Fecal Indole as a Biomarker of Susceptibility to Cryptosporidium Infection

Abstract

e Cryptosporidium causes significant diarrhea worldwide, especially among children and immunocompromised individuals, and no effective drug treatment is currently available for those who need it most. In this report, previous volunteer infectivity studies have been extended to examine the association between fecal indole and indole-producing (IP) gut microbiota on the outcome of a Cryptosporidium infection. Fecal indole concentrations (FICs) of 50 subjects and 19 taxa of common gut microbiota, including six IP taxa (11 subjects) were determined in stool samples collected before and after a challenge with Cryptosporidium oocysts. At the baseline, the mean FIC (؎ the standard deviation) was 1.66 ؎ 0.80 mM in those who became infected after a challenge versus 3.20 ؎ 1.23 mM in those who remained uninfected (P ‫؍‬ 0.0001). Only 11.1% of the subjects with a FIC of >2.5 mM became infected after a challenge versus 65.2% of the subjects with a FIC of <2.5 mM. In contrast, the FICs of infected subjects at the baseline or during diarrhea were not correlated with infection intensity or disease severity. The relative abundances (percent) of Escherichia coli, Bacillus spp., and Clostridium spp. were greater >2.5-fold in volunteers with a baseline FIC of >2.5 mM, while those of Bacteroides pyogenes, B. fragilis, and Akkermansia muciniphila were greater in those with a baseline FIC of <2.5 mM. These data indicate that some IP bacteria, or perhaps indole alone, can influence the ability of Cryptosporidium to establish an infection. Thus, preexisting indole levels in the gut join the oocyst dose and immune status as important factors that determine the outcome of Cryptosporidium exposure.

Microbiota‐derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo

“…In mice with small intestinal enteropathy, indole (20 mg kg −1 ) reduced infiltrating neutrophils and reversed the upregulation of inflammatory genes (including IL‐1α, IL1‐β, TNF‐α, and IL‐6) induced by indomethacin . Local indole exposure levels may be higher in vivo, than we were able to replicate in vitro, eg, human feces have high μmol L −1 to low mmol L −1 indole levels . Tryptamine (bacterially derived, as described above) was an indole derivative that reversed the IFN‐γ‐enhanced permeability in T84 cell monolayers in a concentration‐related manner.…”

“…A reduction in tryptophan‐derived indoles (Figure , pathway 1) in obesity may be a consequence of altered intestinal microbial populations that produce IPA. Indole itself is produced by commensal Escherichia coli and in human feces, a higher prevalence of E.coli , Bacillus spp ., and Clostridium spp tends to be associated with higher fecal indole concentrations . A species known to produce IPA is C. sporogenes .…”

“…For example, Akkermansia mucinophila reduces metabolic endotoxemia in a transgenic mouse model of atherosclerosis at least in part through increasing tight junction protein gene expression . Interestingly, the abundance of A. mucinophila is inversely correlated with fecal indole concentrations in human …”

“…Indole itself is produced by commensal Escherichia coli 24 and in human feces, a higher prevalence of E.coli, Bacillus spp., and Clostridium spp tends to be associated with higher fecal indole concentrations. 25 A species known to produce IPA is C. sporogenes. 11 Another bacaterially derived metabolite is tryptamine but, unfortunately, plasma levels are not reported in the clinical data generated here, nor previously, 23 maybe due to analytical detection challenges in human biosamples.…”

Comment on “Cryptosporidium Infection Risk: Results of New Dose‐Response Modeling” — Discussion of Underlying Assumptions and Their Implications

“…However, many factors are undoubtedly operative in actual exposure scenarios, so that susceptibility is not solely dependent upon oocyst viability, but also on the interaction of the parasite with various innate host factors such as stomach pH, amount of intestinal mucus, and characteristics of the gut microbial community among others. Indeed, in a recent study, the existing concentration of indole, a product of certain gut microbiota, was strongly linked to Cryptosporidium susceptibility . Thus, assuming that most healthy adults have no defensive barriers to infection from exposure to just one Cryptosporidium oocyst is biologically implausible.…”