Obesity: More Than an Inflammatory, an Infectious Disease?

Abstract

Much is discussed if obesity or diet components modify the “healthy” microbiota or if microbiota modifications trigger events that culminate in obesity. This association is probably reciprocal, and inflammation has crucial participation on it. We will discuss recent studies showing gut microbiome as an obesogenic factor and the mechanisms linked to the associated of diet, microbiota, and low-grade inflammation. Obesity is a growing epidemy, despite the efforts to contain it. The inflammation generated by the adipocyte hypertrophy and hyperplasia initiates crosstalk between adipocyte and resident macrophage (M2) in white adipose tissue (WAT). Once activated, both adipocyte and activated macrophage (M1) release several adipokines that trigger the infiltration of other immune cells such as neutrophils, CD8+ and CD4+ T cells (1). Tissue-resident innate lymphocytes also play an important role in the homeostasis of WAT and, consequently, in obesity. Although this resident lymphocyte plays regulatory and anti-inflammatory properties in non-obese individuals, obesity promotes changes in the profile of these cells (2). Invariant Natural Killer cells (iNKT) and mucosal-associated invariant T cells (MAIT) are important examples. The frequency of iNKT is reduced in WAT in obesity and is inversely related to the degree of obesity, insulin resistance and fasting blood glucose, suggesting that these cells play a role against metabolic disorders associated with obesity (1, 2). MAIT cells also present reduced frequency and change of phenotype in WAT in obesity, reducing IL-10 synthesis and gamma interferon (IFNγ) and increasing IL-17 production (1, 2) and can play an important role in the progression of inflammation (3). Adipocytes also produce macrophage colony-stimulating factor (M-CSF-1), causing an increased influx of monocytes from bone marrow-derived precursors and regulating macrophage differentiation and survival (4, 5). The expanded WAT also secrets pro-inflammatory and prothrombotic factors such as interleukin (IL)-1β, IL-6, tumoral necrosis factor (TNF), monocytes and macrophages chemoattractant protein (MCP-1/CCL2), C-reactive protein (CRP), tissue factor and factor VII, plasminogen activator inhibitor type-1 (PAI-1) (6). This pro-inflammatory, prothrombotic environment contributes to the onset of obesity-related complications such as metabolic syndrome, insulin resistance, hypertension, and systemic sterile inflammation. One of the first studies linking obesity and microbiota was conducted by Ley et al. (7), showing that obesity is associated with a specific microbiota profile. The gut microbiota of healthy individuals is mostly composed of Firmicutes (70%) and the Bacteroidetes (30%). Other minor phyla are Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia (8). The genetically obese ob/ob mice have in their microbiota 50% fewer Bacterioidetes and a higher proportion of Firmicutes when compared to lean mice. This altered ratio between Firmicutes and Bacteroidetes (F/B ratio) has also been described in obese individuals (9). Nonetheless, obesity in adulthood is influenced by several factors besides the different profiles of gut microbiota and, until now, studies have not found enough consistency to point out specific obesogenic bacteria (10). However, preclinical studies revealed that the obesogenic microbiota profile could be transmitted from twins discordant for obesity to germ-free (GF) mice. When the fecal microbiota of the obese twin is transplanted to GF mice, the mice eventually become obese, the same occurring with the transplantation of microbiota from the lean twin to GF mice. Moreover, obesity was prevented when mice carrying the obese twin's microbiota were kept in the same cage with mice carrying the lean twin's microbiota (11). The influence of microbiota on obesity development and low-grade inflammation seems to occur even before or immediately after birth. The gut-associated lymphoid tissues (GALT) are formed during embryogenesis and become mature during the microbial colonization, after birth. Bacterial antigens were recognized by the intestinal epithelium via pattern recognition receptors (PRR), such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 1 (NOD-1) (12, 13). Changes in the microbial composition, which occur in the presence of obesity, disrupt the barrier integrity promoted by GALT, increase the intestinal permeability, favor bacterial translocation that triggers the inflammatory process (14). Maternal obesity, caesarian section (CS), infections, and antibiotic utilization were described as factors influencing obesity (15) (Figure 1). Antibiotic therapy in the perinatal period is associated with intestinal microbiota disruption and metabolic changes sufficiently strong to affect body composition in late childhood (16, 17). Indeed, babies from mothers receiving antibiotics during the last gestational trimester presented an 84% higher risk of obesity (16). Moreover, CS is associated with the reduction in Bacteroidetes abundance and microbiota diversity in the first 2 years of life. Systemic levels of CXCL10 and CXCL11 chemokines were also reduced in children born by CS (17). Young adults born by CS have a higher risk for increased central and peripheral adiposity than those born by vaginal delivery (18). These associations are stronger in children whose mothers were obese compared to children of non-obese mothers (19). Figure 1. An overview of the relationships described in this opinion paper. An obesogenic profile (characterized by a very high Firmicutes/Bacteroidetes ratio, F/B) can be caused in the fetus by conditions such as maternal obesity, caesarian section, infections, or antibiotics treatments during pregnancy. The immune and pro-inflammatory response caused by intestinal dysbiosis over life can...