The current nutritional composition of the "American diet" (AD; also known as Western diet) has been linked to the increasing incidence of chronic diseases, including inflammatory bowel disease (IBD), namely Crohn disease (CD). This study investigated which of the 3 major macronutrients (protein, fat, carbohydrates) in the AD has the greatest impact on preventing chronic inflammation in experimental IBD mouse models. We compared 5 rodent diets designed to mirror the 2011-2012 "What We Eat in America" NHANES. Each diet had 1 macronutrient dietary source replaced. The formulated diets were AD, AD-soy-pea (animal protein replaced by soy + pea protein), AD-CHO ("refined carbohydrate" by polysaccharides), AD-fat [redistribution of the ω-6:ω-3 (n-6:n-3) PUFA ratio; ∼10:1 to 1:1], and AD-mix (all 3 "healthier" macronutrients combined). In 3 separate experiments, 8-wk-old germ-free SAMP1/YitFC mice (SAMP) colonized with human gut microbiota ("hGF-SAMP") from CD or healthy donors were fed an AD, an AD-"modified," or laboratory rodent diet for 24 wk. Two subsequent dextran sodium sulfate-colitis experiments in hGF-SAMP (12-wk-old) and specific-pathogen-free (SPF) C57BL/6 (20-wk-old) mice, and a 6-wk feeding trial in 24-wk-old SPF SAMP were performed. Intestinal inflammation, gut metagenomics, and MS profiles were assessed. The AD-soy-pea diet resulted in lower histology scores [mean ± SD (56.1% ± 20.7% reduction)] in all feeding trials and IBD mouse models than did other diets (P < 0.05). Compared with the AD, the AD-soy-pea correlated with increased abundance in Lactobacillaceae and Leuconostraceae (1.5-4.7 log2 and 3.0-5.1 log2 difference, respectively), glutamine (6.5 ± 0.8 compared with 3.9 ± 0.3 ng/μg stool, P = 0.0005) and butyric acid (4:0; 3.3 ± 0.5 compared with 2.54 ± 0.4 ng/μg stool, P = 0.006) concentrations, and decreased linoleic acid (18:2n-6; 5.4 ± 0.4 compared with 8.6 ± 0.3 ng/μL plasma, P = 0.01). Replacement of animal protein in an AD by plant-based sources reduced the severity of experimental IBD in all mouse models studied, suggesting that similar, feasible adjustments to the daily human diet could help control/prevent IBD in humans.

Psychological stress has been previously reported to worsen symptoms of inflammatory bowel disease (IBD). Similarly, intestinal tertiary lymphoid organs (TLOs) are associated with more severe inflammation. While there is active debate about the role of TLOs and stress in IBD pathogenesis, there are no studies investigating TLO formation in the context of psychological stress. Our mouse model of Crohn’s disease–like ileitis, the SAMP1/YitFc (SAMP) mouse, was subjected to 56 consecutive days of restraint stress (RS). Stressed mice had significantly increased colonic TLO formation. However, stress did not significantly increase small or large intestinal inflammation in the SAMP mice. Additionally, 16S analysis of the stressed SAMP microbiome revealed no genus-level changes. Fecal microbiome transplantation into germ-free SAMP mice using stool from unstressed and stressed mice replicated the behavioral phenotype seen in donor mice. However, there was no difference in TLO formation between recipient mice. Stress increased the TLO formation cytokines interleukin-23 (IL-23) and IL-22 followed by up-regulation of antimicrobial peptides. SAMP × IL-23r ^−/− (knockout [KO]) mice subjected to chronic RS did not have increased TLO formation. Furthermore, IL-23, but not IL-22, production was increased in KO mice, and administration of recombinant IL-22 rescued TLO formation. Following secondary colonic insult with dextran sodium sulfate, stressed mice had reduced colitis on both histology and colonoscopy. Our findings demonstrate that psychological stress induces colonic TLOs through intrinsic alterations in IL-23 signaling, not through extrinsic influence from the microbiome. Furthermore, chronic stress is protective against secondary insult from colitis, suggesting that TLOs may function to improve the mucosal barrier.

Psychological distress and gut dysbiosis play key roles in IBD. This study investigated whether specific psychopathological and gut microbiota features predict adverse outcomes in UC patients. This retrospective cohort study included 35 UC patients recruited in 2019. Baseline assessments involved clinical interviews, psychiatric evaluations, and stool sampling. In 2024, follow-up interviews and medical record reviews assessed disease progression, including biologic therapy failure, hospitalization, surgery, and diagnosis changes. Disease activity was measured via the Mayo score. Psychological testing included MMPI-2, STAI-Y2, GSES, CD-RISC, and TAS-20. Patients with biological therapy failure showed increased levels of Proteobacteria, Fusobacteria, Enterobacteriaceae, and Trabulsiella, while Firmicutes were less abundant. UC-related hospitalized patients had lower levels of Rikenellaceae, Ruminococcaceae, Faecalibacterium, Lachnospira, Methanobrevibacter, and Phascolarctobacterium compared to non-hospitalized patients. Hospitalized patients scored higher on the Sc clinical scale and the OBS and HEA content scales. Acidaminococcus and Bilophila were more abundant in patients who underwent surgery. PCA revealed differences between patients with and without biological failure. Logistic regression found that Fusobacteria were negatively correlated with the failure of three or more biologics, while Hy and Pd were positively correlated. Pa and Pt were negatively correlated with multifailure. Obsessiveness, health concerns, somatization, and reduced SCFA-producing bacteria may predict UC-related adverse outcomes.

TL1A and its receptor DR3 are key regulators of mucosal immune responses, but their role in periodontal disease is unknown. Herein, we investigated whether TL1A/DR3 signaling contributes to mucosal immune amplification and tissue-destructive inflammation in periodontitis using SAMP1/YitFc (SAMP) mice, which develop spontaneous ileitis and periodontal disease. DR3 deficiency markedly attenuated alveolar bone loss and improved periodontal architecture, restoring a phenotype comparable to healthy AKR (parental) controls. Gingival tissues from wild-type SAMP mice exhibited increased expression of both Tnfsf15 (encoding TL1A) and Tnfrsf25 (encoding DR3), with both positively correlating with disease severity. This was accompanied by elevated levels of IL-17, TNF-α, and IL-1β, and by increased numbers of CD4 ⁺ T helper cells and neutrophils. Conversely, SAMPxDR3 ^−/− mice exhibited reduced inflammatory cytokine production and immune cell accumulation. These findings support a model in which the TL1A/DR3 axis is associated with amplification of mucosal immune responses in periodontal disease, linking effector T cell activation, increased cytokine production, and recruitment of innate immune cells. Altogether, our data identify the TL1A/DR3 cytokine-receptor pair as a potential regulator of inflammatory circuits that drive periodontal pathology. Blocking this pathway may provide a therapeutic modality for patients affected by chronic periodontitis.

Objective Death receptor 3 (DR3) and its ligand tumor necrosis factor like ligand 1A (TL1A), are involved in the regulation of the balance between effector and regulatory T cells in IBD. New evidence suggests a role of IL-9-secreting Th9 cells in the pathogenesis of ulcerative colitis (UC), although the molecular pathways through which IL-9 and Th9 cells may mediate intestinal inflammation in Crohn’s disease (CD) are still unclear. Design We investigated the role of DR3 signaling in the differentiation of Th9 cells in mouse models of CD-like ileitis and colitis, including SAMP1/YitFc (SAMP) mice. Results Polarized-Th9 cells with functional DR3 from SAMP WT (Th9_WT) harbor a pro-inflammatory signature compared to DR3-deficient Th9 cells that were obtained from DR3^-/-×SAMP mice (Th9_KO). Conversely, ablation of DR3 signaling generated anti-inflammatory responses, as reflected by higher numbers of IL-10 producing cells in DR3^-/-×SAMP mice. Additionally, RNA-seq and phosphoproteomic analyses showed that inflammatory pathways are significantly more activated in Th9_WT than in Th9_KO cells. Finally, in the T-cell adoptive transfer model, Th9_KO cells were less colitogenic than Th9_WT, while IL-9 blockade diminished the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in Th9 cells pathogenicity. Conclusion We describe herein that a functional DR3 receptor is required for the pathogenicity of Th9 cells, thus, constituting a novel mechanism by which TL1A/DR3 signaling mediates experimental CD-like ileitis. The TL1A/DR3/Th9 pro-inflammatory pathway may offer a novel therapeutic target for patients with CD. What is already known on this topic – TL1A/DR3 system plays a pivotal role in the pathogenesis of Crohn’s disease like ileitis. – Th9 cells are a novel subset of T lymphocytes mainly producing the pro-inflammatory cytokine IL-9 which contributes to intestinal inflammation. – Those finding provided us with a strong rationale to investigate IL-9-producing cells in our SAMP1/YitFc mouse model of CD-like ileitis. What this study adds – DR3 receptor is involved in the regulation and progression of intestinal inflammation by promoting Th9 cell differentiation and pathogenicity. – Using RNA-seq and phosphoproteomic comparative analyses we were able to characterize Th9 cells with and without functional DR3 receptor showing that presence of DR3 confers a pro-inflammatory signature to Th9 cells. – We describe a novel role of DR3 in Th9 cells development that appears to regulate their pro-inflammatory phenotype in models of CD-like ileitis and colitis. How this study might affect research, practice or policy – TLA1/DR3 axis and Th9 cells may be useful as therapeutic targets in CD.