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The gut-brain axis (GBA) plays a pivotal role in human health and wellness by orchestrating complex bidirectional regulation and influencing numerous critical processes within the body. Over the past decade, research has increasingly focused on the GBA in the context of inflammatory bowel disease (IBD). Beyond its well-documented effects on the GBA-enteric nervous system and vagus nerve dysregulation, and gut microbiota misbalance-IBD also leads to impairments in the metabolic and cellular functions: metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton dysregulation. These systemic effects are currently underexplored in relation to the GBA; however, they are crucial for the nervous system cells' functioning. This review summarizes the studies on the particular mechanisms of metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton impairments in IBD. Understanding the involvement of these processes in the GBA may help find new therapeutic targets and develop systemic approaches to improve the quality of life in IBD patients.

Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots-curcumin (Cur)-along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na 2 GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na 2 GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus -infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na 2 GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes ( Cyp7A1 , Fxr , and Rxra ), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na 2 GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na 2 GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na 2 GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.

The combination of 4-week repeated social defeat stress (RSDS) and Opisthorchis felineus infection was modeled in C57BL/6 mice. Various parameters were compared between three experimental groups of male mice (SS: mice subjected to RSDS, OF: mice infected with O. felineus, and OF + SS: mice subjected to both adverse factors) and behavior-tested and intact (INT) controls. The combination caused liver hypertrophy and increased the blood level of proinflammatory cytokine interleukin 6 and proteolytic activity of cathepsin B in the hippocampus. Meanwhile, hypertrophy of the spleen and of adrenal glands was noticeable. Anxious behavior in the elevated plus-maze test was predominantly due to the infection, with synergistic effects of an interaction of the two adverse factors on multiple parameters in OF + SS mice. Depression-like behavior in the forced swimming test was caused only by RSDS and was equally pronounced in SS mice and OF + SS mice. Helminths attenuated the activities of cathepsin B in the liver and hypothalamus (which were high in SS mice) and increased cathepsin L activity in the liver. The highest blood level of corticosterone was seen in SS mice but was decreased to control levels by the trematode infection. OF mice had the lowest level of corticosterone, comparable to that in INT mice. Thus, the first data were obtained on the ability of O. felineus helminths-even at the immature stage-to modulate the effects of RSDS, thereby affecting functional connections of the host, namely "helminths → liver↔brain axis.", (Copyright © 2022. Published by Elsevier Inc.)

Aims: The food-born trematode Opisthorchis felineus colonizes bile ducts of the liver of fish-eating mammals including humans. There is growing evidence that this liver fluke is a risk factor for cholangiocarcinoma (CCA). Cancer cell lines are necessary for drug screening and for identifying protein markers of CCA. The aim was to establish a cell line derived from cholangiocarcinoma associated with opisthorchiasis felinea., Main Methods: Allotransplantation, immunohistochemistry, karyotype analysis, cell culture techniques, immunocytochemistry and real-time PCR., Key Findings: Here we repot the establishment of first CCA cell line, CCA-OF, from a primary tumor of an experimental CCA in Syrian hamsters treated with low doses of dimethyl nitrosamine and associated with O. felineus infection. The cell line was found to be allotransplantable. Expression of epithelial and mesenchymal markers (cytokeratin 7, glycosyltransferase exostosin 1, Ca 2+ -dependent phospholipid-binding protein annexin A1 and vimentin) was demonstrated by immunostaining of the primary tumors, CCA-OF cells, and allotransplants. CCA-OF cells were found to express presumed CCA biomarkers previously detected in both human and experimental tumors associated with the liver fluke infection. The cells were diploid-like (2n = 42-46) with complex chromosomal rearrangements and have morphological features of epithelial-like cells. The usefulness of the CCA-OF cell model for antitumor activity testing was demonstrated by an analysis of effects of resveratrol treatment. It was shown that resveratrol treatment inhibited the proliferation and the migration ability of CCA-OF cells., Significance: Thus, the allotransplantable CCA-OF cell line can be used in studies on helminth-associated cholangiocarcinogenesis and for the testing of antitumor drugs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In recent years, silicon dioxide nanoparticles have been widely used in medicine and the pharmaceutical industry, however, their effect on the brain has hardly been studied. We assessed the effects of long-term consumption of 5-nm amorphous silicon dioxide nanoparticles (SiO 2 -NPs) by Syrian hamsters infected with the trematodes Opisthorchis felineus on the hippocampus and frontal cortex. Spectroscopic determination of brain neurometabolites, performed using a horizontal Magnetic Resonance Imaging system at 11.7 Tesla magnetic field, has shown that the ratio of the excitatory neurotransmitters (glutamate + glutamine + aspartate) to the inhibitory ones (GABA + glycine) was higher in the animals infected with O. felineus. However, pre-consumption of the SiO 2 -NPs solution prevented this imbalance. In addition, the protective effect of SiO 2 -NPs on the level of myo-inositol and glycine was found. It is concluded that the use of SiO 2 -NPs can neutralize the negative effects of infectious factors on the brain.

A model of chronic opisthorchiasis combined with social stress is examined; this situation is more likely for humans and animals than a separate impact of the infectious factor. For this purpose, we evaluated the effects of Opisthorchis felineus ("OP" group) and 30-day social stress (confrontations between males, "SS" group) alone and in combination ("OP + SS" group) in inbred C57BL/6 male mice and compared these effects according to the parameters listed below. The animals exposed to neither factor formed the control group ("CON"). All animals were assayed for blood biochemical parameters, changes in blood cell composition, and pattern of bone marrow hematopoiesis. By the end of the experiment, we have observed crucial effects of the two factors on the blood and liver of "OP" and "OP + SS". Eosinophil and basophil counts increased and relative segmented neutrophil and monocyte counts decreased in "OP + SS" mice on the background of activated myelopoiesis, mainly determined by social stress. Despite depressed erythropoiesis, "OP" mice displayed no changes in the relative peripheral erythrocyte counts. On the contrary, social stress, which stimulated erythropoiesis in "SS" and "OP + SS" mice, was accompanied by a decrease in the relative erythrocyte counts and hematocrit. Hepatosplenomegaly was observed on the background of these two impacts. Changes in transaminase (ALT and AST) and alkaline phosphatase activities as well as an increase in cholesterol and product of lipid peroxidation suggest a pronounced destruction of the liver. Altogether, social stress exacerbates many of the assayed blood parameters in the mice infected with the liver fluke., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The effects of two influences, social stress and acute opisthorchiasis, were investigated in inbred C57BL/6J male mice. In the model of social stress, mice were repeatedly attacked and defeated by aggressive outbred ICR male mice and were in continuous sensory contact with an aggressive conspecific mouse in their home cage for 20 days. Acute opisthorchiasis was provoked by invasion of Opisthorchis felineus (50 larvae per animal) on the fourth day after the social stress was induced. Simultaneous action of both factors caused the hypertrophy of adrenal glands, as well as elevated the activity of cathepsins B and L in the spleen. This effect on the activity of the cysteine proteases in the hippocampus and hypothalamus following O. felineus invasion was the predominant result of simultaneous action with social stress. Acute opisthorchiasis, social stress, and their combination caused an increase in the level of blood IL-6 in approximately 30% of the animals. Social stress induced a more pronounced effect on mouse plus-maze behavior than O. felineus invasion. Our results suggest a more severe negative effect of the simultaneous influence of both factors on most of the parameters that were investigated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Opisthorchis felineus (Trematoda) is widespread in the Russian Federation, especially in Siberia, and other countries of Europe. Infestation of endemic area population with O. felineus reaches 80%. On animal models of the infection of closely related Opisthorchis viverrini combined with the nitrosamines' intake it has been shown that the parasite induces cholangiocarcinoma. However carcinogenic potential of O. felineus is still poorly studied. The present study is aimed to investigate the role of O. felineus in cholangiocarcinoma carcinogenesis in hamster treated additionally by dimethylnitrosamine (DMN). Golden hamsters were divided into 4 groups (15 specimens in the control group and 20 for other groups): (I) untreated control, (II) 12.5 ppm DMN solution intake, (III) infected with 50 metacercariae of O. felineus and (IV) infected with 50 metacercariae of O. felineus and 12.5 ppm DMN solution intake. According to the histological data, in the. O. felineus-infested group significant hyperplastic and dysplastic biliary changes were found considered as a precancerogenic state. Such pathological changes of bile ducts were more severe in group treated with both factors, with cholangiocarcinoma being found out at 18th week in all the animals of this group. These results demonstrate that O. felineus could play promoting role in two-step model in cholangiocarcinoma carcinogenesis and may be used to define the O.felineus group in the International Agency for Research on Cancer classification of agents, mixtures and exposures (IARC categories).

European liver fluke (Opisthorchis felineus) and Asian liver fluke (Opisthorchis viverrini) are similar in morphology but comparative pathology of the infections has not been described. We therefore did comparative histopathology of both parasites in an experimental animal model. The study was conducted in 3 groups of 105 Syrian golden hamsters; the first and second groups fed with 50 metacercariae of O. felineus (OF) or O. viverrini (OV) and the last group was uninfected controls. Five hamsters in each group were euthanized on weeks 1, 2, 4, 8, 12 and 24 post-infection. The liver tissue was fixed and processed for routine histopathology and immunohistochemistry for proliferation markers (BrdU or PCNA). Overall, the liver histopathology of O. felineus and O. viverrini infection was generally similar. However, various histopathogical features including intense inflammation, fibrosis, biliary and goblet cell hyperplasia and dysplasia occurred earlier in the OF group. In addition, the existence of precancerous lesions such as cholangiofibrosis in a long-term infection was observed only in this group. O. felineus is larger in size than O. viverrini which, together with its excreted and secreted antigens, likely is crucial in the induction of liver fluke induced disease. The differences in nature and timing of the histopathological profile indicate that opisthorchiasis caused by the European liver fluke O. felineus is more pathogenic than its Asian relative O. viverrini., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)