Eubiotic effect of rifaximin is associated with decreasing abdominal pain in symptomatic uncomplicated diverticular disease: results from an observational cohort study | BMC Gastroenterology

To the best of our knowledge, this study is the first to evaluate the long-term (i.e., 6 months) effect of rifaximin on the gut microbiota in patients with SUDD. We show here that rifaximin significantly reduced the severity of abdominal pain, which is consistent with previous studies [9,10,11,12]. Whereas treatment with rifaximin over the 6 months was not accompanied by significant changes in the abundance of most major taxa of the fecal microbiome, increases in the abundance of Akkermansia, Verrucomicrobia, and Ruminococcaceae were observed and inversely correlated with the severity of abdominal pain.

Changes in the abundance of Veillonellaceae, Dialister, and Anaerostipes were also observed after 6 months of rifaximin, however, they were not correlated with abdominal pain severity. Thus, it is likely that these bacteria are not involved in the development of abdominal pain in SUDD.

In our study, Akkermansia were identified in the fecal microbiome of 2 patients (16.7%) at inclusion and in 9 patients (75.0%) after 6 months of rifaximin, whereas these bacteria were detected in 90.5% of healthy individuals in a separate study (p < 0.001) (unpublished data from [23]). However, a significantly higher abundance of A. muciniphila has previously been reported in fecal samples of patients with SUDD compared with healthy controls [7]. It should be noted, however, that both our study and the study by Tursi and colleagues [7] excluded patients with a recent history of acute diverticulitis. It is possible that, in patients with diverticulosis, the number of Akkermansia may increase as a compensatory reaction. Therefore, patients with abundant Akkermansia develop asymptomatic diverticulosis or SUDD, while patients who do not have high enough numbers of Akkermansia for this compensatory reaction develop acute diverticulitis. It should also be noted that, in the study by Tursi and colleagues [7], patients with SUDD had a lower abundance of A. muciniphila in the gut microbiota than patients with asymptomatic diverticulosis, however, this difference did not reach the limits of significance, which may have been due to the small patient population (15 and 13 patients, respectively). New larger studies should be performed to resolve this problem.

Akkermansia is the main representative of the Verrucomicrobia phylum in the gut microbiome. This bacterium has several beneficial properties, including an anti-inflammatory effect [28,29,30,31,32]. Specifically, the presence of Akkermansia increases the thickness of the mucin layer and improves the intestinal epithelial barrier, preventing the translocation of harmful bacteria and their components into the intestinal wall [31]. This bacterial translocation results in low-level inflammation, which is believed to play an important role in the pathogenesis of abdominal pain in SUDD [1]. Moreover, the intensity of infiltration of the mucous membrane of the diverticula by inflammatory cells inversely correlates with the abundance of Akkermansia in the mucosal microbiome [5].

The positive effect of Akkermansia on the epithelial barrier and mucous layer is believed to be because these bacteria degrade mucin to molecules that stimulate its formation by feedback and are used by bacteria from the family Ruminococcaceae that form butyrate [29, 31], which is known to strengthen the intestinal barrier [33, 34]. In our study, the abundance of Akkermansia and Ruminococcaceae increased significantly after treatment with rifaximin. However, while the increase in the abundance of Akkermansia was significant at both 3 and 6 months, the increased abundance of Ruminococcaceae was only significant after 6 months of treatment with rifaximin. This result supports the hypothesis of the synergistic effect of these two groups of bacteria on decreasing intestinal permeability, bacterial translocation, low-level inflammation, and abdominal pain associated with patients with SUDD.

Although rifaximin has been reported to increase the abundance of bacteria under the Ruminococcaceae family, there have been no published data to show that its use increases the abundance of Akkermansia [13]. In a previous study [22], rifaximin significantly altered the relative abundance of specific bacteria in patients with SUDD, with a significantly greater abundance of Bacteroidaceae, Citrobacter, and Coprococcus, and a deficiency of Mogibacteriaceae, Christensenellaceae, Dehalobacteriaceae, Pasteurellaceae, Anaerotruncus, Blautia, Eggerthella lenta, Dehalobacterium, SMB53, and Haemophilus parainfluenzae (p-adj < 0.05) reported. However, as patients received only 7 days of treatment with rifaximin, these results must be viewed with caution as they may not represent the long-term effect of rifaximin on the gut microbiota in patients with SUDD.

Two small studies investigated the difference in the gut microbiome between patients with asymptomatic diverticulosis and SUDD [5, 7]. Although neither study reported a significant between-group difference in the abundance of Akkermansia in the gut microbiome, counts of A. muciniphila species were numerically lower in patients with SUDD than in those with asymptomatic diverticulosis (-3.56 ± 1.27 versus − 3.41 ± 1.13, respectively) [7]. However, larger studies are required to confirm the hypothesis that the decreased abundance of Akkermansia in patients with diverticulosis is associated with their transition from asymptomatic to symptomatic. Furthermore, a cohort study of patients with asymptomatic diverticulosis and periodic analysis of their gut microbiota may identify predictors of SUDD.

All patients in our study consumed dietary fiber to prevent constipation, a risk factor for complications of diverticular disease. However, since we selected patients who had consumed dietary fiber for a minimum of 6 months before enrollment, this is unlikely to have influenced our results. In addition, we did not evaluate the severity of stool disturbances or bloating in our patients, since these may depend on dietary fiber intake.

Several limitations of the present study must be acknowledged. Firstly, the number of participants was low, and a substantial proportion of patients were lost at follow-up. Nonetheless, our preliminary results are promising and may support the design of larger controlled studies. The small number of participants can also be explained by self-termination of rifaximin due to persistent improvement or other divergences that led to the exclusion of these patients from the study analysis. Another significant limitation of our study is the lack of a placebo control arm essential to demonstrate an unambiguous symptomatic benefit of rifaximin. Large randomized controlled trials are therefore required to support our findings.

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