The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.

Protein corona determines fate and cytotoxicity of nanoparticles in biological systems.

Psoriasis has long been associated with inflammatory bowel disease (IBD); however, a causal link is yet to be established. Here, we demonstrate that imiquimod-induced psoriasis (IMQ-pso) in mice disrupts gut homeostasis, characterized by increased proportions of colonic CX₃CR₁^hi macrophages, altered cytokine production, and bacterial dysbiosis. Gut microbiota from these mice produce higher levels of succinate, which induce de novo proliferation of CX₃CR₁^hi macrophages ex vivo, while disrupted gut homeostasis primes IMQ-pso mice for more severe colitis with dextran sulfate sodium (DSS) challenge. These results demonstrate that changes in the gut environment in psoriasis lead to greater susceptibility to IBD in mice, suggesting a two-hit requirement, that is, psoriasis-induced altered gut homeostasis and a secondary environmental challenge. This may explain the increased prevalence of IBD in patients with psoriasis.

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer’s patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation in vitro and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies.

Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.

IntroductionBacterial species that inhabit the colon interact with the host, promoting the development and function of immune cells locally and systemically. These interactions are mediated by bacterially derived metabolites such as short-chain fatty acids (SCFAs), which have been identified as critical inducers of immune subsets (1–3) key for protecting mice from disease development (2–5), emphasizing the role of the microbiota in gut homeostasis and host health.The colonic epithelium acts as a physical barrier between the host and the gut microbiota. The secretion of mucus by goblet cells provides a barrier to microbial infiltration. Further, Paneth cells release antimicrobial peptides that protect against pathogen invasion as well as regulate gut microbiota composition (6). Expression of tight junction proteins by enterocytes also limits bacterial penetration. Epithelial function can be regulated by the gut microbiota via SCFAs, by stimulating mucus production (7) and tight junction assembly (8). In contrast, dysbiosis, marked by detrimental changes in gut microbiota composition, triggers increased gut permeability and gut inflammation (9). Alterations in antimicrobial peptide production, mucus layer thickness and/or epithelial permeability have been implicated in the development of a broad range of diseases such as colitis and colorectal cancer (10). These diseases have also been linked to abnormal interactions between the host epithelium and the gut microbiota through the formation of biofilm. Biofilms consist of aggregates of adherent and planktonic bacteria protected by an extracellular matrix and have been observed in the proximal colon of patients diagnosed with such diseases (11). The mechanisms behind the formation and the role of biofilm in the gut are not fully understood, but biofilm formation has been shown to impact both disease development and resolution. Both in a colitis rat model and in humans, biofilm in the colon has been shown to facilitate pathobiont adherence to the epithelium and translocation to the host (12, 13). In human inflammatory bowel disease, biofilm formation at the site of epithelial wound healing has been shown to negatively affect healing by impairing epithelialization and tissue repair (14). Finally, a recent study has shown that inoculation of germ-free mice with biofilm positive human colon inocula was carcinogenic (15).The identification of environmental factors that can affect gut homeostasis is thus a critical first step in preventing the development of so-called “western lifestyle diseases,” encompassing autoimmune, allergic and metabolic diseases. A broad range of environmental factors can affect gut homeostasis, with diet composition being the major driver (16). Western-like diets enriched in fat and simple carbohydrates and deficient in dietary fiber have been shown to trigger dysbiosis, increases gut permeability and inflammation (16). While the impact of these macronutrients on gut homeostasis has been extensively studied (17), the role of food additives prevalent in processed food remains poorly defined. Food additives are used to improve the texture, preservation and aesthetics of food. Food grade titanium dioxide (TiO2) or E171, is a whitening agent present in over 900 commonly consumed food products. The average adult consumes between 0.7 and 5.9 mg of TiO2 per kg of body weight (BW) per day throughout their life and children are the most exposed, consuming up to 32.4 mg TiO2/kg BW/day in maximally exposed individuals (18). Despite the fact that regulatory bodies do not define strict guidelines around its consumption, new evidence from animal studies has emerged, highlighting that TiO2 may potentiate cancer development (19) and exacerbate inflammatory bowel disease (20).The effect of TiO2 on gut homeostasis is poorly understood yet evidence suggests that TiO2 interacts with gut epithelial cells. In vivo and in vitro studies have demonstrated the accumulation of TiO2 in the mucus layer (21) and its uptake by colonic epithelial cells (22, 23). A study in rats has shown that TiO2 affects immune cells in the Peyer's patches associated with a decreased regulatory T cell proportion (19). However, the impact of TiO2 on colonic immune cells, the site where microbiota is the densest, has never been investigated. While the impact of TiO2 on the colonic microbiota has been previously investigated in a short term study (2.5 mg TiO2/kg BW/day for 1 week) (24) and using a high dose (100 mg TiO2/kg BW/day) for up to 4 weeks (25), the impact of TiO2 on the small intestine microbiota is unknown.The aim of the present study is to establish the effects of food grade TiO2 on gut homeostasis in vivo. We investigated the impact of physiological doses (2 and 10 mg TiO2/kg BW/day) and a high dose of TiO2 (50 mg TiO2/kg BW/day) on mouse colonic and small intestine microbiota composition and function, epithelial function and mucosal inflammation after 3–4 weeks of treatment via drinking water.Materials and MethodsE171 CharacterizationSize and MorphologyFood grade TiO2 was purchased from All Colour Supplies PTY. Average hydrodynamic diameter, polydispersity index and zeta potential of the TiO2 nanoparticles dispersed in drinking water were determined with a Malvern Zetasizer Nano ZS at 25°C. The dispersion was measured 3 times for both size and zeta potential. The size distribution and shape of the TiO2 nanoparticles dispersed in mice drinking water were determined using a NanoSight NS300 (equipped with a sCMOS camera) at 25°C. The dispersion was measured 5 times (1 min per measurement). The size distribution and shape of the TiO2 nanoparticles dispersed in drinking water were further investigated using a Zeiss Ultra Plus scanning electron microscope operated at an accelerating voltage of 10 kV. A drop of the nanoparticle dispersion was allowed to dry on a stub, after which ~20 Å of platinum metal was sputter...