Lactococcus lactis sb. cremoris orchestrates signal events in the gut epithelium via TLR2 to promote tissue restitution

The use of beneficial bacteria to promote gastrointestinal heath is widely practiced, however, the mechanisms whereby many of these microbes elicit their beneficial effects remain elusive. Previously, we conducted a screen for the discovery of novel beneficial microbes and identified the potent cytoprotective effects of a strain of Lactococcus lactis subsp. cremoris. Here, we show that dietary supplementation with L. lactis subsp. cremoris induced transcript enrichment of a set of genes within the colon whose functions are associated with host cell and microbe interactions. Specifically, L. lactis subsp. cremoris induced the expression of tlr2, which we show was required for L. lactis subsp. cremoris to elicit its beneficial effects on the intestine. L. lactis subsp. cremoris did not confer beneficial effects in mice deficient in TLR-2, or deficient in its adaptor protein Myd88 in chronic gut injury models. In addition to cytoprotection, culture supernatant from L. lactis subsp. cremoris accelerated epithelial migration in a cultured epithelial cell scratch wound assay; and effect that was abrogated by a TLR-2 antagonist. Furthermore, L. lactis subsp. cremoris accelerated epithelial tissue restitution following the infliction of a colonic wound biopsy in a TLR-2 and Myd88-dependent manner. Within colonic wounds, L. lactis subsp. cremoris induced the activation of signaling pathways that function in tissue restitution following injury, including the ERK signaling pathway, and of focal adhesion complex (FAC) proteins. Together, these data demonstrate that L. lactis subsp. cremoris signals via the TLR2/MyD88-axis to confer cytoprotection and accelarated tissue restituion in the gut epithelium. These data point to evolving adaptations where beneficial gut microbes moduate innate immune signaling to excert positive influnces on host physiology.

Anal skin-like epithelium mediates colonic wound healing

Intestinal epithelial wound healing, which is essential for health, is compromised and represents a therapeutic target in inflammatory bowel disease (IBD). While studies have elucidated important subpopulations of intestinal epithelial cells in repair, these have yet to translate to therapies. Here, in mouse models of acute colitis, we demonstrate a distinct and essential source of wound-healing cells that re-epithelialize the distal colon. Using 3-d imaging, lineage tracing, and single-cell transcriptomics, we show that neighboring skin-like (squamous) cells of the anus rapidly migrate into the injured colon and establish a permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, at the boundary of colonic and anal epithelium, that resists colitis. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair. Thus, heterologous cell-types at tissue junctions represent unique reserve cells capable of repair and plasticity.

Curcumin Loading on Alginate Nano-Micelle for Anti-Infection and Colonic Wound Healing

Despite the antibacterial, and anti-inflammatory properties of curcumin (C), its effect on wound healing, especially in the colorectal, is ambiguous. Moreover, due to the hydrophobic properties of C, its use is limited. Therefore, to reduce the bioavailability challenge and improve the transfer to colon area, we designed a C-alginate-based nano-micelle (C-A-NM). After fabrication of C-A-NM (55.5 nm) and physicochemical studies with the TEM, DLS and XRD, the C release rate based on gastrointestinal state was evaluated. Furthermore, the effects of C-A-NM on the survival of HCT-8 cells at 24 and 48 hours by MTT method and its antibacterial effects were also evaluated. To explain the effects of wound healing in rats, in addition to colonoscopy on the 14th-day, the repaired tissue on the 7th and 14th days were examined by Hematoxylin and Eosin method. Also, for evaluating wound healing in the colon, the protein/collagen concentration, and TGFβ1/NFκB gene expression were determined. The results of C cumulative release showed that the NM allows the drug to be loaded in the colon in a favourable manner. Also, the toxicity outputs revealed that C-A-NM at a concentration of 7.5 mg had no negative effects on cell viability. While the activity of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, bacteria decreased based on the minimum inhibitory concentration value with 153, 245 and 319 (μg/mL). The use of C-A-NM not only increases protein and collagen in damaged sites, but also increases TGFβ1 expression in contrast to NFκB. Based on these results, and the results of histopathology and colonoscopy, it was found that C-A-NM accelerates the healing of damaged areas. Overall, the results show that the use of C-A-NM can significantly accelerate the healing of wounds in the gastrointestinal tract based on collagen induction and reduced bacterial activity.