Melatonin Mitigates Oxazolone-Induced Colitis in Microbiota-Dependent Manner

Abstract

Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.

Intestinal microbiota and melatonin in the treatment of secondary injury and complications after spinal cord injury

“…It suggested that melatonin may strengthen the tight connection between cells, regulate intestinal permeability, repair and maintain the stability of intestinal mechanical barrier, which effectively prevent toxins and other bacterial metabolites in the intestine from entering the blood and cause cascading chain inflammatory reaction. A similar effect was also observed in the oxazolone induced colitis model ( Zhao et al, 2021 ), indicating that melatonin’s preservation of the intestinal barrier was not confined to stress damage and that its barrier protective role had a broader application. In addition, melatonin accelerates the emptying effect of the gastrointestinal tract in mice after SCI ( Jing et al, 2019 ), demonstrating that melatonin enhances gastrointestinal function, promotes peristalsis and strengthens the mechanical barrier.…”

“…In addition, melatonin enhances the abundance of bacteria and decrease the ratio of firmicum to Bacteroides in a high-fat diet-induced obesity mouse model ( Xu P. et al, 2017 ; Yin et al, 2018 ). In the ochratoxina induced liver injury model, melatonin increase the abundance of Bacteroides, verrucous microorganisms and actinomycetes, while decrease the abundance of firmicum and Lactobacillus ( Zhang H. et al, 2021 ; Zhao et al, 2021 ). In terms of microbial metabolism, melatonin significantly reduces the relative abundance of the microbiome in the cysteine and methionine metabolism and peptidoglycan biosynthesis pathway in the restraint stress mouse model, while increasing the relative abundance of the microbiome in the tryptophan metabolism, aminobenzoic acid degradation, renin angiotensin system, γ-aminobutyric acid ergic synapses and type II diabetes pathway ( Lin et al, 2021 ).…”

“…It was demonstrated that in a mouse model of SCI, melatonin displayed anti-inflammatory effects by reducing the upregulation of IL-17, interferon-gamma (IFN- γ) and monocyte chemoattractant protein-1 (MCP1) ( Jing et al, 2019 ). In the oxazolone induced colitis model, melatonin could inhibit the production of IL-5, IL-13 and their mRNA in type 2 innate lymphocytes (ILC2s) and affect the type 2 immune response ( Zhao et al, 2021 ). Ghareghani et al (2018) and Xiong et al (2022) demonstrated that melatonin modulates intestinal immune function through the expression of nod-like receptor-related genes and TLRs.…”

Melatonin–Microbiome Two-Sided Interaction in Dysbiosis-Associated Conditions

“…Firstly, in animal colitis models, MT increased bacterial richness and diversity in the gut [ 135 , 136 ]. This finding might have a translational impact, as a decrease in these parameters strongly correlates with IBD [ 140 , 141 ].…”

Opioid-Use, COVID-19 Infection, and Their Neurological Implications

“…Melatonin is synthesized in the enterochromaffin (EC) cells throughout the gut, and deficiencies in melatonin have been linked to increased permeability of the gut, increasingly associated with a range of diseases ( 135 , 136 ). A recent study conducted by Zhao et al demonstrated that melatonin reverses Oxazolone-induced colitis by suppressing type 2 immune response and attenuating intestinal permeability and neutrophil infiltration ( 137 ). Melatonin's role in treating intestinal co-morbidities associated with OUD and SARS-CoV-2 infection should be further explored.…”