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We read with interest the informative and required investigation of bile-acid dysmetabolism, dysbiosis and inflammation in inflammatory bowel diseases (IBD) by Duboc et al.1 The paper suggests that a characteristic finding of IBD is reduced faecal secondary bile acids (BA), increased conjugated BA and increased sulphated BA.1 The authors link the luminal dysmetabolism of BA to dysbiosis, and the loss of microbiota deconjugation, transformation and desulphation enzymatic functions.1 The authors report convincing evidence demonstrating that a decrease in bacteria-bearing bile salt hydrolase (BSH) activities may be involved in the increase in conjugated BA remaining in the faeces, and show that germ-free mice have a similar loss of microbiota enzymatic function and display similar faecal BA irregularities.1 In addition to their role in dietary lipid absorption, BA are signalling modules activating nuclear receptors, including the farnesoid-X-receptor, the constitutive androstane receptor, the pregnane-X-receptor and the vitamin D receptor (VDR), as well as the G-protein-coupled receptor TGR5.2 Recent work demonstrates a significant immune-modulating function of TGR5 activation in the prevention of atherosclerosis and, more generally, the metabolic syndrome.3 Duboc et al describe how in human beings, the strongest activators of the TGR5 anti-inflammatory effect are produced by the gut microbiota, and that BA inhibit the secretion of TNF-α, IL-1β, and IL-6 in macrophages.1
Our group has recently conducted a randomised, double-blind, placebo-controlled, parallel-arm, multicenter study evaluating the effects of a BSH-active strain of Lactobacillus reuteri (NCIMB 30242) in otherwise healthy hypercholesterolemic adults.4 A total of 127 subjects received either L reuteri NCIMB 30242 or placebo capsules over a 9-week intervention period. Subjects were asked to complete a 93-question ROME III diagnostic gastrointestinal (GI) questionnaire prior to the baseline and endpoint visits of the study as a secondary evaluation of changes in GI function. A total of 86 functional GI diagnoses were seen at baseline in 11 of 28 subcategories, and no significant differences were observed in the proportion of subjects reporting functional diagnoses at baseline or at endpoint (p>0.05); however, a significantly higher proportion of subjects in the L reuteri treatment group reported improved symptoms for diagnosis of irritable bowel syndrome (p=0.038) and unspecified functional bowel disorders (p=0.046) over the course of the study. As a result of increased intraluminal BSH activity, treated subjects showed an increase of 1.00 µmol/l (p=0.025) in plasma-deconjugated BA,4 and a significantly reduced molar percent of conjugated BA, relative to placebo, over the course of the study (figure 1). Further, investigation of the inflammatory markers’ high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (Il-6) and tumour necrosis factor-α (TNF-α) showed hs-CRP was reduced by 1.05 mg/l (p=0.005) in treated subjects relative to placebo,4 and that reductions in Il-6 and TNF-α were positively correlated with reductions seen in hs-CRP (table 1).
Although the sample sizes of our functional bowel disorder populations were not large enough to gain significance on changes in circulating BA, and the study evaluated functional disorders in otherwise healthy hypercholesterolemic patients while Duboc et al report on patients with previously diagnosed IBD,1 it may be interesting to readers that oral delivery of a BSH-active probiotic organism resulted in increased intraluminal deconjugation of BA, increased circulating deconjugated BA and a reduction in markers of inflammation. We believe that future work should evaluate the potential for correcting the enzymatic dysregulation of BA in patients with IBD by delivering enzymatically active strains, and should continue to elucidate the mechanisms by which changes in the BA pool appear to exert anti-inflammatory effects through TGR5.
Contributors MLJ, SP and CJM designed the study and prepared the letter. All authors have read and approved the final manuscript.
Funding This work was supported by Micropharma Limited.
Competing interests MLJ and SP acknowledge a conflict of interest as they are cofounders and shareholders of Micropharma. CJM is employed by, and is a shareholder of, Micropharma.
Patient consent Obtained.
Ethics approval The study was conducted according to the principles of the Declaration of Helsinki. Otherwise healthy hypercholesterolemic adults were recruited from six centres in Prague, Czech Republic. The protocol was approved by the Ethics Committee for multicentric clinical trials of the University Hospital Motol, Czech Republic (FDA/OHRP IORG registration no. IORG0000612). The trial was registered on www.clinicaltrials.gov under study number NCT01341613.
Provenance and peer review Not commissioned; internally peer reviewed.
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