Reductions in microbiota that produce short-chain fatty acids (SCFA) were evident in obesity, including Alistipes species and Odoribacter splanchnicus. Depleted concentrations of Akkermansia muciniphila and Bifidobacterium longum, microbiota associated with intestinal gut barrier integrity were also observed.
A subsequent 2022 study published in Frontiers in Endocrinology also revealed reduced microbial diversity in obese individuals, with an increase in the Firmicutes to Bacteroidetes ratio.
Based on these findings, researchers theorize the loss of microbial diversity in obesity may be responsible for impeded homeostatic functions observed. This further underscores the vast regulatory functions of the collective microbiome. Altered microbiota composition is indicated to play a role in obesity by disrupting metabolism, lipogenesis, and gut-brain signaling that regulate appetite and satiety, as well as inducing chronic inflammation in the body.
Microbiota modulate metabolism, adipose tissue, appetite and food reward signaling— all having important roles in obesity as further evidenced in a 2022 review published in The Journal of Clinical Laboratory Analysis.
A growing body of research supports the bidirectional signaling of the gut-brain axis (GBA) in the pathophysiology of obesity. The GBA has been implicated to modulate metabolic, neuroendocrine, and immune system mechanisms relative to obesity. Alterations in neuromodulators such as serotonin and dopamine have been observed in obese individuals, in addition to GABA.
Dysregulation of hormone signaling pathways involved in reward circuitry relative to feeding behaviors in the hypothalamus–pituitary–adrenal (HPA) axis have also been evidenced to play a role in obesity; including disruptions in ghrelin, leptin and CCK.
A 2023 review published in Current Gastroenterology Report also demonstrated that altered gut microbial composition in obesity was associated with increased intestinal permeability, which can impair immune function and produce inflammatory molecules such as lipopolysaccharides (LPS) and toxins into the system; this is also suggested to have a role in the development of obesity-associated insulin resistance (IR). The chronic inflammatory response in obesity is also suggested to occur as a result of excess adipose tissue.
Immunological pathways have been shown to be altered in obesity through these inflammatory mechanisms, which have extensive homeostatic functions in the body. Obesity impedes immune functioning by altering cell-mediated immune responses and white cell counts. Excess adipose tissue, stimulation of lipolysis and dietary factors have all been indicated to trigger systemic inflammation in the body, stimulating the expression of inflammatory genes, while activating immune cells.
Obesity activates both the innate and adaptive arms of the immune system, causing alterations in immune function. The adaptive immune system forms an innate memory of metabolic signals in obesity. Over time, the altered inflammatory and metabolic conditions associated with obesity interfere with the immune system’s ability to function efficiently and mount appropriate immune responses.
Reactive oxygen species (ROS) from environmental toxins and ultra processed foods have also been shown to induce tissue-specific alterations, including insulin secretion and systemic inflammation. Food additives and environmental toxins contribute to obesity through alterations in the composition and activity of the gut microbiota and impairing immune function.
Processed foods have also been demonstrated to impede the mucosal lining of the gut, thereby disrupting signaling pathways. This can also result in altered intestinal permeability and inflammation which can further compromise the immune system.
Titanium dioxide, a chemical found in a number of processed foods, has been exhibited to have immune compromising properties, while also inducing inflammation. This is suggested to be related to the ability of TiO2 nanoparticles (NPs) to cross biological barriers in the body, and therefore accumulate in various systemic organs, including the pancreas, liver and spleen—further impeding overall metabolic and immune health.
A 2024 review underscores the need for more nuanced treatment modalities for obesity, such as addressing modifications in microbiota and immune functions. Fecal microbiota transplants (FMT) have emerged as promising treatments for obesity.
A 2023 systematic review and meta-analysis aimed to investigate the effects of FMT on obesity. A total of ten randomized controlled trials (RCTs) comprising 334 participants showed that FMT was favorably associated with the following markers of obesity: CRP, caloric intake, fasting glucose, HOMA-IR, blood pressure and cholesterol. While more research is needed, this further illustrates the critical relevance of the microbiota in obesity pathophysiology.
Probiotics, prebiotics and synbiotics have also been suggested to improve obesity by addressing these underlying mechanisms of disruptions in microbiota, immune function, inflammatory molecules and neuroendocrine/GBA signaling pathways. In addition to diet and environmental factors, chronic stress, sedentary lifestyles, and insufficient sleep patterns can further impede homeostatic functions in the body relative to obesity.
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