Urolithin-A attenuates neurotoxoplasmosis and alters innate response towards predator odor

Abstract

Neurotoxoplasmosis, also known as cerebral toxoplasmosis, is an opportunistic chronic infection caused by the persistence of parasite Toxoplasma gondii cysts in the brain. In wild animals, chronic infection is associated with behavioral manipulation evident by an altered risk perception towards predators. In humans, reactivation of cysts and conversion of quiescent parasites into highly invasive tachyzoites is a significant cause of mortality in immunocompromised patients. However, the current standard therapy for toxoplasmosis is not well tolerated and is ineffective against the parasite cysts. In recent years, the concept of dietary supplementation with natural products derived from plants has gained popularity as a natural remedy for brain disorders. Notably, urolithin-A, a metabolite produced in the gut following consumption of ellagitannins-enriched food such as pomegranate, is reported to be blood-brain barrier permeable and exhibits neuroprotective effects in-vivo . In this study, we investigated the potential of pomegranate extract and urolithin-A as anti-neurotoxoplasmosis agents in-vitro and in-vivo . Treatment with pomegranate extract and urolithin-A reduced the parasite tachyzoite load and interfered with cyst development in differentiated human neural culture. Administration of urolithin-A also resulted in the formation of smaller brain cysts in chronically infected mice. Interestingly, this phenomenon was mirrored by an enhanced risk perception of the UA-treated infected mice towards predatory cues. Together, our findings demonstrate the potential of dietary supplementation with urolithin-A-enriched food as a novel natural remedy for the treatment of acute and chronic neurotoxoplasmosis.

Gut microbiota composition does not associate with toxoplasma infection in rats

“…Toxoplasma parasites were maintained in monolayers of immortalized human foreskin fibroblasts (ATCC no. CRL‐4001) and harvested through syringe lysis with a 25‐gauge needle, as previously described (Tan et al, 2020; Vyas, Kim, Giacomini, et al, 2007). A type II Prugniaud (Pru) Toxoplasma gondii strain was used in the experiments.…”

The therapeutic efficacy of curcumin nanoemulsion versus Spiramycin in Toxoplasma gondii (ME49 strain) chronically infected mice

“…Pomegranate is a rich source of Urolithin-A, a powerful protecting agent against neurodegeneration. Its administration significantly reduced brain cysts number and size in chronically infected mice than those in untreated animals [36] . One year later, three studies were conducted also investigating natural products [1,37,38] .…”

Impact of Plant-Based Foods and Nutraceuticals on Toxoplasma gondii Cysts: Nutritional Therapy as a Viable Approach for Managing Chronic Brain Toxoplasmosis

“…Interestingly, chronic infection reduces innate fear of mice towards predatory odour (26,41,42). However, UA attenuated the anxiolytic behaviour in chronically infected mice, as evident from the increased fear of these animals towards predatory odour compared with untreated animals (94).…”

“…Our group recently showed that pomegranate and UA exhibit anti-T. gondii activity. Urolithin-A treatment interfered with intracellular tachyzoite growth and cyst formation in infected neural cells (94). In vivo, daily injection of UA shortly after PRU T. gondii infection reduced the severity of chronic CNS infection, which was evident from the smaller brain cysts in chronically infected mice than those in untreated animals (94).…”

“…Urolithin-A treatment interfered with intracellular tachyzoite growth and cyst formation in infected neural cells (94). In vivo, daily injection of UA shortly after PRU T. gondii infection reduced the severity of chronic CNS infection, which was evident from the smaller brain cysts in chronically infected mice than those in untreated animals (94). Interestingly, chronic infection reduces innate fear of mice towards predatory odour (26,41,42).…”