Biology subjects

Josephson, J. K.

Publications and source records attributed to Josephson, J. K..

3 recordsLinked to original sources

bioRxiv2026

A Bioengineered Live Biotherapeutic Exploits Inflammation to Restore Gut Liver Brain Axis Function under Diet-Induced Stress

Systemic inflammatory diseases can be influenced by dietary intake, with gastrointestinal dysfunction driving both metabolic and behavioural changes mirroring the altered inflammatory profile. Additionally, the use of live biotherapeutic products (LBPs) shows promise for treating metabolic and inflammatory diseases, but their efficacy is limited by poor persistence in inflamed gut environments. Designed to utilize inflammatory byproducts, the LBP EcN::ttr has proven efficacy in the treatment of acute and chronic colitis, however its effects on the metabolic and behavioural patterns remain uncharacterized. We evaluated the effects of EcN::ttr on mice fed a proinflammatory omega-6 PUFA-rich diet. EcN::ttr-treated mice exhibited notable changes in the gut, including an improved expression of tight junction protein occludin, accompanied by reduced serum lipopolysaccharide (LPS) - binding protein, indicating protection against endotoxemia. EcN::ttr improved insulin sensitivity compared to the parental strain, associated with increased hepatic insulin receptor expression and reduced GSK3{beta} activation and endoplasmic reticulum stress. Secondary bile acids in mice treated with EcN::ttr were more abundant, with increases in those associated with resolving diarrhea and bile acid detoxification. Behavioural assessment highlighted a normalization of long-term memory along with a reduction of stress management behaviours. Altogether, EcN::ttr restores gut-liver-brain axis function through coordinated modulation of inflammation, barrier integrity, and bile acid metabolism. HighlightsO_LILive Biotherapeutic Product EcN::ttr, designed with a fitness advantage to survive inflammation, and provides protection against a proinflammatory omega 6-rich diet C_LIO_LIAdministration of EcN::ttr improved metabolic outcomes including increasing insulin sensitivity C_LIO_LIEcN::ttr increased the abundance of secondary bile acids including those that modulate bile acid detoxification C_LIO_LIBehavioural parameters were normalized in mice given EcN::ttr C_LIO_LIEcN::ttr partially normalizes gut-liver-brain axis through restoring barrier integrity, modulating inflammation and improving secondary bile acid metabolism C_LI

systems biology↗

bioRxiv2024

Bio-engineering a common probiotic to exploit colonic inflammation promotes reliable efficacy in translational models of colitis

The intricate balance between the gut microbiome and host health inspires innovations in drug development. Commensal bacteria provide a multi-targeted approach ideal for treating complex medical conditions, like inflammatory bowel disease (IBD). These bacteria are self-replicating factories with broad targets that promote balanced intestinal inflammation, mucosal barrier function, and eubiosis. Yet, the lack of superiority to gold-standard treatments and their clinical inconsistency makes most probiotics unreliable for disease treatments. Intestinal inflammation, a driving factor in many diseases, often overwhelms commensal bacteria, which lack the stress-resistance mechanisms necessary to withstand host immune defenses. To address this, we introduced a persistence platform BioPersist into E. coli Nissle 1917. We hypothesized that a bio-engineered probiotic, or genetically engineered microbial medicine (GEMM), designed to persist during inflammation would enhance probiotic bioavailability during colitis, leading to sustained therapeutic outcomes. We evaluated BioPersist in multiple translational colitis models such as in mice and pigs. BioPersist delayed the onset and reduced the severity of both chronic and acute colitis, proving more effective than 5-aminosalicylate. BioPersist thrived during inflammation promoting tolerogenic immune responses that limited infiltrating leukocyte activity and decreased TNF- from resident myeloid cells in the mesentery. The persistence feature of BioPersist allowed the probiotic to overcome the damaging inflammatory response, eliciting mucosal healing evident by the increase in microbially-derived butyric acid. Based on these preclinical results, BioPersist may be a novel therapeutic option for both human and veterinary applications that sustains efficacy during colitis. One Sentence SummaryAdding a persistence feature to a probiotic enhances its efficacy for colitis treatment, enhancing future human and veterinary therapeutic applications.

microbiology↗

bioRxiv2024

Prenatal glyphosate exposure disrupts the gut-brain axis across several generations in mice.

Glyphosate, a widely used herbicide in North America, has become prevalent in the food supply, raising concerns about potential health impacts. In this exploratory study, male and female F0 mice were exposed to glyphosate through drinking water during mating and gestation. We investigated whether prenatal exposure at dietary-relevant levels (0.01 mg/kg/day, Average American Diet, [AAD]) or the U.S. EPAs acceptable daily intake (1.75 mg/kg/day, [EPA upper limit]) altered gut, metabolic, and behavioral outcomes across two generations in mice with or without genetic susceptibility to colitis (Muc2+/- and Muc2-/-, respectively). Healthy (Muc2+/-) offspring of glyphosate-exposed mice exhibited colonic goblet cell depletion, reduced mucin-2 expression, and pro-inflammatory cytokine profiles in both F1 and F2 generations. These healthy (Muc2+/-) offspring also developed metabolic dysfunction, including impaired glucose tolerance, insulin resistance, and reduced GLP-1 in serum. Behavioral deficits were also observed in healthy (Muc+/-) mice including reduced locomotion and working memory, and these changes were associated with altered microbiome composition and gut-brain mediators. These findings suggest that prenatal glyphosate exposure, even below regulatory thresholds, may disrupt multiple physiological systems across generations, highlighting the need for further research and regulatory consideration.

pharmacology and toxicology↗