Rada, P. | bioRxiv Science

bioRxiv2026

Trichomonas vaginalis targets Lactobacillus jensenii via pseudopodia-independent phagocytosis and secreted lysozyme TvGH25

A low abundance or absence of protective lactobacilli during acute trichomoniasis is a well-known phenomenon that is associated with T. vaginalis (TV) infection. However, a crucial question that remains unanswered is whether alterations in the lactobacilli population precede TV infection or whether the parasite plays an active role in lactobacilli disappearance. Our findings showed that TV efficiently phagocytosed one of the dominant Lactobacillus species L. jensenii (LJ). Phagocytosis proceeds via a pseudopodia-independent mechanism reminiscent of sinking with a preference for viable cells. The presence of viable LJ leads to an increase in secretion of 27 TV proteins, including TvGH25 lysozyme. This enzyme cleaves peptidoglycan, a major component of the bacterial cell wall. TV overexpressing TvGH25 effectively lowers the bacterial cell count, evidencing the enzymes antimicrobial potential. These data support the notion that TV cells can suppress the Lactobacillus population through a combination of targeted secretory response and phagocytic activity, revealing novel potential targets for developing alternative therapeutic strategies against trichomoniasis. Significance StatementTrichomonas vaginalis (TV) is a sexually transmitted parasite that causes trichomoniasis and is connected to the disruption of the healthy vaginal microbiome, dominated by Lactobacillus species. However, the nature of the interactions between TV and Lactobacillus is poorly understood. In this study, we show that TV uses an unusual form of pseudopodia-independent phagocytosis to engulf L. jensenii alongside a targeted secretory response to the bacterial encounter, involving TvGH25 lysozyme. We found that TV acquired this enzyme by lateral gene transfer from bacteria and repurposed it against bacteria to degrade the major bacterial cell wall component peptidoglycan. TvGH25 thus represents an effective component of TVs antibacterial arsenal. Our findings provide new insights into the mechanistic disruption of the protective Lactobacillus microbiota.

microbiology↗

bioRxiv2026

A hypothalamus-liver-skeletal muscle axis controlled by JNK1 and FGF21 mediates olanzapine-induced insulin resistance in an intraperitoneal treatment in male mice

BackgroundOlanzapine (OLA), a widely prescribed second-generation antipsychotic, is associated with adverse metabolic effects. We recently showed that oral OLA treatment in male mice induces weight gain and hepatic steatosis, whereas intraperitoneal (i.p.) administration leads to weight loss due to higher hypothalamic OLA levels and activation of brown adipose tissue. Since clinical studies report insulin resistance in individuals treated with OLA, here we investigated the impact of OLA i.p. treatment on insulin sensitivity, focusing on the liver- skeletal muscle axis. Material and MethodsWild-type male mice were treated with OLA (10 mg/kg, i.p.) for 8 weeks or received a single intrahypothalamic injection (15 nmol). Glucose homeostasis parameters were assessed. Mechanistic studies were performed in vagotomized mice, mice lacking JNK in either the hypothalamus or liver, mice overexpressing hepatic FGF21, and PTP1B-deficient mice (PTP1B-KO). ResultsOLA i.p. treatment induced systemic insulin resistance, pyruvate intolerance, and reduced insulin signaling in both liver and skeletal muscle. These effects were accompanied by increased hepatic JNK phosphorylation and IRS1 serine phosphorylation. A single intrahypothalamic OLA injection similarly impaired peripheral insulin action and activated hepatic JNK. Deletion of hypothalamic or hepatic JNK1, as well as vagotomy, prevented these defects. OLA reduced hepatic Fgf21 expression, an effect reversed by hypothalamic JNK1 deletion or vagotomy. Hepatic FGF21 overexpression prevented OLA-induced insulin resistance in skeletal muscle but not in liver. PTP1B-KO mice were protected from all metabolic impairments. ConclusionAlthough OLA i.p. treatment prevents weight gain, it decreases peripheral insulin sensitivity through a hypothalamus-liver axis driven by hypothalamic JNK1, which activates hepatic JNK via the vagus nerve, suppresses hepatic FGF21 and ultimately impairs insulin signaling in skeletal muscle. Importantly, the protection conferred by PTP1B deficiency against OLA-induced insulin resistance strongly suggests that targeting PTP1B might prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

physiology↗