Impact of the gut microbiota on inflammation, obesity, and metabolic disease

Abstract

The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.

Figures

Fig. 1

Crosstalk between the gut microbiota and the mammalian host in inflammation and metabolism. The gut microbiota can contribute to host insulin resistance, low grade inflammation, and fat deposition through a range of molecular interactions with the host and therefore can indirectly participate in the onset of obesity and metabolic diseases

Fig. 2

Metabolic and immune interactions between gut microbes and the host in obesity and the metabolic syndrome. The gut microbiota is involved in a molecular crosstalk with the host that modulates host physiology, metabolism, and inflammatory status. In particular, the gut microbiota participates in the physiology and motility of the digestive tract and in the digestion of polysaccharides, which directly influences host energy availability. The gut microbiota inhibits fasting-induced adipose factor (FIAF) in the intestine and monophosphate activated protein kinase (AMPK) in several organs such as the brain and muscle, which results in increasing fat deposition. The short-chain fatty acids (SCFAs) produced by bacteria from polysaccharides interact with G protein-coupled receptors (GPCRs; GPR41, GPR43, and GPR109A), which stimulates gut motility and host immunity. The gut microbiota also contributes to fat deposition through the regulation of the farnesoid X receptor (FXR), the bile acid receptor responsible for the regulation of bile acid synthesis and hepatic triglyceride accumulation. The gut microbiota converts choline to trimethylamine, thus influencing the bioavailability of choline for host use and indirectly affecting phosphatidylcholine production and hepatic triglyceride transport by very-low-density lipoproteins (VLDLs)

Fig. 3

Induction of inflammatory signals in proinflammatory macrophages and their connection with insulin pathways. a After translocation of gut bacteria to other tissues, the bacterial lipopolysaccharides (LPS) in the circulation and organs activate the transcription of cytokines via Toll-like receptor (TLR)4. Activated TLR4 mediates inflammatory signals involving myeloid differentiation primary response gene 88 (MyD88)-dependent pathways. The downstream responses trigger the activation of mitogen-activated protein kinase (MAPK) pathways, including those involving extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinases (JNK), p38, and inhibitor of IκB kinase complex (IKKβ). These pathways participate in the activation of transcription factors nuclear factor κB (NF-κB) and activator protein 1 (AP-1) and cytokine production. ERK1/2 and JNKs are also involved in the induction of insulin signaling pathways. b Pattern-recognition receptors such as TLR4, TLR2, and TLR8 are activated by LPS, cytokines, or lipotoxicity. The intracellular nucleotide oligomerization domain (NOD)-like receptors also recognize LPS, which leads to induction of thioredoxin-interacting protein (which is encoded by TXNIP) and recruitment of other effector molecules such as those that are components of inflammasome pathways [28]. Inflammasomes are multiprotein complexes composed of three proteins: nucleotide-binding domain leucine-rich repeat containing (NLR) protein, adaptor protein ASC, and caspase-1. Inflammasome activation contributes to the maturation of the cytokines interleukin (IL)-1β and IL-8

Fig. 4

Effects of a healthy gut microbiota and dysbiosis on the gut and metabolic health of the host. A healthy microbiota comprises a balanced representation of symbionts (bacteria with health-promoting functions) and pathobionts (bacteria that potentially induce pathology). A shift toward dysbiosis results from a decrease in symbionts and/or an increase in pathobionts and is likely to be triggered by environmental factors (such as diet, stress, antibiotics, and infections). Low bacterial gene counts have also been associated with altered gut microbial functions and dysbiosis and have been linked to increased fat accumulation, lipopolysaccharide-induced inflammation, insulin resistance, obesity, and the metabolic syndrome. Individuals with these characteristics are more likely to develop metabolic diseases (such as diabetes, cardiovascular diseases, and inflammatory bowel diseases). LBP LPS-binding protein, SCFA short-chain fatty acid