The gut-microbiota-brain changes across the liver disease spectrum.

Gut microbiota dysbiosis plays a significant role in the progression of liver disease, and no effective drugs are available for the full spectrum. In this study, we aimed to explore the dynamic changes of gut microbiota along the liver disease spectrum, together with the changes in cognition and brain metabolism. Sprague-Dawley rats were divided into four groups reflecting different stages of liver disease: control diet (NC); high-fat, high-cholesterol diet (HFHC), emulating non-alcoholic steatohepatitis; control diet + thioacetamide (NC + TAA), simulating acute liver failure; and high-fat, high-cholesterol diet + thioacetamide (HFHC + TAA) to assess the effect of the superimposed damages. The diet was administered for 14 weeks and the thioacetamide was administrated (100 mg/kg day) intraperitoneally over 3 days. Our results showed changes in plasma biochemistry and liver damage across the spectrum. Differences in gut microbiota at the compositional level were found among the experimental groups. Members of the Enterobacteriaceae family were most abundant in HFHC and HFHC + TAA groups, and Akkermansiaceae in the NC + TAA group, albeit lactobacilli genus being dominant in the NC group. Moreover, harm to the liver affected the diversity and bacterial community structure, with a loss of rare species. Indeed, the superimposed damage group (HFHC + TAA) suffered a loss of both rare and abundant species. Behavioral evaluation has shown that HFHC, NC + TAA, and HFHC + TAA displayed a worsened execution when discriminating the new object. Also, NC + TAA and HFHC + TAA were not capable of recognizing the changes in place of the object. Furthermore, working memory was affected in HFHC and HFHC + TAA groups, whereas the NC + TAA group displayed a significant delay in the acquisition. Brain oxidative metabolism changes were observed in the prefrontal, retrosplenial, and perirhinal cortices, as well as the amygdala and mammillary bodies. Besides, groups administered with thioacetamide presented an increased oxidative metabolic activity in the adrenal glands. These results highlight the importance of cross-comparison along the liver spectrum to understand the different gut-microbiota-brain changes. Furthermore, our data point out specific gut microbiota targets to design more effective treatments, though the liver-gut-brain axis focused on specific stages of liver disease.

Akkermansia muciniphila and environmental enrichment reverse cognitive impairment associated with high-fat high-cholesterol consumption in rats.

Nonalcoholic steatohepatitis (NASH) is one of the most prevalent diseases globally. A high-fat, high-cholesterol (HFHC) diet leads to an early NASH model. It has been suggested that gut microbiota mediates the effects of diet through the microbiota-gut-brain axis, modifying the host's brain metabolism and disrupting cognition. Here, we target NASH-induced cognitive damage by testing the impact of environmental enrichment (EE) and the administration of either Lacticaseibacillus rhamnosus GG (LGG) or Akkermansia muciniphila CIP107961 (AKK). EE and AKK, but not LGG, reverse the HFHC-induced cognitive dysfunction, including impaired spatial working memory and novel object recognition; however, whereas AKK restores brain metabolism, EE results in an overall decrease. Moreover, AKK and LGG did not induce major rearrangements in the intestinal microbiota, with only slight changes in bacterial composition and diversity, whereas EE led to an increase in Firmicutes and Verrucomicrobia members. Our findings illustrate the interplay between gut microbiota, the host's brain energy metabolism, and cognition. In addition, the findings suggest intervention strategies, such as the administration of AKK, for the management of the cognitive dysfunction related to NASH.

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases.

Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which, upon absorption by the host is converted into trimethylamine-N-oxide (TMAO) in the liver. A high accumulation of both components is related to cardiovascular disease, inflammatory bowel disease, non-alcoholic fatty liver disease, and chronic kidney disease. However, the relationship between the microbiota production of these components and its impact on these diseases still remains unknown. In this review, we will address which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., the genotype) and diet affect TMA production, and the colonization of these microbes and the reversal of dysbiosis as a therapy for these diseases.

Equipment for Repetitive Transcranial Magnetic Stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used for the treatment of a great variety of neurological disorders. The technique involves applying a magnetic field in certain areas of the cerebral cortex in order to modify neuronal excitability outside the skull. However, the exact brain mechanisms underlying rTMS effects are not completely elucidated. For that purpose, and in order to generate a pulsed magnetic field, a half-bridge converter controlled by a microcontroller has been designed to apply rTMS in small animals. Moreover, the small size of the rodent head makes it necessary to design a magnetic transducer, with the aim of focusing the magnetic field on selected brain areas using a specific and a small magnetic head. Using such devices, our purpose was to compare the effects of five different rTMS dosages on rat brain metabolic activity. The experimental results showed that one day of stimulation leads to an enhancement of brain metabolic activity in cortical areas, meanwhile with three days of stimulation it is possible to also modify subcortical zones, results that were not found when extending the number of rTMS applications up to seven days. In consequence, the number of pulses delivered might be an important parameter in rTMS protocols, highlighting its importance in rTMS impact.

Autophagy is required for performance adaptive response to resistance training and exercise-induced adult neurogenesis.

Endurance training promotes exercise-induced adaptations in brain, like hippocampal adult neurogenesis and autophagy induction. However, resistance training effect on the autophagy response in the brain has not been much explored. Questions such as whether partial systemic autophagy or the length of training intervention affect this response deserve further attention. Therefore, 8-week-old male wild-type (Wt; n = 36) and systemic autophagy-deficient (atg4b-/- , KO; n = 36) mice were randomly distributed in three training groups, resistance (R), endurance (E), and control (non-trained), and in two training periods, 2 or 14 weeks. R and E maximal tests were evaluated before and after the training period. Forty-eight hours after the end of training program, cerebral cortex, striatum, hippocampus, and cerebellum were extracted for the analysis of autophagy proteins (LC3B-I, LC3B-II, and p62). Additionally, hippocampal adult neurogenesis was determined by doublecortin-positive cells count (DCX+) in brain sections. Our results show that, in contrast to Wt, KO were unable to improve R after both trainings. Autophagy levels in brain areas may be modified by E training only in cerebral cortex of Wt trained for 14 weeks, and in KO trained for 2 weeks. DCX + in Wt increased in R and E after both periods of training, with R for 14 weeks more effective than E. Interestingly, no changes in DCX + were observed in KO after 2 weeks, being even undetectable after 14 weeks of intervention. Thus, autophagy is crucial for R performance and for exercise-induced adult neurogenesis.

Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits.

Non-alcoholic steatohepatitis (NASH) is one of the most prevalent diseases worldwide. While it has been suggested to cause nervous impairment, its neurophysiological basis remains unknown. Therefore, the aim of this study is to unravel the effects of NASH, through the interrelationship of liver, gut microbiota, and nervous system, on the brain and human behavior. To this end, 40 Sprague-Dawley rats were divided into a control group that received normal chow and a NASH group that received a high-fat, high-cholesterol diet. Our results show that 14 weeks of the high-fat, high-cholesterol diet induced clinical conditions such as NASH, including steatosis and increased levels of ammonia. Rats in the NASH group also demonstrated evidence of gut dysbiosis and decreased levels of short-chain fatty acids in the gut. This may explain the deficits in cognitive ability observed in the NASH group, including their depressive-like behavior and short-term memory impairment characterized in part by deficits in social recognition and prefrontal cortex-dependent spatial working memory. We also reported the impact of this NASH-like condition on metabolic and functional processes. Brain tissue demonstrated lower levels of metabolic brain activity in the prefrontal cortex, thalamus, hippocampus, amygdala, and mammillary bodies, accompanied by a decrease in dopamine levels in the prefrontal cortex and cerebellum and a decrease in noradrenalin in the striatum. In this article, we emphasize the important role of ammonia and gut-derived bacterial toxins in liver-gut-brain neurodegeneration and discuss the metabolic and functional brain regional deficits and behavioral impairments in NASH.

Current State of Transcranial Magnetic Stimulation and its use in Psychiatry.

INTRODUCTION: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that could be used as a therapeutic intervention in order to treat psychiatric disorders. AIM: Reviewing the effectiveness of TMS in the modulation of cognitive functions and also detailing its potential applications in psychiatric treatments. DEVELOPMENT: TMS has been traditionally used for the treatment of a great variety of neurological or psychiatric conditions by modulating the activity in brain areas and networks. Therapeutic benefit has been found in depressive disorders, anxiety, schizophrenia, addiction, and neurodevelopmental disorders as well as in brain damage and neurodegenerative disorders. Moreover, TMS is a technique which offers great tolerance and can be used as complement with other therapies. However, it is not easy to define an optimal treatment for every pathology: the parameters of stimulation are variable, and its effects at the cellular level of the nervous system are not well-known. CONCLUSION: While it is true that TMS provides many therapeutic benefits, it requires further investigation. It is necessary to detail the action mechanism of the stimulation and the long-term side effects, if any. This information would allow the design of specific treatment protocols for different psychiatric disorders.

High frequency repetitive transcranial magnetic stimulation improves neuronal activity without affecting astrocytes and microglia density.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique capable of producing changes in the electrical potential of neurons. Currently, the application of rTMS in clinical practice and as a neurophysiological tool is increasing. However, the exact cellular mechanisms underlying rTMS-based therapies are not completely clear. Additionally, glial cells have been studied less. Our aim was to investigate the effect of three days of high-frequency rTMS on neuronal metabolism and neuronal activation, in addition to its effect on glial cells. For this purpose, we performed histochemistry and immunohistochemistry procedures: the histochemistry of cytochrome oxidase (COx) to assess neuronal metabolic activity, and the immunohistochemistry of c-Fos (marker of neuronal activity), GFAP (marker of astrocytic reactivity), and Iba1 (selective marker of reactive microglia). Our results showed enhanced metabolic activity after rTMS in the retrosplenial and parietal cortex and CA1 and CA3 subfields of the hippocampus. Moreover, higher c-Fos activity was found in the agranular retrosplenial cortex. Finally, we did not find changes between groups in the induction of astrocyte and microglia reactivity in any of the immunostained regions. In conclusion, we can assume that three days of high-frequency rTMS applied in healthy rats does not alter astroglia reactivity or inflammatory responses, such as microglia proliferation. Because we have shown an upregulation of neuronal metabolic activity in many limbic brain structures, in addition to higher c-Fos levels in the nearest cortical area to the rTMS, our work provides novel insight into the effectiveness and safety of rTMS as a brain modulation therapy.