Endogenous intestinal microflora and environmental factors, such as diet, play a central role in immune homeostasis and reactivity. In addition, microflora and diet both influence body weight and insulin-resistance, notably through an action on adipose cells. Moreover, it is known since a long time that any disturbance in metabolism, like obesity, is associated with immune alteration, for example, inflammation. The purpose of this review is to provide an update on how nutrients-derived factors (mostly focusing on fatty acids and glucose) impact the innate and acquired immune systems, including the gut immune system and its associated bacterial flora. We will try to show the reader how the highly energy-demanding immune cells use glucose as a main source of fuel in a way similar to that of insulin-responsive adipose tissue and how Toll-like receptors (TLRs) of the innate immune system, which are found on immune cells, intestinal cells, and adipocytes, are presently viewed as essential actors in the complex balance ensuring bodily immune and metabolic health. Understanding more about these links will surely help to study and understand in a more fundamental way the common observation that eating healthy will keep you and your immune system healthy.
The relationship between nutrition and the immune system has been a topic of study for much of the 20th century. Consequently, the dramatic increases in the understanding of the organization of the immune system and the factors that regulate immune function have supported the close concordance between host nutritional status and immunity.
Classically, the mammalian immune system consists of innate and adaptive mechanisms that protect the host from environmental pathogens. Innate mechanisms function independently of previous exposure of the host to the infectious agent, and include mechanical barriers (e.g., skin, mucosal epithelium) and cellular components (e.g., mostly macrophages and neutrophils). In contrast to the innate immune system, the cellular (e.g., mostly B- and T-lymphocytes) and molecular basis of adaptive mechanisms relies on specific recognition of the invading agent and, like innate immunity, leads to the generation of immunological memory, that is, a property whereby an individual, after contacting an antigen for the first time, acquired the capacity to respond better and quicker upon reexposure to the same antigen.
Both innate and adaptive mechanisms are based on the general process of “immune recognition,” which has always been one of the main points of interest in immunology. For innate immunity, recognition is based on the use of germline-encoded receptors, whereas in adaptive immunity it involves somatically generated receptors. Nevertheless, beyond the different genetic nature of the receptors, the distinction between the two types of immune recognition—although useful in many ways—may obscure the heterogeneity of receptors and mechanisms of innate immune recognition.
The more recent advances in the field strongly suggest that the separation between innate and adaptive immunity may be too simplistic, notably at the cellular level. The actual concept is based on the existence of a continuum of immune cell populations highlighting the complex interplay between diverse cells of both innate and adaptive immune responses.
Below we will review the most recent findings in the field, focusing on the TLRs, which are now known to be the key regulators of both innate and adaptive immunities. Interestingly, we will indicate how the same TLRs have been reported to participate in metabolic integrity of a healthy individual.
As mentioned above, the innate immune system allows a first-line protection to a broad variety of environmental pathogens independent of previous exposure to the infectious agent. It responds quickly and without memory capability, as opposed to adaptive immunity.
The innate immune system, through germline-encoded receptors, recognizes a limited set of conserved components of bacteria, parasites, fungi, or viruses, known as “pathogen-associated molecular patterns” (PAMPs). These receptors have therefore been called “pattern recognition receptors” (PRRs). Host cells express various PRRs that sense diverse PAMPs, ranging from lipids, lipopolysaccharides, lipoproteins, proteins,
and nucleic acids. Recognition of these PAMPs by PRRs results in the activation
of intracellular signaling pathways that culminate in the production of
inflammatory cytokines, chemokines, or interferons, thus alerting the organism
to the presence of infection [
Amongst others, PRRs include the members of the TLRs family [
To date, the best characterized PRRs are the TLRs, a family of transmembrane receptors, the ligand-binding leucin-rich repeat domains of which interact with extracellular or membrane-enclosed (i.e., endosomal) intracellular PAMPs. Remarkably,
TLRs are evolutionary conserved from plants to vertebrates. In mammals, 13 TLRs
have been identified so far: 10 human (TLR1-10) and 12 murine (TLR1-9 and
11–13) receptors, of which some are homologous [
TLRs are broadly expressed in cells of
the innate immune system such as macrophages, epithelial and endothelial cells,
and in organ parenchyma cells, and have therefore specific roles in local
innate immune defense [
Besides this first line of host defense towards microbial infections, the adaptive immune system is elicited later (around 4 to 7 days post-infection) and includes a specific and long-lasting immunity that is based on the rearrangement and the clonal expansion of a vast and random repertoire of antigen-specific receptors expressed on B- and T-lymphocytes (resp., B cell receptor: BCR and T cell receptor: TCR).
Interestingly, various TLRs are also expressed in cells of the adaptive immune system including B cells, mast cells, T cells, and dendritic cells (DCs), which are the key cells initiating the adaptive immune response. Indeed, TLR signals induce DC differentiation and cytokine production, consequently influencing the outcome of their interactions with T cells and therefore the subsequent development of the adaptive immune responses [
Therefore, in addition to cells of the innate immune system, cells of the adaptive immune response, notably T- or B-lymphocytes and dendritic cells, express certain TLRs and respond directly to corresponding ligands in concert with TCR or BCR signals of lymphocytes. Thus in addition to their well-described role in innate immunity, TLRs are also crucial in shaping the adaptive immune response from its initiation to the development of immunological memory.
Human and other mammalian mucosal surfaces are colonized by a vast, complex, and dynamic bacterial community. In human, the number of microbes associated with mucosal
surfaces exceeds by 10 times the total number of body cells. This microbiota is
constituted of more than 400 species, the collective genome of which being
estimated to contain 100 times more genes than the human genome [
The intestinal flora plays an important role in normal gut function and maintenance of the host’s health. It is established almost immediately after birth and is now
considered to be essential in priming the immune system during ontogeny and in
the development and maturation of both mucosal and systemic immune systems [
The microbiota is composed of potentially pathogenic bacteria besides numerous health-promoting nonpathogenic microorganisms.
To control the resident colonizing microflora, as well as to fight pathogens, the
human body has developed a variety
of host defense mechanisms that in most cases effectively prevent the development of
invasive microbial diseases [cf. Sections
Most interestingly, it was recently suggested that disruption of the
mucosal barrier leads to the exposure of a multitude of commensal-derived TLR
ligands that could interact with TLRs-expressing immune cells, consequently
leading to potent inflammatory responses [
Paradoxically, nonpathogenic bacteria are thought to contribute to immune homeostasis, not only by maintaining microbial equilibrium but also by regulating the gut immune system. Indeed, commensal bacteria may directly influence the intestinal
epithelium to limit immune activation. As mentioned before
(cf. Section
Recent findings also reported a novel
function of TLR signaling in intestinal homeostasis. Using knock-out mice,
Rakoff-Nahoum et al. [
Besides TLRs, other PRRs have recently been shown to be involved in these processes, notably members of the NOD-like receptor (NLR) family. NLRs can detect bacterial components such as muramyldipeptide (MDP) (recognized by NOD-2) and muropeptides containing mesodiaminopimelic acid (recognized by NOD-1).
It is known that NOD
signaling involves the activation of NFκB pathway, but surprisingly,
mutations in the
It is now well accepted that homeostasis versus chronic intestinal inflammation is
determined by the presence or absence of appropriate control mechanisms that
could be linked to a balance between protective (“good”) and aggressive (“bad”)
luminal bacteria. Indeed, recent findings reported notable influence of the
microbiota composition on the incidence of emerging pathologies such as
inflammatory bowel diseases (IBD) and obesity. Metagenomic analysis indicates
that the microflora of IBD patients is unstable and presents a reduced
complexity of the bacterial phylum Firmicutes. Conversely, a shift in the ratio
of Bacteroidetes to Firmicutes has been observed in obese patients as well as
in leptin-deficient obese mice (
Interestingly, in addition to playing a crucial role in immunity, some of the mammalian TLRs have been described to regulate bodily energy metabolism, mostly through acting on adipose tissue. This has recently opened new avenues of research on the role of TLRs in pathologies related to metabolism, such as obesity, insulin resistance, or atherosclerosis.
As previously discussed (Section
Starting from these observations, Lee and collaborators postulated in 2001 that fatty acids could possibly directly modulate TLR activation and expression of target gene products [
Compared to TLR4, the direct interaction of TLR2 with lipids is less documented, but the existence of a link between lipids and TLR2-signaling has been suggested.
Activation of TLR2 is mainly involved in promoting vascular inflammation and
the development of the atherosclerotic plaque. Inactivation of TLR2 expression
by knockout technology was shown to protect atherosclerosis-susceptible mice
from the development of disease [
In conclusion, beside its primary function in alerting the immune system to the presence of pathogenic microorganisms, TLRs could also sense pathological levels of lipids. In this context, it is interesting to notice that LPS presented an anorexigenic
effect that was blunted in TLR4-deficient mice [
TLRs are widely distributed in the body
notably in the brain where these receptors are expressed by glial cells [
Insights obtained over the last years
have shown adipose tissue to be a true immunocompetent organ and adipocytes as
intricate components of the innate immune system. Indeed, adipocytes produce
numerous inflammatory molecules such as IL-6 or TNF-
An additional similarity between adipocytes and macrophages was further revealed with the reporting of the expression of TLR4 (the TLR mostly known to sense LPS) by the murine preadipose cell line 3T3-L1 [
The observations summed up above may indicate that the triad “adipocyte-macrophage-TLR4” might be involved in the inflammatory process occurring in obesity. Indeed in the obese state, a marked infiltration of macrophages is observed within the adipose tissue. Suganami et al. showed that lipolysis and proinflammatory cytokine production were reduced when adipocytes isolated from obese mice were cocultured with
TLR4-deficient macrophages, compared to wild-type macrophages [
This seems to be the
case, since mice genetically deficient in TLR4 or in CD14 (a coreceptor for
TLR4) were reported to be of “ideal body type” when fed on regular chow, having
increased bone mineral content, density, and size, as well as decreased body
fat [
However, this approach has to be
considered with caution since contradictory results have been obtained with
high-fat-fed TLR4-deficient mice. Indeed, while some reports described no
effect on body weight [
Along the same lines another PRR, known as receptor of advanced glycation end products (RAGE), has recently been put in the spotlight. The interaction between RAGE and its ligands, advanced glycation end products (AGEs) such as lipids and nucleic
acids resulting from oxidative stress and hyperglycemia [
Despite the apparent independence between the fields of immunology and nutrition, myriad observations, some quite old and some quite new, clearly show that the immune system cannot function under circumstances of malnutrition, whether over- or undernutrition [
Indeed, lipids consumed in the diet (e.g., fatty acids, cholesterol, or fat-soluble vitamins), glucose, or oligoelements (e.g., zinc, copper, and iron) deeply affect the immune system. Revealing this strong dependence of the immune system upon nutrition, is the fact that nutritional deficiencies are presently considered to be the most common cause of secondary immunodeficiencies in humans.
Historically, the model of zinc-deficiency states as the best characterized nutritional-immunological paradigm. Zinc-deficiency was shown to impact on B-cell lymphopoiesis and to induce potent atrophy of the thymus, subsequently leading to a decline in the number of peripheral T-lymphocytes, both in a murine model of zinc deficiency and in zinc-deficient humans [
Considering the influence of dietary lipids on immune function, it is rather surprising that this relation was only seriously investigated during the past two decades. It is clear from whole-animal studies that obesity and consumption of high fat-diets, particularly saturated fat, depress both innate and adaptive immunocompetences by affecting the activity of immune cells such as macrophages, dendritic cells, or T lymphocytes, thereby enhancing the risk for serious infection and cancers.
The relationship between lipids and immune response is complex, multifactorial, and still poorly understood. Beside individual susceptibility, linked to genetic
factors, the deleterious effect of fat depends largely on the quantity and the
quality of the lipid species consumed. Classically, saturated fatty acids are
presented as “bad lipids” by increasing total cholesterol and as being
associated with inflammation and increased cardiovascular events. In contrast,
unsaturated fats and particularly omega-3 fatty acids are considered to be “good
lipids” by decreasing cholesterol and by preventing adverse symptoms of
metabolic syndrome such as insulin resistance and inflammation. Exhaustive
reviews treating the effects of fat ingestion on molecular and cellular aspects
of immunity have been published [
Besides modulation of immune responses via interactions with Toll-like receptors at the surface of immune cells (see Section
In case of a foreign attack, energy needs to be delivered very rapidly, allowing an immediate reaction of the body. An essential contribution of the adipose tissue is then to supply immune cells with fatty acids, which will serve as fuel, as well as
lipid-based messenger molecules. Indeed, arachidonic acid and
docohexanoic acid, two lipid-derived messenger molecules originating from
polyunsaturated fatty acids (PUFAs), are key factors in innate immune
processes, since they are the precursors for prostaglandins and leukotrienes,
both largely involved in inflammation [
Moreover, lipids are major components of cell membranes, and combinational
associations of different lipid species will generate microheterogeneity in cell
membranes, leading to the formation of microdomains, termed rafts [
As we will describe in the last section
(cf. Section
The immune system—both innate and adaptive—is essential to prevent or limit infection but is equally important in the overall process of repair and recovery from any type of injury. As described in
Section
Indeed, early studies using lymphocytes stimulated with B- or T-specific mitogens (such as pokeweed mitogen (for B cells), concanavalin-A, or phytohemagglutinin-A (for T cells)) revealed the importance of glucose uptake and catabolism in providing energy for their proliferative, biosynthetic, and secretory activities [
Later, the crucial role of glucose in lymphocyte activation was also reported to be expandable to cells of the innate immune system like macrophages [
To conclude, generating an efficient and effective immune response involves large increases in cellular proliferative, biosynthetic, and secretory activities, processes which all require high energy consumption. As mentioned, adaptive as well as innate immune cells must be able to rapidly respond to the presence of pathogens, shifting from a quiescent phenotype to a highly active state within hours after stimulation. For that purpose, cells must dramatically alter their metabolism in order to support these increased synthetic activities based on extracellular signals as fuels, amongst which glucose is the most essential one.
Lymphocyte development is tightly controlled, starting from multipotent medullary progenitors to mature lymphoid cells in the periphery. For T cell lineages, that were more extensively studied for their glucose metabolism than the B-cell lineages, a crucial checkpoint in T-lymphocyte development occurs in the thymus where the Notch and the IL-7 receptor (IL-7R) signaling pathways both maintain cell viability and promote thymocyte differentiation [
Interestingly,
it was recently reported that increased extracellular concentrations of glucose
can protect neutrophils from apoptotic death and that this protective effect is
correlated with the rate of glucose utilization by the cells [
Recently, a combination of independent and complementary studies has provided molecular insights into the regulation of energy metabolism in immune cells, involving the coordination by signal transduction pathways which act directly onto the modulation of nutrient uptake and metabolism.
First of all, both the major glucose-transporter (GLUT) proteins and the insulin receptor (InsR) were shown to be expressed on immune cells (e.g., monocytes/macrophages, neutrophils, and B- and T-lymphocytes) [
The pattern of GLUT upregulation differs
among different types of immune cells. For example, differentiation of
monocytes to macrophages is associated with an increased expression of GLUT3
and GLUT5, even if their precise physiological role in macrophages still
remains uncertain [
In addition to the increased expression
of GLUT isoforms upon immune stimulation (i.e., by mitogen or LPS),
insulin withdrawal on immune cells was also reported to modulate GLUT
expression, notably GLUT3 and GLUT4. It has been proposed that expression of
the Insulin receptor is essential for immune cell division, size, and survival
[
Secondly,
regarding the signaling pathways that modulate the glucose uptake and
metabolism of immune cells, it was reported before that treatment of
B- or T-cells with inhibitors of phosphatidylinositol3-kinase (PI3-K) blunted the
ongoing increase in cell size, and therefore the subsequent proliferation,
probably as a result of a block at a critical early growth checkpoint [
In T cells, it is known that ligation of
the costimulatory receptor CD28 activates the PI3-K/Akt pathway [
The precise signaling mechanisms by which
growth factors or cytokines (glucose, insulin, and IL-7 as the most important
ones) prevent atrophy and promote cellular metabolism in immune cells still
remain uncertain. Nevertheless, PI3-K and mammalian target of rapamycin (mTOR)
have been shown to simulate cellular metabolism and are activated by a variety
of growth stimuli such as glucose, insulin, and IL-7. PI3-K and its downstream signaling molecule Akt can promote glucose uptake and metabolism [
Regarding IL-7, an immune cytokine
essential for survival, cell size, and T cell activation, it was shown to
maintain glucose metabolism in vitro. Indeed, the addition of IL-7 to T cell
cultures was found to be sufficient to maintain glucose metabolism to
approximately normal levels. In addition, like for insulin/glucose, the trophic
effect of IL-7 requires PI3-K and mTOR activities [
In conclusion, when considering the signaling pathways involved in glucose metabolism in immune cells, it is generally accepted that glucose uptake and metabolism are promoted by PI3-K and its downstream signaling molecule Akt (both in T- and B-lymphocytes). mTOR appears to be more critical in favoring efficient protein translation and inhibiting protein degradation. Interestingly, the crucial role of IL-7 on T-lymphocyte homeostasis (in mice and human)—known for a long time—was demonstrated to depend upon these metabolic pathways since IL-7, alike insulin, promotes T cell survival and size in a PI3-K/Akt and mTOR-dependent manner.
After having described the intricate relations between the immune system, selected nutrients such as glucose or lipids, and the endogenous microflora, we will illustrate below how malnutrition (mostly overnutrition) can affect immunocompetence.
The incidence of obesity and associated
comorbidities—such as type 2 diabetes, insulin resistance, and cardiovascular
diseases—is reaching worldwide epidemic proportions [
After a meal, fatty acids and glucose enter the blood. As shown above, both factors greatly influence immune homeostasis and reactivity. In obesity, the body is literally soaked in excess fat and glucose, likely participating to the profound alterations of immune responsiveness—innate and adaptive—occurring in the obese state.
Indeed, macrophages
accumulated proportionally to adipocyte size and numbers within the white
adipose tissue of obese mice. In addition, macrophages from this “obese adipose
tissue” displayed impaired functionality with a reduced phagocytic capacity and
a defective oxidative burst [
This marked impairment of the immune
system associated with human obesity has also been reported in several animal
models. Obese dogs have a decreased capacity to resist
Finally, obesity is also characterized by
an imbalance of the cytokine network, resulting in a low-grade systemic
inflammatory status described in both obese humans and animals [
Thus, obesity is presently viewed as an
inflammatory disease, referred to as “obesitis,” affecting both innate and acquired
immune systems [
Although many research groups have
studied the immune system of obese individuals or animals, there is still
scarce information regarding the effects of obesity on dendritic cells (DCs),
despite their essential role in innate immunity and in the induction and
regulation of antigen-specific adaptive responses [
Therefore, we
recently characterized DCs in the model of obese leptin-deficient
Among these immune alterations, we demonstrated that
despite displaying normal phenotypic and functional characteristics, both
homeostasis and functionality of DCs were disturbed in
Along those lines, we also reported the impairment of immune cells as a consequence of high fat diet- (HFD-) induced weight gain (a more physiological model of obesity
than the
Altogether, we demonstrated for the first time that the immune deficiency observed in leptin-deficient obese mice, and maybe in other types of obesity, was associated with an impairment of dendritic-cell function, the key immune cell that bridges innate and adaptive immunities.
As stated in the introduction to
this last section, fat and glucose controls are linked: obese people develop
insulin resistance and then diabetes, conditions in which glucose uptake and
production are impaired due to defective insulin action [
In diabetes, where
insulin action is defective and hyperglycemia chronic, immune T cell
functionality is impaired with reduced ability to produce IL-2 [
Nevertheless, despite the fact that increased susceptibility to infections affects the morbidity and mortality of diabetic patients—which is of critical clinical importance—little is known about how diabetes precisely impair immunity. Regarding the essential role played by glucose and insulin on immune cells, variations in their levels which occur in diabetes are most likely involved in immune disorders associated with this trait.
As previously described (cf. Section
As indicated
above, the assembly of the gut microflora commences at birth and its
composition will undergo dramatic changes during postnatal development. When
space and nutrients are not limited, commensals with high division rates will
predominate. As the population increases and nutrients are depleted, niches
become occupied with more specialized species [
Diet is clearly a key factor which
regulates the sequence and the nature of colonization. In breast-fed infants,
the intestinal flora is dominated by bifidobacteria, while formula-fed infants
have a more diverse flora [
Although the composition of the microbiota varies along the length of the gut and during the life of the host, it is quite stable during a considerable part of a normal human lifespan.
Recent metagenomic studies, however, showed that the microbial balance is
altered in some immune disorders. Notably, a significant reduction in the
diversity of the phyla Firmicutes has been reported in patients with Crohn’s
disease (CD). While 43 distinct ribotypes of Firmicutes were identified in
healthy microbiota, only 13 ribotypes were detected in CD patients, indicating
a serious degree of microbial dysbiosis [
Given the
worldwide epidemic in obesity, there is a growing interest concerning the
interaction of the microbiota with the host in obese state. Previous
experiments showed that colonization
of the gut of germ-free mice with microbiota isolated from conventional animals
led to a dramatic increase of 42% in body fat within 10–14 days, despite
decreasing food consumption. Along the same lines, it was later shown that colonization of germ-free mice with an obese microbiota resulted in
a significant greater increase in total body fat than colonization with a lean
microbiota [
Interestingly, similar results were
reported in obese patients showing a decrease in the relative proportion of
Bacteroidetes as compared to lean individuals [
All these studies suggest that the obese state is associated with modifications in microbiota composition and that changes in microbial fermentation of dietary polyssacharides will influence intestinal absorption of monosaccharides and short-chain fatty acids and consequently their conversion to more complex lipids in the liver and deposit of lipids in adipocytes.
Individual human health is determined by
a complex interplay between genes, environment, diet, lifestyle, and symbiotic
gut microbial activity. Recognition of the interplay between genes and diet in
the development of certain diseases and for maintenance of optimal metabolism
has led to nutrigenomic or nutrigenetic approaches. These might allow to
propose personalized or individualized nutrition in order to prevent, delay,
and/or reduce the symptoms of some chronic diseases [
The human microbiome project [
The
demonstration of the importance of human gut microbiota in health restoration
and maintenance has kindled an interest in probiotics, defined as microbial
food supplements which beneficially affect the host by improving its intestinal
microbial balance. It is now well accepted that supplemented probiotic bacteria
might have the capacity to improve the functions of both the innate immune
system and the gut physiology. Indeed,
regular intake of probiotic bacteria has been shown to maintain the gut immune
homeostasis by altering microbial balance or by interacting with the gut immune
system, explaining their potential effect in gastrointestinal diseases.
Probiotics have proven benefits in treatment or prevention of certain type of
diarrhea [
Regarding
obesity, only few studies have addressed the potential effects of probiotics in
the management of this disease. Since obesity is presently viewed as an
inflammatory disease, affecting both innate and acquired immune systems [
From the limited, yet convincing, studies performed so far, one can predict that nutrigenomics will improve our knowledge on the function of gut microbiota and allow therapeutic manipulation of the gut ecosystem to become a valid and realistic future prospect.
The rapid rise in the numbers of obese patients, partly due to a lifestyle that promotes overeating and inactivity, is presently a critically important health issue worldwide. Obesity is associated with a number of diseases collectively summarized as the “metabolic syndrome,” involving insulin resistance, type 2 diabetes, and cardiovascular diseases.
Although obesity results from complex and multiple interactions between genetic and environmental factors, numerous studies provide strong corroborative evidences that overnutrition can promote metabolic diseases.
Like other chronic disorders of metabolic homeostasis, we showed that obesity is also associated with immune disbalances, involving low but chronic level of inflammation, as well as infiltration of adipose tissue with activated macrophages.
It has been proposed that chronic activation of the innate immune system could be regarded as a possible risk factor in the development of obesity and its associated inflammation. Indeed, signaling receptors of the innate immune system (such as TLRs) induce signal transduction pathways that lead to the activation of transcription factors which are also activated in response to proinflammatory cytokines and which ultimately suppress the insulin signaling pathway. Therefore innate immunity, in addition to its immediate response to pathogens, may also be involved in whole-body and organ-specific insulin sensitivity as well as in the regulation of the energy balance. Interestingly TLRs, notably TLR4, expressed on both innate and adaptive immune cells, are also found on cells of insulin-responsive tissue such as adipocytes. TLRs may therefore represent a potential molecular gate linking inflammation with insulin resistance, diabetes, and obesity.
The second aspect developed in this review concerns the critical importance of the gut microbiota in the development of metabolic diseases, particularly obesity. As described, this hypothesis started with the fascinating observation that young adult germ-free mice had only half of the body fat of their conventional counterparts receiving the same diet. We attempted to compile the numerous benefits that arise from a healthy intestinal microbiota (extraction of nutriments from food; participation in the development and maturation of the gut immune system, and regulation of fat storage within adipocytes) and discussed the potential role of a disturbed flora in metabolic disorders such as obesity. Again, TLRs appeared to be the link between nutrition, microbiota, and inflammation.
Finally, we showed that immune cells, both from the innate and adaptive
immune systems, express TLRs and that immune responses depend on a critical
increase in energy requirements, preferably met by glucose. Such observations
allow to deduce a quasi parallel between lymphocyte glucose metabolism and
bodily metabolism mostly via the insulin signaling pathway, and
reinforce the link between nutrition, immune system, energy metabolism, and gut
microbiota, resumed in Figure
After a meal, fatty acids and glucose, through intestinal absorption, enter the blood. Both serve as fuels for cells or tissues, glucose being the most important to fulfill the energy requirement of immune cells, and lipids representing major components of cell membranes. Besides, food-derived fatty acids, as well as intestinal bacteria-derived fatty acids could be sensed by Toll-like receptors (TLRs) which are expressed on immune cells, adipocytes or intestinal gut, resulting in activation of the immune system. Depending on the intensity, the time lasting, and the control of these events, it will either favor the development of an efficient immune defense, or lead to a drift towards metabolic diseases such as obesity.