A role for intestinal TLR4-driven inflammatory response during activity-based anorexia

Abstract

Anorexia nervosa (AN) is associated with low-grade systemic inflammation and altered gut microbiota. However, the molecular origin of the inflammation remains unknown. Toll-like receptors are key regulators of innate immune response and their activation seems also to be involved in the control of food intake. We used activity-based anorexia (ABA) model to investigate the role of TLR4 and its contribution in anorexia-associated low-grade inflammation. Here, we found that ABA affected early the intestinal inflammatory status and the hypothalamic response. Indeed, TLR4 was upregulated both on colonic epithelial cells and intestinal macrophages, leading to elevated downstream mucosal cytokine production. These mucosal changes occurred earlier than hypothalamic changes driving to increased levels of IL-1β and IL-1R1 as well as increased levels of plasma corticosterone. Paradoxically, TLR4-deficient mice exhibited greater vulnerability to ABA with increased mortality rate, suggesting a major contribution of TLR4-mediated responses during ABA-induced weight loss.

Colonic Mucosal Proteome Signature Reveals Reduced Energy Metabolism and Protein Synthesis but Activated Autophagy during Anorexia‐Induced Malnutrition in Mice

“…ABA Procedure : Female 8‐week‐old C57BL/6 mice (Janvier Labs, Le Genest St Isle, France) were acclimatized 1 week at 23 °C with a reversed 12‐hour light‐dark cycle (dark phase: 10:30 a.m.–10:30 p.m.) and then were randomized into three groups as previously described . Briefly, the ABA model mice ( n = 16) were placed in cages with an activity wheel connected to Running Wheel software (Intellibio, Seichamps, France), while both limited‐food access mice (LFA, n = 16) and ad libitum mice (Control, n = 16) were placed in standard cages.…”

“…Undernutrition, dysbiosis, alteration of gut barrier function, stress, and inflammatory response are multiple factors that could be involved in the occurrence of associated intestinal disorders. Recently, by using the activity‐based anorexia (ABA) model mimicking restrictive anorexia and long‐term body weight loss, we reported an increased colonic permeability associated with decreased colonic protein content and TLR4 activation leading to an inflammatory response . It is well established that AN patients exhibit altered microbiota, as also observed during the ABA model .…”

Delayed gastric emptying and altered antrum protein metabolism during activity‐based anorexia

“…Female 8‐week‐old C57BL/6 mice (Janvier Labs, Le Genest St Isle, France) were acclimatized 1 week at 23°C with a reversed 12‐hour light‐dark cycle (dark phase: 10:30 am – 10:30 pm ). ABA procedure was performed as previously described . Briefly, mice were randomized into 3 groups: activity‐based anorexia model mice (ABA) were placed in cages with an activity wheel connected to Running Wheel ® software (Intellibio, Seichamps, France), while both limited food access mice (LFA) and ad libitum mice (Control) were placed in standard cages.…”

“…Activity‐based anorexia (ABA) model is frequently used to study the pathophysiology of AN. ABA model has been initially developed in rats and then adapted in mice, with a progressive decrease of time access to food allowing long‐term study . ABA exhibited disturbed behavior, changes in central nervous system, and peripheral changes, ie, gut dysbiosis .…”

Association between Toll-Like Receptor 4 T399I Gene Polymorphism and the Susceptibility to Crohn’s Disease: A Meta-Analysis of Case-Control Studies

“…In addition, TLR4 signaling in immune cells plays a crucial role in maintaining chronic inflammatory state via producing inflammatory cytokines [11]. Several studies from animal models have showed that tissue inflammation correlating with IL-1, IL-6, and IL-17 expression is mediated by TLR4 signaling in chronic inflammatory diseases [12]. Recent studies found that an imbalance in T cell subsets, such as Th1, Th17, T regulatory cells, and the resulting altered profile of cytokine secretion from these cells, affects the susceptibility of CD [13].…”