Microbiome-based therapies such as probiotics and live biotherapeutic products (LBPs) are being developed to treat complex diseases like inflammatory bowel diseases (IBD). However, studies in people with IBD treated with probiotics or LBPs show inconsistent effectiveness. Since the inflamed gut limits the persistence of beneficial bacteria, the Gibson Lab developed EcN::ttr, derived from the probiotic Escherichia coli Nissle 1917 (EcN) and bioengineered to harbour the ttr operon. EcN::ttr can utilize tetrathionate (an inflammation-derived byproduct) as an electron acceptor, conferring a fitness advantage in the inflamed gut. Here, EcN::ttr was characterized in diverse colitis models to assess its effects on intestinal inflammation and metabolism. Given before symptoms appeared, its effects were characterized in 1) DSS model of acute colitis, 2) Muc2-deficient (Muc2⁻⧸⁻) model of chronic and spontaneous colitis with metabolic dysfunction, and in 3) mice fed a high omega-6 diet as a model of mild inflammation and metabolic dysfunction. In Muc2⁻⧸⁻ mice, EcN::ttr bloomed during colitis; 60% retained EcN::ttr after a single dose versus 7% for unmodified EcN. EcN::ttr treatment delayed colitis onset, lowered histopathological scores, and limited bacterial infiltration and translocation. In the DSS model, EcN::ttr reduced colon damage by 55%, outperforming 5-ASA and EcN. EcN::ttr preserved mucosal architecture, decreased fecal calprotectin concentration and leukocyte infiltration, and increased production of butyrate and expression of IL-22. In Muc2⁻⧸⁻ mice, EcN::ttr reduced macrophage and neutrophil infiltration, increased T-regulatory cells (Tregs), but decreased TNF-α⁺ macrophages and resident (CD103⁺) cells. This was dependent on IL-10, as EcN::ttr-treated IL-10⁻⧸⁻ mice did not show differences in Tregs and had increased proportions of TNF-α⁺ resident cells. Mice fed a high omega-6 diet and treated with EcN::ttr showed increased butyrate concentration, lower pro-inflammatory cytokines in the colon, and improved epithelial occludin’s distribution. This reduced LPS-binding protein in circulation, subtly improving insulin signalling and reducing liver endoplasmic reticulum stress. However, this metabolic protection was restricted in Muc2⁻⧸⁻ mice. Altogether, this study highlights the importance of the inflammation-tolerant ttr operon in EcN for its immunomodulatory effects on the inflamed gut and metabolic dysfunction, underscoring its potential as a platform to enhance other LBPs' persistence and therapeutic potential in inflamed intestines.
Andrea Alejandra Verdugo Meza (Thu,) studied this question.