Animal retroviruses are known for their transforming potential, and this is also true for the ones hosted by humans, which have gathered expanding attention as one of the potent causative agents in various disease, including specific cancer types. For instance, Human T Lymphotropic virus (HTLV) is a well-studied class of oncoviruses causing T cell leukemia, while human immunodeficiency virus (HIV) leads to acquired immunodeficiency syndrome (AIDS), which is linked to a series of defining cancers including Kaposi sarcoma, certain types of non-Hodgkin lymphoma, and cervical cancer. Of note, in addition to these “modern” exogenous retroviruses, our genome harbors a staggering number of human endogenous retroviruses (HERVs). HERVs are the genetic remnants of ancient retroviral germline infection of human ancestors and are typically silenced in normal tissues due to inactivating mutations and sequence loss. While some HERV elements have been appropriated and contribute to human physiological functions, others can be reactivated through epigenetic dysregulations to express retroviral elements and promote carcinogenesis. Conversely, HERV replication intermediates or protein products can also serve as intrinsic pathogen-associated molecular patterns that cause the immune system to interpret it as an exogenous infection, thereby stimulating immune responses against tumors. As such, HERVs have also been targeted as a potential internal strategy to sensitize tumor cells for promising immunotherapies. In this review, we discuss the dynamic role of human retroviruses in cancer development, focusing on HIV and HERVs contribution. We also describe potential treatment strategies, including immunotherapeutic targeting of HERVs, inhibiting DNA methylation to expose HERV signatures, and the use of antiretroviral drugs against HIV and HERVs, which can be employed as prospective anti-cancer modalities.

Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines-interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)-were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota in Alzheimer's disease (AD) has garnered increasing attention, although the functional implications of these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, and gut microbiota interact in male 3 × Tg-AD and B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) and 12 months-old (12-MO). Employing a combination of behavioral assessments, diffusion kurtosis imaging (DKI), microbiota profiling, cytokine analysis, short-chain fatty acids (SCFAs), and immunohistochemistry, we explored the progression of AD-related pathology. Significant memory impairments in AD mice at both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation and microstructural damage. We observed elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, and IFN-γ, in the serum, which were associated with increased activity of microglia and astrocytes in brain regions critical for memory. Although gut microbiota analysis did not reveal significant changes in alpha diversity, it did show notable differences in beta diversity and a diminished Firmicutes/Bacteroidetes (F/B) ratio in AD mice at 12-MO. Furthermore, a reduction in six kinds of SCFAs were identified at two time points of 6-MO and 12-MO, indicating widespread disruption in gut microbial metabolism. These findings underscore a complex bidirectional relationship between systemic inflammation and gut dysbiosis in AD, highlighting the gut-brain axis as a crucial factor in disease progression. This study emphasizes the potential of integrating DKI metrics, microbiota profiling, and SCFA analysis to enhance our understanding of AD pathology and to identify new therapeutic targets.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by abnormalities in brain microstructure, neuroinflammation, and social behavior deficits. In addition, children with ASD frequently exhibit irritable bowel syndrome and other gastrointestinal symptoms linked to anxiety. This study investigated if central thalamic nucleus deep brain stimulation (CTN-DBS) can improve social behavior, suppress neuroinflammation, restore brain microstructure, and reverse gut dysbiosis in the valproic acid-induced rat model of ASD by modulating the microbiota-gut-brain (MGB) axis. Daily CTN-DBS for 7 days (30 min/day) enhanced neuronal density, organization, and microstructural complexity as evidenced by increases in the diffusion kurtosis imaging (DKI) metrics-mean kurtosis (MK), axial kurtosis (AK), and radial kurtosis (RK). These neurostructural improvements were associated with reduced astrocyte and microglial activation, two core hallmarks of neuroinflammation in ASD, and lower systemic levels of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, signaling factors that may increase gut permeability and disrupt gut microbial composition. Indeed, CTN-DBS enhanced gut barrier function, promoted the proliferation of beneficial Bacteroides spp., and improved short-chain fatty acid (SCFA) metabolism, thereby restoring normal gut acetate and butyrate levels and counteracting dysbiosis. Specific energy absorption rate and thermal effect analyses demonstrated that CTN-DBS is safe under DKI. These findings support CTN-DBS as a safe and efficacious therapeutic strategy to reduce neuroinflammation, restore gray matter circuit function, and improve gut microbial composition in ASD via MGB axis modulation. Furthermore, DKI can reveal neurobiomarkers indicative of these improvements in ASD model rats.