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Simple Summary: After being fed an antibiotic-free diet, some rabbits showed typical diarrhea symptoms. In order to explore the reasons, this study used multiple omics analysis. Bacteroidetes and Proteobacteria were significantly upregulated in the colon of diarrhea rabbits, and the ratio of Firmicutes to Bacteroidetes was decreased. The significantly upregulated differential genes were mainly enriched in the IL-17 signaling pathway and were involved in promoting inflammatory response. The different metabolites were mainly enriched in tryptophan metabolism and bile secretion, which affected the anti-inflammatory function. In addition, Bacteroides is positively correlated with 4-Morpholinobenzoic acid and Diacetoxyscirpenol, which is believed to be an important cause of inflammation. The enrichment of Proteobacteria is also related to the high expression of the IL-17 signaling pathway. Diarrhea symptoms appeared after antibiotics were banned from animal feed based on the law of the Chinese government in 2020. The colon and its contents were collected and analyzed from diarrheal and healthy rabbits using three omics analyses. The result of the microbial genomic analysis showed that the abundance of Bacteroidetes and Proteobacteria increased significantly (p-value < 0.01). Transcriptomes analysis showed that differentially expressed genes (DEGs) are abundant in the IL-17 signaling pathway and are highly expressed in the pro-inflammatory pathway. The metabolome analysis investigated differential metabolites (DMs) that were mainly enriched in tryptophan metabolism and bile secretion, which were closely related to the absorption and immune function of the colon. The results of correlation analysis showed that Bacteroidetes was positively correlated with 4-Morpholinobenzoic acid, and 4-Morpholinobenzoic acid could aggravate inflammation through its influence on the bile secretion pathway. The enriched DMs L-Tryptophan in the tryptophan metabolism pathway will lead to the functional disorder of inhibiting inflammation by affecting the protein digestion and absorption pathway. Thus, the colonic epithelial cells were damaged, affecting the function of the colon and leading to diarrhea in rabbits. Therefore, the study provided an idea for feed development and a theoretical basis for maintaining intestinal tract fitness in rabbits. [ABSTRACT FROM AUTHOR]

Simple Summary: In July 2020, China completely banned the addition of antibiotics to feed, which had a huge impact on animal husbandry, such as the increased incidence of some intestinal diseases. In this study, the pathogenesis of diarrhea in rabbits fed with antibiotic-free diet was studied by multi-omics analysis. The study found that the relative abundances of Firmicutes and Proteobacteria in the cecum of diarrhea-afflicted rabbits changed significantly. Most of the differential expression genes identified were related to cecum inflammation and immune response, and a total of 652 differential metabolites were identified, mainly involved in inflammation-related metabolic pathways such as bile secretion, folic acid resistance, and tryptophan metabolism. In addition, Fournierella was positively correlated with myricetin and ursolic acid; thus, it might further cause bile secretion and tryptophan metabolism disorders, aggravate intestinal inflammation, change intestinal permeability, reduce host immunity, and lead to diarrhea in rabbits. With the comprehensive prohibition of antibiotics in the feed industry in China, the incidence of diarrhea in rabbits increased, such as loss of appetite, vomiting, and excretion of atheromatous feces. In order to explore the pathological and the molecular mechanisms of the diarrhea in the rabbitry fed with antibiotic-free diet, we used microbial metagenomics, transcriptome, and non-targeted metabolomics sequencing. The results showed that the Firmicutes level was significantly decreased (p < 0.001) and the Proteobacteria level was significantly increased (p < 0.05). The functional enrichment of cecum revealed that most differentially expressed genes (DEGs) were expressed in immune, inflammatory, and metabolic processes. The enrichment of the cecal fecal metabolites focused on the bile secretion, antifolate resistance, and tryptophan metabolism pathways, which are mainly associated with inflammation. The results of correlation analysis showed that Fournierella was positively correlated with myricetin, ursolic acid, and furtherly might cause bile secretion and tryptophan metabolism disorder, aggravate intestinal inflammation, change intestinal permeability, and reduce host immunity, leading to diarrhea in rabbits. This study provides a theoretical basis for illustrating the reason for diarrhea and developing new feeds for the health of rabbits. [ABSTRACT FROM AUTHOR]