Obesity and the gut microbiota: implications of neuroendocrine and immune signaling

Abstract

Obesity is a major health challenge due to its high prevalence and associated comorbidities. The excessive intake of a diet rich in fat and sugars leads to a persistent imbalance between energy intake and energy expenditure, which increases adiposity. Here, we provide an update on relevant diet-microbe-host interactions contributing to or protecting from obesity. In particular, we focus on how unhealthy diets shape the gut microbiota and thus impact crucial intestinal neuroendocrine and immune system functions. We describe how these interactions promote dysfunction in gut-to-brain neuroendocrine pathways involved in food intake control and postprandial metabolism and elevate the intestinal proinflammatory tone, promoting obesity and metabolic complications. In addition, we provide examples of how this knowledge may inspire microbiome-based interventions, such as fecal microbiota transplants, probiotics, and biotherapeutics, to effectively combat obesity-related disorders. We also discuss the current limitations and gaps in knowledge of gut microbiota research in obesity.

Keywords: diet; enteroendocrine hormones; gut microbiota; inflammation; obesity.

Fig. 1

Crosstalk between the gut microbiota and the gut connectome in health and obesity. (A) Nutrient ligands and other molecules originated from the gut microbiota, either structural or bacterial‐derived metabolites, modify the three components of the gut connectome via membrane receptors expressed in enteroendocrine cells, enteric neurons, and sensory afferent neurons. Figure 1 shows the most relevant gut microbiota‐gut connectome interactions described in the main text. Specifically, bacterial subcellular components (PDG, LPS, flagellin, ClpB, and CpG ODN) binding to TLRs, or bacterial metabolites (indole, I3P, SCFAs, unsaturated LCFAs, and secondary BAs) binding to GPCRs expressed in EECs along the gastrointestinal tract induce secretion of hormones (CCK and ghrelin in the upper intestine, and GLP‐1, PYY in the distal intestine) or neurotransmitters (5‐HT) associated with satiety and hunger signaling. These hormones directly modulate intestinal functions such as gut motility by interacting with excitatory or inhibitory enteric motor neurons (ChAT‐ and nNOS‐expressing neurons, respectively), and also interact with vagal afferent neurons that, through the integration of signals in the NG, ultimately reach the brainstem and the hypothalamus. The brainstem and hypothalamus then coordinate responses to modulate feeding behavior and energy metabolism in peripheral tissues. The gut microbial‐induced secreted hormones also reach the brain and peripheral organs via humoral pathways to regulate energy balance. (B) Exposure to a Western diet alters how the gut microbiota influences gut neuroendocrine signaling pathways that affect energy metabolism, contributing to obesity. The altered gut microbiota induced by the intake of high‐calorie diets damages the gut barrier integrity and causes a dysfunctional enteroendocrine secretion. For example, LPS in the intestinal lumen induces rapid secretion of GLP‐1 via TLR4 expressed in L cells, suggesting a role for GLP‐1 as an intestinal pathogen and injury sensor; indeed, GLP‐1 enhances an anti‐inflammatory response by activating its receptor expressed in IELs, which in turn minimizes the release of inflammatory cytokines to locally protect against gut barrier damage in response to Western diet‐induced dysbiosis (*). Furthermore, an increased abundance of Acinetobacter induced by high‐fat diet feeding triggers endoplasmic reticulum stress in EECs and impairs postprandial PYY secretion. Abbreviations: 5‐HT, 5‐hydroxytryptamine (serotonin); ARC, arcuate nucleus of the hypothalamus; BA, bile acid; CaSR, calcium‐sensing receptor; CCK, cholecystokinin; ClpB, caseinolytic peptidase B protein; ECC, enterochromaffin cell, ER, endoplasmic reticulum; FFR2/3, free fatty acid receptors 2 and 3; GLP‐1, glucagon‐like peptide 1, GLP‐1R, GLP‐1 receptor; GPR, G protein‐coupled receptor; IAId, indole‐3‐carboxaldehyde; IEL, intraepithelial lymphocyte; LCFA, long‐chain fatty acid; LPS, lipopolysaccharide; MC4R, melanocortin 4 receptor; NG, Nodose ganglion, nNOS, nitric oxide synthase; NO, nitric oxide; NOD2, nucleotide‐binding oligomerization domain containing 2; NTS, the nucleus of the solitary tract; PDG, peptidoglycan; PYY, peptide tyrosine tyrosine; SCFA, short‐chain fatty acids; TGR5, takeda G protein‐coupled receptor 5; TLR: toll‐like receptor; trans‐UFAs: trans‐unsaturated fatty acid; TRPA1, transient receptor potential akrin1.

Fig. 2

Gut microbiota and immunity in obesity. Under normal conditions, the gut microbiota is physically separated from the host by the presence of a thick layer of mucus and a continuous barrier of tightly packed epithelial cells. In addition, there is a balanced dialog between the host immune system and the gut microbiota that prevents colonization and overgrowth of potential pathogens through the release of secretory IgA and AMPs, while promoting anti‐inflammatory and tolerogenic responses, such as those mediated by IL‐22 and IL‐10. By contrast, obesogenic diets profoundly alter the function and composition of the gut microbiota and the immune system through a loss of microbial diversity and an increase in opportunistic bacterial species, pro‐inflammatory products (such as LPS) and metabolites (such as TMAO). Additionally, there is a shift in the intestinal inflammatory potential characterized by an increase in pro‐inflammatory cell subsets (Th1, CD8 T cells, ILC1s and pro‐inflammatory M1 macrophages), the impairment of AMPs and IgA production, and a decrease in regulatory cell subsets, such Treg, ILC3 or Th17. These changes contribute to the breakdown of the mucus barrier and the tight junctions between epithelial cells, ultimately leading to intestinal leakage. Overall, this leads to a breakdown in intestinal homeostasis, which leads to systemic inflammation and contributes to metabolic failure. AhR, aryl hydrocarbon receptor; BAs, bile acids; EEC, enteroendocrine cell; FAs, fatty acids; IgA, immunoglobulin A; ILCs, innate lymphoid cells; LPS, lipopolysaccharide; SCFAs, short‐chain fatty acids; Th, T helper cells; TMAO, trimethylamine‐N‐oxide; Tregs, T regulatory cells. Figure was generated with BioRender.

Fig. 3

Microbiome‐based strategies for obesity management. Microbiota manipulation through different approaches has been investigated to prevent or mitigate obesity‐related complications. These approaches include (i) Fecal microbiota transplantation (FMT) from healthy donors to subjects with metabolic alterations to replace the gut microbiota as a whole; (ii) FMT combined with daily supplementation of fiber to enhance the response to the microbiota replacement; (iii) administration of specific intestinal bacteria (probiotics or live biotherapeutics), which are depleted in obese subjects and positively associated with a healthy metabolic phenotype in epidemiological studies and could contribute to the gain or loss of crucial functions for restoring energy homeostasis; (iv) probiotics or live biotherapeutics combined with fibers (synbiotics) that act as nutrient sources for the bacteria potentiating their metabolic activities and may also exert independent effects on metabolism (reducing lipid absorption and glycemia). The modes of action of bacteria evaluated in obesity models include their ability to restore the mucus layer and the gut barrier (GLP‐2), reduce inflammation, and improve enteroendocrine hormone secretion (GLP1, PYY) that regulate glucose metabolism and appetite, which overall explain their contribution to reduced diet‐induced adiposity and body weight. BMI, body mass index; FMT, fecal microbiota transplantation; GLP‐1, glucagon‐like peptide 1; HOMA‐IR, insulin resistance index homeostatic model assessment; PYY, peptide YY. Figure was generated with BioRender.