Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn’s disease

Haq, Sabah; Wang, Huaqing; Grondin, Jensine A; Banskota, Suhrid; Marshall, John K.; Khan, Irfan; Chauhan, Usha; Côté, Francine; Kwon, Yun Han; Philpott, Dana J.; Brumell, John H.; Surette, Michael G.; Steinberg, Gregory R.; Khan, Waliul I.

doi:10.1126/sciadv.abi6442

Cited by 27 publications

(15 citation statements)

References 71 publications

(122 reference statements)

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“…Recent studies have shown that autophagy in the TME plays a dual role [6,7]: it can inhibit as well as promote tumor growth by regulating the immune response [8] and the survival, apoptosis, differentiation, activation, effector function, and metastasis of immune cells [9]. For example, autophagy promotes the survival and differentiation of T cells in the TME [10], while autophagy of naive T cells protects them from mitochondrial apoptosis induced by reactive oxygen [11].…”

Section: Introductionmentioning

confidence: 99%

Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy

Cheng

Wang

Zhang

et al. 2022

BMC Med

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Background The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. Methods Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). Results PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the “immune-cold” environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. Conclusions Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy

Cheng

Wang

Zhang

et al. 2022

BMC Med

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“…The human gut microbiota is comprised of a community of microorganisms, and a person's microbiome contains > 150-fold more genes compared to the human genome [8].A wide range of neurotransmitters are produced by gut microbiota and can be traveled across the blood-brain barrier [43]. For example, increased serotonin enhances susceptibility to experimental Crohn's disease and colitis [44]. In contrast, serotonin receptor dysfunction is involved in the pathogenesis of ALS [45].…”

Section: Discussionmentioning

confidence: 99%

“…A wide range of neurotransmitters are produced by gut microbiota and can be traveled across the blood-brain barrier [43]. For example, increased serotonin enhances susceptibility to experimental Crohn’s disease and colitis [44]. In contrast, serotonin receptor dysfunction is involved in the pathogenesis of ALS [45].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Bowel Disease and Neurodegenerative Disorders: Integrated Evidence from Mendelian Randomization, Shared Genetic Architecture and Transcriptomics

Zeng

Wang

Jiang

et al. 2022

Preprint

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Objective Published observational studies have revealed the connection between inflammatory bowel disease (IBD) and neurodegenerative disorders, whereas the causality remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between IBD and neurodegenerative disorders. Design A series of two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci and functional interpretation were further investigated for IBD and ALS. The transcriptomic expressions of shared genes were evaluated in patients with IBD and ALS. Results Genetic predisposition to IBD is associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD is not genetically associated with an increased risk of AD, PD, or MS. Four shared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) were derived, and SCFD1, G2E3, HEATR5A were further identified as novel risk genes with enriched function related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with IBD or ALS. Conclusion Our study reveals the casually protective role of IBD on ALS, and does not support the causality of IBD on AD, PD, or MS. Our findings indicate possible shared genetic architecture and pathways between IBD and ALS. The altered expressions of shared risk genes might contribute to the susceptibility to IBD and the protective effects for ALS. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.

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“…Serotonin exhibits anti-inflammatory properties in rodents, regulating gut permeability and mucosal inflammation ( 118 – 120 ). Indeed, a recent study showed that elevated serotonin levels in mice inhibited autophagy and increased susceptibility to colitis, and elevated serotonin levels in humans were associated with worsening inflammation and Crohn’s disease flareups ( 121 ). In a large IBD cohort study, patients with active disease have increased levels of tryptophan metabolites, especially quinolinic acid, suggesting an increase in tryptophan degradation compared to controls ( 122 ).…”

Section: Nutrient-immune System Interactions In Inflammatory and Gast...mentioning

confidence: 99%

The Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease

et al. 2022

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Diet is an important lifestyle factor that is known to contribute in the development of human disease. It is well established that poor diet plays an active role in exacerbating metabolic diseases, such as obesity, diabetes and hypertension. Our understanding of how the immune system drives chronic inflammation and disease pathogenesis has evolved in recent years. However, the contribution of dietary factors to inflammatory conditions such as inflammatory bowel disease, multiple sclerosis and arthritis remain poorly defined. A western diet has been associated as pro-inflammatory, in contrast to traditional dietary patterns that are associated as being anti-inflammatory. This may be due to direct effects of nutrients on immune cell function. Diet may also affect the composition and function of gut microbiota, which consequently affects immunity. In animal models of inflammatory disease, diet may modulate inflammation in the gastrointestinal tract and in other peripheral sites. Despite limitations of animal models, there is now emerging evidence to show that anti-inflammatory effects of diet may translate to human gastrointestinal and inflammatory diseases. However, appropriately designed, larger clinical studies must be conducted to confirm the therapeutic benefit of dietary therapy.

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Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn’s disease

Abstract: Elevated gut serotonin inhibits autophagy via mTOR promoting a disrupted microbiota and enhanced susceptibility to colitis.

Cited by 27 publications

References 71 publications

Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy

Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy

Inflammatory Bowel Disease and Neurodegenerative Disorders: Integrated Evidence from Mendelian Randomization, Shared Genetic Architecture and Transcriptomics

The Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease

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