Gut microbiota and metabolites drive chronic sickle cell disease pain

Abstract

Pain is a debilitating symptom and leading reason for hospitalization of individuals with sickle cell disease. Chronic sickle cell pain is poorly managed because the biological basis is not fully understood. Using transgenic sickle cell mice and fecal material transplant, we determined that the gut microbiome drives persistent sickle cell pain. In parallel patient and mouse analyses, we identified bilirubin as one metabolite that induces sickle cell pain by altering vagus nerve activity. Furthermore, we determined that decreased abundance of the gut bacteria Akkermansia mucinophila is a critical driver of chronic sickle cell pain. These experiments demonstrate that the sickle cell gut microbiome drives chronic widespread pain and identify bacterial species and metabolites that should be targeted for chronic sickle cell disease pain management.

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

“…The gut microbiota is a diverse community of bacteria, viruses, fungi, protozoa, archaea, and other single-celled organisms living symbiotically in the GIT [ 22 , 23 ]. The GIT hosts a vast bacterial population, numbering between 9 and 10 [ 13 , 14 ]. In the colon alone, a diverse community of 160–500 bacterial species with varied characteristics thrives [ 24 ].…”

“…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.…”

“…Experiments with SCD mice highlight the role of the gut microbiota in driving chronic pain, as an oral administration of faecal content from these mice-induced pains [ 14 ]. Dysbiosis in this population has significant implications, promoting the proliferation of pathogenic bacteria, diminishing beneficial bacteria, and leading to chronic inflammation and immune activation.…”

“…This altered gut microbiota potentially worsens SCD pathology. Studies suggest a significant role of the gut microbiota and associated metabolites in chronic pain and SCD-related complications [ 14 ]. Identifying specific bacterial species with the potential to alleviate chronic pain and manage SCD issues is crucial.…”

“…A. muciniphila contributes to gut health by preserving barrier integrity, enhancing mucin production for thicker mucus, influencing tight junctions, and reducing inflammation—offering relief from chronic pain [ 14 – 17 ]. Roseburia spp., a key butyrate-producing bacterial group, produces the anti-inflammatory short-chain fatty acid (SCFA) butyrate [ 18 ].…”