The gut-brain axis: is intestinal inflammation a silent driver of Parkinson\u2019s disease pathogenesis?

Despite effective antiretroviral therapies, chronic inflammation and spontaneous viral "blips" occur in HIV-infected patients. Given the roles for monocytes/macrophages in HIV pathogenesis and extracellular vesicles in intercellular communication, we performed this systematic review to delineate the triad of HIV, monocytes/macrophages, and extracellular vesicles in the modulation of immune activation and HIV activities. We searched PubMed, Web of Science, and EBSCO databases for published articles, up to 18 August 2022, relevant to this triad. The search identified 11,836 publications, and 36 studies were deemed eligible and included in this systematic review. Data were extracted for the characteristics of HIV, monocytes/macrophages, and extracellular vesicles used for experiments and the immunologic and virologic outcomes in extracellular vesicle recipient cells. Evidence for the effects on outcomes was synthesized by stratifying the characteristics by outcomes. In this triad, monocytes/macrophages were potential producers and recipients of extracellular vesicles, whose cargo repertoires and functionalities were regulated by HIV infection and cellular stimulation. Extracellular vesicles derived from HIV-infected monocytes/macrophages or the biofluid of HIV-infected patients enhanced innate immune activation and HIV dissemination, cellular entry, replication, and latency reactivation in bystander or infected target cells. These extracellular vesicles could be synthesized in the presence of antiretroviral agents and elicit pathogenic effects in a wide range of nontarget cells. At least eight functional types of extracellular vesicles could be classified based on the diverse extracellular vesicle effects, which were linked to specific virus- and/or host-derived cargos. Thus, the monocyte/macrophage-centered multidirectional crosstalk through extracellular vesicles may help sustain persistent immune activation and residual viral activities during suppressed HIV infection.

The Gut Microbiome in Health and Disease

Mutations in the GBA1 (glucosylceramidase beta 1) gene cause the most common lysosomal storage disorder, Gaucher disease (GD), characterized by the lysosomal accumulation of glucosylceramide and lysosomal dysfunction. Downstream of defects in lysosomal-autophagosome fusion, GD cells display autophagic dysfunction. Immune activation and inflammation are also known features of GD pathogenesis. However, the precise link between autophagy and immune activation, and the tissue-specific nature of these pathologies, are yet to be determined. Here we summarize our recent manuscript, which probes the role of autophagy in stimulating a chronic innate immune response in a Drosophila GD model. The gut-brain axis is increasingly being implicated in disease pathology, and accordingly, we demonstrated gastrointestinal dysfunction and gut microbiome dysbiosis in GD flies. Moreover, intestinal cells display lysosomal-autophagic defects like those seen in the GD fly brain. Stimulation of autophagy with rapamycin treatment is sufficient to lower NF- B signaling in the gut. Our research suggests that autophagic impairment in GD flies drives microbiome dysbiosis and chronic immune activation, with deleterious consequences on organismal health. We highlight pharmacological activation of autophagy, targeting tissues such as the gut, as a potential therapeutic strategy in GD. Abbreviations AMP, antimicrobial peptide; DAMP, damage associated molecular pattern; GBA1, glucosylceramidase beta 1; LC3, microtubule-associated protein 1 light chain 3; MEGF10, multiple EGF like domains 10; mTOR, mammalian target of rapamycin; PGRP, peptidoglycan recognition protein receptor; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β.

Chapter 10 - Cellular Immune Responses in Natural and Non-natural Hosts of Simian Immunodeficiency Virus Infection

MSC-EVs protect mice from graft-versus-host disease pathology in a preparation dependent manner

HIV disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Cognitive frailty, defined as the coexistence of mild cognitive impairment symptoms and physical frailty phenotype in older persons, is increasingly considered the main geriatric condition predisposing to dementia. Recent studies have demonstrated that gut microbiota may be involved in frailty physiopathology by promoting chronic inflammation and anabolic resistance. The contribution of gut microbiota to the development of cognitive impairment and dementia is less defined, even though the concept of “gut–brain axis” has been well demonstrated for other neuropsychiatric disorders. The aim of this systematic review was to summarize the current state-of-the-art literature on the gut microbiota alterations associated with cognitive frailty, mild cognitive impairment and dementia and elucidate the effects of pre- or probiotic administration on cognitive symptom modulation in animal models of aging and human beings. We identified 47 papers with original data (31 from animal studies and 16 from human studies) suitable for inclusion according to our aims. We concluded that several observational and intervention studies performed in animal models of dementia (mainly Alzheimer’s disease) support the concept of a gut–brain regulation of cognitive symptoms. Modulation of vagal activity and bacterial synthesis of substances active on host neural metabolism, inflammation and amyloid deposition are the main mechanisms involved in this physiopathologic link. Conversely, there is a substantial lack of human data, both from observational and intervention studies, preventing to formulate any clinical recommendation on this topic. Gut microbiota modulation of cognitive function represents, however, a promising area of research for identifying novel preventive and treatment strategies against dementia.

Purpose: Irritable Bowel Syndrome (IBS) is the most common functional bowel disease in the world, particularly in the western society. The estimated prevalence is 10-20%. The exact etiology is still not elucidated. It is multifactorial with various etiologies postulated including discordant communication in the brain gut axis, genetic, environmental, infectious, stress and possible intra mucosal immune disarray. Mast cell proctopathy has been described in diarrheal type of IBS (IBS-D). Tight junction dysfunction has been proposed for the constipation type of IBS (IBS-C). Intra epithelial predominance of immune cell activation has also been observed. We proposed a clinico-pathological pilot study to correlate mucosal immune activity (intraepithelial CD3+, CD4+ and mast cells) quantitatively with subsets of IBS (IBS-C and IBS-D). Methods: Sixty (N=60) patients (age range: 29 to 45) satisfying ROME III criteria for IBS were enrolled from an urban community practice with diverse ethnicity in New York City, equally divided into IBS-D (n=20), IBS-C (n=20) and twenty patients (n=20) without IBS or Inflammatory Bowel Disease(IBD) as age-matched controls. Initial Blood work and stool samples were taken to rule out any concomitant inflammatory bowel disease or other active bowel infections. All patients underwent flexible sigmoidoscopy and four quadrant proximal descending colonic biopsies. All samples were evaluated for mast cells in high power with Tryptase stain and a quantitative immuno-histochemical stain for CD3+ and CD4+ in lamina propria. (Caris Laboratories, Irving, Texas) Exclusions: Patients with HIV, IBD, Microscopic and lymphocytic colitis, Celiac disease, bacterial or parasitic gastrointestinal Infections or infestations, those on drugs altering Gut immunity (steroids, Chemotherapy, radiotherapy, Interferons, TNF Alfa antagonists, immunosuppressives etc.) Results:Tables 1 and 2.Table 1Table 2Conclusion: This study demonstrates that intra-epithelial immune activity plays a definite role in IBS population. Further statistical analysis reveals no significant difference between IBS-D and IBS-C subsets. Larger prospective studies will further establish immune activity and its role in induction of symptoms in IBS and its subsets.

Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt signaling modulator DKK1 is expressed in a variety of tumor types and elevated levels frequently correlate with poor survival. DKK1 promotes tumor growth by stimulating proliferation, metastasis, and angiogenesis, and has been implicated in contributing to an immune suppressive tumor microenvironment. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and selectivity. It is currently being evaluated clinically as a monotherapy and in combination with chemotherapies and other immunotherapies in a variety of solid tumors. Here we demonstrate that efficacy from a murine version of DKN-01 (mDKN-01) in a syngeneic tumor model requires NK cells. mDKN-01 also reduces lung metastasis, further supporting a model where DKK1 neutralization stimulates a NK mediated anti-cancer response. In addition, DKN-01 has efficacy in a human prostate xenograft model that expresses high levels of DKK1 and retains functioning NK cells. Taken together, these data support an innate immunotherapeutic mechanism of action of DKN-01 and suggest that tumor expression of DKK1 may predict response. As such, evaluation of peripheral blood and tumor biopsies from patients undergoing treatment with DKN-01 in combination with chemotherapy or other immunotherapies are underway to demonstrate innate immune mediated anti-tumor activity and validate DKK1 expression as a biomarker. Citation Format: Michael Haas, Heidi Heath, Franziska Schurpf-Huber, Yinyuan Wu, Xinjun Zhang, Xi He, Min Yang, Walter Newman, Michael Kagey. Mechanistic insight into anti-tumor activity of DKN-01, a therapeutic antibody with immune modulatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2404.

The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard biochemical outcome measures to achieve a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

Enteric Neuroscience: The Dawn of a New Discipline

The functions of probiotics, particularly Lactic acid bacteria, have been studied in a range of human diseases, including cancer, infectious diseases, gastrointestinal disorders, and allergies. Among the many ben- efits associated with the consumption of probiotics, modulation of immune activity has received the most attention. This study aimed at investigating the improved immune stimulatory and stability of L. plantarum when cultivated on modified basal media supplemented with the Undaria pinnatifida co-cultured with L. plantarum. An in vitro test showed that U. pinnatifida media cultured L. plantarum is strong enough to survive in the gastric juice (gastric and bile acid). Mouse macrophage-derived cell lines RAW 264.7 was used to measured immune stimulating activity of L. plantarum. When U. pinnatifida media cultured by L. plantarum was NO and TNF-α production is significantly increased compared to basal media cultured L. plantarum. These results show that U. pinnatifida could be applied for a component for cultivation of L. plantarum. This optimized U. pinnatifida medium can be used the improving of sta- bility and immune function on production of probiotics.

ObjectiveRecent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given...

Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.

The gut–brain axis (GBA) is a complex communication network interfacing the gut and the brain of a single individual. The central (CNS) and enteric (ENS) nervous systems are, of course, communicating; however, other pathways are involved in GBA, among which are immune activation, intestinal barrier function, and enteroendocrine signaling. All these communication lines are bidirectional and involve neuro-immuno-endocrine mediators. The reason for the development of such a complex network is to maintain gastrointestinal homeostasis keeping in mind its links with cognitive and affective functions. Recently, the role of enteric flora, or microbiota, has been recognized as a part of the gut–brain axis. The gut microbiota can modulate brain function, forming a crucial link in the bidirectional interactions between the intestine and the nervous system.