Introduction:
Primary Bile Acid Diarrhea (PBAD) is a debilitating gastrointestinal disorder characterized by excessive bile acid secretion leading to chronic diarrhea. This study aimed to investigate fecal bile acid changes in PBAD diagnosed using SeHCAT testing.

Methods:
Fecal samples from 26 subjects with PBAD were compared with 21 healthy controls. 38 bile acids were analyzed using ultra-high-performance liquid chromatography-mass spectrometry. We extended the range of bile acids measured to include various epimers including iso- (3-beta-OH) forms, several oxo- (keto-) intermediates, and some allo- (5-alpha) species, and 3-sulfated forms. Quantified results were obtained for 24 bile acids and semi-quantified, relative results on a further 14.

Results:
The total measured bile acid median value was 2.87-fold higher in the PBAD group. As reported before, most bile acids were unconjugated with low levels of glycol- and tauro-conjugated bile acids. Primary bile acids accounted for a median of 6% in controls and 11% in PBAD when their iso variants were included. Deoxycholic was the most abundant, in both groups (50% controls, 60% PBAD). Lithocholic was next at 25% in controls, but was only 10% in PBAD, where 12-oxo-lithocholic was the second commonest, at 11% in both groups. Various iso-forms were slightly more abundant in PBAD, but iso-ursodeoxycholic was increased 8-fold, as was the intermediate 7-oxo-lithocholic. For the sulfated forms, the largest relative increase was found for ursodeoxycholic-3-sulfate, where a median ratio of 8.9 was found. Interestingly, the bile acids in the allo-pathway (3-oxo-cholanic, 5α-cholanic acid-3-one, allolithocholic, and isoallolithocholic) were all less abundant in the PBAD group. In particular, the PBAD: control ratio of medians for isoallolithocholic was only 0.1 (p<0.0001).

Conclusion:
This study has identified differences for various bile acids in SeHCAT-diagnosed PBAD subjects, providing evidence that bile acid metabolism by the fecal microbiome is likely to have significant differences. Bacterial species which possess the enzymes capable of modifying these bile acids have been identified and these, together with further specific bile acids studies, may provide insight into the pathogenesis, diagnosis and treatment of PBAD.

Danielle Carson

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