Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth

Funkhouser-Jones, Lisa J.; Xu, Rui; Wilke, Georgia; Fu, Yong; Schriefer, Lawrence A.; Makimaa, Heyde; Rodgers, Rachel; Kennedy, Elizabeth A.; VanDussen, Kelli L.; Stappenbeck, Thaddeus S.; Baldridge, Megan T.; Sibley, L. David

doi:10.1016/j.celrep.2023.112680

Cited by 8 publications

(2 citation statements)

References 73 publications

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“…Alternatively, we suggest that the epithelial cells uptake the bacterial metabolites and the parasite retrieves these second-hand compounds, following cell invasion. Some studies have already investigated the impact of microbiota-derived metabolites on Cryptosporidium infection in mice [ 91 , 92 ]. One study demonstrated that medium- or long-chain saturated fatty acids inhibited the growth of C. parvum , whilst long-chain polyunsaturated fatty acids promoted C. parvum infection in mice [ 92 ].…”

Section: Discussionmentioning

confidence: 99%

“…One study demonstrated that medium- or long-chain saturated fatty acids inhibited the growth of C. parvum , whilst long-chain polyunsaturated fatty acids promoted C. parvum infection in mice [ 92 ]. Another recent study shows that indole has an inhibitory effect on the growth of C. parvum in mice and on host mitochondrial respiration in HCT-8 cells which could affect the parasites ability to scavenge essential metabolites from the host [ 91 ]. These studies further endorse the described approach as a potential therapeutic avenue against cryptosporidiosis, however further investigation is required to ascertain the interaction between Cryptosporidium and the microbiota-derived metabolites in cattle.…”

Section: Discussionmentioning

confidence: 99%

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Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis

Hares,

Griffiths,

Johnson

et al. 2023

anim microbiome

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Background Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites’ biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. Results In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case–control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. Conclusions The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%