors as well as γBB are linked with metabolic complications.

Research focusing on tryptophan-derived microbe metabolites has also expanded over the last decade173. Indeed, production of indole propionic acid (IPA) by some intestinal bacteria, such as Clostridium sporogenes and Clostridium botulinum, contributes to metabolic improvements by reinforcing the gut barrier function, enhancing the immune system, exerting anti-inflammatory effects and exhibiting antioxidant properties in animal models174,175. In humans, recent data have indicated that IPA might lower the risk of type 2 diabetes by exerting a protective effect on β cell function, resulting in increased insulin secretion. Moreover, a negative correlation has been observed between this metabolite and low-grade inflammation176,177. In light of these previous studies, indole and indole-3-acetate (I3A), two other gut microbiota-derived tryptophan molecules, are also known to modulate host metabolism by reducing liver inflammation and acting on GLP-1 secretion178,179,180. Moreover, recent data from Koh et al.181 have elegantly demonstrated that the levels of imidazole propionate are elevated in subjects with type 2 diabetes. A bacterial metabolite produced following the transformation of histidine, imidazole propionate has been shown to directly contribute to the development of insulin resistance and diabetes by blocking the insulin signalling pathway. More specifically, imidazole propionate activates the p38γ–p62–mTORC1 pathway and hence inhibits the IRS proteins, the complex mTORC1 and, in turn, insulin receptor signal transduction181.

Finally, it is important to note that the impact of metabolites derived from the gut microbiota presented in this Review are most likely only the tip of the iceberg since microorganisms produce numerous metabolites. Therefore, identification of these metabolites as well as their metabolic activities remains an attractive field of research to discover new therapeutic targets in the context of obesity and metabolic syndrome.


Over the last decade, astounding progress has been made in unravelling the role of the gut microbiota in the regulation of host metabolism and energy homeostasis. Despite the complexity and number of complementary mechanisms discovered to date, the field remains at the beginning of a new era aimed at targeting the gut microbiota to regulate energy homeostasis and health. Both nutritional and pharmacological interventions will likely provide new therapeutic opportunities in the coming years (Box 1). For nutritional interventions, the dosage of specific nutrients (for example, fibres and polyphenols) will be important for observing the effects on the gut microbiome; simple dietary interventions are unlikely to be sufficient (Box 1). That said, more translational research in humans is required to determine the most suitable type and dose of any nutritional intervention. Therefore, nutritional supplementation seems to be necessary, but appropriate guidelines are also required182, as the effective dose varies depending on the type of fibres and the expected clinical outcomes. Nevertheless, care must also be taken when proposing possible solutions based on microbial modulation to target host metabolism, such as prebiotics, probiotics and postbiotics. Evidence suggests that the solution will probably not consist of a single unique strategy to tackle such complex host metabolic processes, but rather will involve various possibilities, including combinations with conventional drug treatments183. Along these lines, it is important to acknowledge the tremendous work that has been done on probiotics and their impact, for instance, on the prevention of diarrhoea associated with antibiotics (for review and meta-analysis, see refs. 184,185,186). It is worth noting that, contrary to some recent erroneous conclusions, probiotics do not need to colonize the intestine or even change the overall microbiota in order to provide beneficial effects187,188. However, it is true that many factors must be considered when choosing the appropriate tools devoted to targeting the microbiota in view of improving health: the individual microbiota configuration, the diet, the potential drugs that may contribute to specific differences in the response to the dietary intervention and even probiotics or faecal material transplantation (FMT) (Box 1). Recent data corroborate these assumptions and have shown, for example, that the response to FMT in the context of obesity is strongly linked with the baseline microbiota composition189. The same observation has been made in a cohort of subjects exposed to specific dietary fibres and suggests that individuals harbouring a higher Prevotella/Bacteroides ratio respond to dietary fibre supplementation in terms of improved glucose metabolism190. Similarly, the response of the host to specific dietary items in terms of glucose metabolism is highly dependent on the microbiota composition and can even be used as a tool for prediction of the impact of a given diet on glucose levels191.

In conclusion, the last 15 years of research has revealed many new insights into how the microbiome affects organismal energy homeostasis. Almost all of the data indicate that future interventions and clinical studies must be approached with a personalized medicine-oriented view. There is good reason to believe that successful therapeutic interventions using the gut microbiota or targeting specific bacteria can be achieved when the initial composition of the microbiota, as well as the presence of specific microbes and their metabolic activity, is taken into account. Therefore, there is a strong hope for the emergence of gut microbiota-based therapies that modulate host metabolism to improve health.


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P.D.C. is a senior research associate at FRS-FNRS (Fonds de la Recherche Scientifique). A.E. is a research associate and MR research fellow at the FRS-FNRS. P.D.C. is a recipient of grants from FNRS, FRFS-WELBIO, under grant no. WELBIO-CR-2017-C02. This research was supported by the FRS-FNRS under The Excellence Of Science (EOS 30770923). This work is supported in part by the Funds Baillet Latour (Grant for Medical Research 2015). P.D.C. is a recipient of the POC ERC grant 2016 (European Research Council, Microbes4U_713547) and ERC Starting Grant 2013 (Starting grant 336452-ENIGMO).

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P.D.C. designed and conceived the outline of the Review. All authors have equally contributed to the writing.

Corresponding author

Correspondence to Patrice D. Cani.

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Competing interests

P.D.C. and A.E. are inventors on patent applications (PCT/EP2013/073972; PCT/EP2016/071327, PCT/EP2016/060033 filed in European Patent Office (EP), Australia (AU), Brazil (BR), Canada (CA), China (CN), Eurasian Patent Organization (EA), Israel (IL), India (IN), Hong Kong (HK), Japan (JP), South Korea (KR), Mexico (MX), New Zealand (NZ), and the United States (US)) about the therapeutic use of A. muciniphila and its components. P.D.C. is co-founder of A-Mansia biotech SA.

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Cani, P.D., Van Hul, M., Lefort, C. et al. Microbial regulation of organismal energy homeostasis. Nat Metab 1, 34–46 (2019). https://doi.org/10.1038/s42255-018-0017-4

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