Intestinal barrier dysfunction in murine sickle cell disease is associated with small intestine neutrophilic inflammation, oxidative stress, and dysbiosis

Lewis, Curtis A.; Hassan, Sazzad; Sawan, Mariem A.; Joseph, Giji; Darby, Trevor; VanInsberghe, David; Naudin, Crystal; Archer, David; Taylor, W. Robert

doi:10.1096/fba.2022-00121

Cited by 6 publications

(6 citation statements)

References 41 publications

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“…6,21 Ischemia can decrease blood flow and oxygen supply to the intestinal tissue, while reperfusion promotes the accumulation and burst of harmful factors such as reactive oxygen species. 21 In addition, SCD has been associated with intestinal injuries and abnormal intestinal barrier, 37,89 with lower expression levels of junctional complexes such as claudin (CL-1, CL-3, and CL-15) and occludin-1, 66,107 ultimately affecting the barrier balance and leading to gut dysbiosis. 104…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

Kashyap,

Wang

2023

Pain

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Pain is the most common symptom experienced by patients with sickle cell disease (SCD) throughout their lives and is the main cause of hospitalization. Despite the progress that has been made towards understanding the disease pathophysiology, major gaps remain in the knowledge of SCD pain, the transition to chronic pain, and effective pain management. Recent evidence has demonstrated a vital role of gut microbiota in pathophysiological features of SCD. However, the role of gut microbiota in SCD pain is yet to be explored. We sought to evaluate the compositional differences in the gut microbiota of transgenic mice with SCD and nonsickle control mice and investigate the role of gut microbiota in SCD pain by using antibiotic-mediated gut microbiota depletion and fecal material transplantation (FMT). The antibiotic-mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in mice with SCD. Fecal material transplantation from mice with SCD to wild-type mice resulted in tactile allodynia (0.95 ± 0.17 g vs 0.08 ± 0.02 g, von Frey test, P < 0.001), heat hyperalgesia (15.10 ± 0.79 seconds vs 8.68 ± 1.17 seconds, radiant heat, P < 0.01), cold allodynia (2.75 ± 0.26 seconds vs 1.68 ± 0.08 seconds, dry ice test, P < 0.01), and anxiety-like behaviors (Elevated Plus Maze Test, Open Field Test). On the contrary, reshaping gut microbiota of mice with SCD with FMT from WT mice resulted in reduced tactile allodynia (0.05 ± 0.01 g vs 0.25 ± 0.03 g, P < 0.001), heat hyperalgesia (5.89 ± 0.67 seconds vs 12.25 ± 0.76 seconds, P < 0.001), and anxiety-like behaviors. These findings provide insights into the relationship between gut microbiota dysbiosis and pain in SCD, highlighting the importance of gut microbial communities that may serve as potential targets for novel pain interventions.

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Section: Discussionmentioning

confidence: 99%

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

Kashyap,

Wang

2023

Pain

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“…Gut microbiota dysbiosis has been observed in individuals affected by SCD, including children and adults, particularly involving bacteria known for their strong proinflammatory properties [ 13 , 38 , 39 ]. The imbalance in gut microbes has also been replicated in mouse models of SCD [ 13 , 14 , 35 , 40 ], further emphasising the association between gut microbiota changes and the pathophysiology of SCD. Understanding and addressing dysbiosis in SCD not only have implications for VOCs but also for the broader spectrum of health issues associated with an imbalanced gut microbiota.…”

Section: Literature Searchmentioning

confidence: 99%

“…Dysbiosis in the gut microbiota can lead to a decreased production of short-chain fatty acids (SCFAs), thereby impacting bone health in SCD by reducing IGF-1 [ 35 ]. Moreover, gut microbiota dysbiosis in murine SCD is associated with intestinal barrier dysfunction, neutrophilic inflammation, and oxidative stress [ 40 ], indicating diverse mechanisms through which the gut microbiota may influence SCD pain.…”

Section: Literature Searchmentioning

confidence: 99%

“…There are five known Roseburia species: Roseburia intestinalis , Roseburia hominis, Roseburia inulinivorans, Roseburia faecis, and Roseburia cecicola [ 52 ]. All of these species are primary butyrate-producing bacterial clusters [ 31 ] and have been found to have reduced abundance in mouse models and individuals with SCD [ 13 , 38 , 40 ]. Butyrate plays a crucial role in reducing colonic inflammation and oxidative stress, maintaining the gut barrier integrity [ 53 , 54 ], and inducing the production of HbF [ 19 ], which is associated with fewer SCD complications.…”

Section: Potential Bacteria Candidates With Therapeutic Implications ...mentioning

confidence: 99%

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Gut Microbiota: Potential Therapeutic Target for Sickle Cell Disease Pain and Complications

Agbalalah,

Bur,

Nwonu

et al. 2024

Anemia

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Aim. Sickle cell disease has witnessed a 41.4% surge from 2000 to 2021, significantly affecting morbidity and mortality rates, particularly in children from regions with elevated under-5 mortality rates. Gut microbiota dysbiosis is increasingly recognised in SCD, exacerbating complications, particularly chronic pain, marked by significant alterations of proinflammatory bacteria abundance. This review explores the therapeutic potential of Akkermansia muciniphila and Roseburia spp. in alleviating SCD-related complications, emphasising their roles in maintaining gut barrier integrity, reducing inflammation, and modulating immune responses. Method. A literature search up to November 2023 using PubMed, MEDLINE, and Google Scholar databases explored SCD pathophysiology, gut microbiota composition, Akkermansia muciniphila and Roseburia spp. abundance, pain and gut dysbiosis in SCD, and butyrate therapy. Result. A. muciniphila and Roseburia spp. supplementation shows promise in alleviating chronic pain by addressing gut dysbiosis, offering new avenues for sustainable SCD management. This approach holds the potential for reducing reliance on reactive treatments and improving overall quality of life. This research underscores the pivotal role of the gut microbiome in SCD, advocating for personalised treatment approaches. Conclusion. Further exploration and clinical trials are needed to harness the full potential of these gut bacteria for individuals affected by this challenging condition.

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“…The gut microbiota is believed to play a role in the severity of SCD because the permeability of the intestinal barrier is compromised. This is connected with gene silencing of continuous intercellular network proteins, enhanced inflammation, and oxidative stress, which are all specific to the small intestine [ 136 ].…”

Section: Influence Of Gut Microbiome In Sickle Cell Diseasementioning

confidence: 99%

Sickle Cell Disease Update: New Treatments and Challenging Nutritional Interventions

Bell,

Varzakas,

Psaltopoulou

et al. 2024

Nutrients

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Sickle cell disease (SCD), a distinctive and often overlooked illness in the 21st century, is a congenital blood disorder characterized by considerable phenotypic diversity. It comprises a group of disorders, with sickle cell anemia (SCA) being the most prevalent and serious genotype. Although there have been some systematic reviews of global data, worldwide statistics regarding SCD prevalence, morbidity, and mortality remain scarce. In developed countries with a lower number of sickle cell patients, cutting-edge technologies have led to the development of new treatments. However, in developing settings where sickle cell disease (SCD) is more prevalent, medical management, rather than a cure, still relies on the use of hydroxyurea, blood transfusions, and analgesics. This is a disease that affects red blood cells, consequently affecting most organs in diverse manners. We discuss its etiology and the advent of new technologies, but the aim of this study is to understand the various types of nutrition-related studies involving individuals suffering from SCD, particularly in Africa. The interplay of the environment, food, gut microbiota, along with their respective genomes collectively known as the gut microbiome, and host metabolism is responsible for mediating host metabolic phenotypes and modulating gut microbiota. In addition, it serves the purpose of providing essential nutrients. Moreover, it engages in direct interactions with host homeostasis and the immune system, as well as indirect interactions via metabolites. Nutrition interventions and nutritional care are mechanisms for addressing increased nutrient expenditures and are important aspects of supportive management for patients with SCD. Underprivileged areas in Sub-Saharan Africa should be accompanied by efforts to define and promote of the nutritional aspects of SCD. Their importance is key to maintaining well-being and quality of life, especially because new technologies and products remain limited, while the use of native medicinal plant resources is acknowledged.

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Intestinal barrier dysfunction in murine sickle cell disease is associated with small intestine neutrophilic inflammation, oxidative stress, and dysbiosis

Cited by 6 publications

References 41 publications

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

Gut Microbiota: Potential Therapeutic Target for Sickle Cell Disease Pain and Complications

Sickle Cell Disease Update: New Treatments and Challenging Nutritional Interventions

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