Gut Microbiota and Behcet's Syndrome: a Dietary Intervention Trial (MAMBA Study)
Condition: Behcet Syndrome
MeSH terms: Behcet Syndrome; Syndrome
Study type: Interventional

Summary: 
      Behçet's syndrome (BS) is an idiopathic, chronic, multi-systemic inflammatory disorder
      characterized by ocular disease, skin lesions, vascular, neurological and gastrointestinal
      involvement. A recent study showed a peculiar dysbiosis of gut microbiota (GM) in BS
      patients, with specific changes in the profiles of short-chain fatty acids, especially
      butyrate. Over the last few years, a growing interest on the role of GM in metabolic
      disturbances has been manifested. Diet is one of the major factors driving the GM composition
      and functionality. In this context, the influence of diets generally recognized healthy on GM
      has been explored, but consistent data on autoimmune and inflammatory diseases are not
      available. The aim of this intervention study is to investigate whether a
      lacto-ovo-vegetarian diet enriched in substrates with potential for butyrate production or a
      Mediterranean diet supplemented with oral butyrate could be beneficial for GM and metabolic
      risk profile in BS.
    

Detailed description: 
      Background / State of Art:

      Behçet's syndrome (BS) is a systemic inflammatory disorder characterized by a wide range of
      potential clinical manifestations with no gold-standard therapy. Although BS is usually not a
      life-threatening condition, mortality can be associated with vascular-thrombotic and
      neurological affections.

      A recent study by our group, for the first time, provided evidence of a peculiar gut
      microbiota (GM) dysbiosis in BS patients, with reduced biodiversity, and decrease in
      short-chain fatty acid (SCFA)-producers and butyrate production. In light of this, controlled
      dietary interventions specifically designed to favor the increase of butyrate-producing
      members of the GM may support the recovery of a healthy GM ecosystem. Lacto-ovo-vegetarian
      diet is characterized by abstention from consuming meat and meat products, poultry, seafood
      and flesh from any other animal and by a large amount of plant- derived foods. This dietary
      pattern has been largely demonstrated to be beneficial for both patients with an established
      disease and for subjects with traditional risk factors for chronic diseases. Indeed, dietary
      patterns rich in plant-based food have been found to promote a more favorable GM profile,
      according to the high amount of dietary fiber and fermentable substrate, which are sources of
      metabolic fuel for GM fermentation that, in turn, result in end products - mainly SCFA - that
      are key microbial metabolites with a multifactorial role on the host health.

      Hypothesis and Specific aims:

      Although the pathogenesis of BS is currently unknown, it has been recently classified at the
      crossroad between autoimmune and autoinflammatory syndromes. GM has been found to deeply
      influence our metabolic and immunological health, and specific perturbed GM configurations
      have been indicating a fascinating link between intestinal microbes and health status. A
      recent study from our group showed that a peculiar dysbiosis of the GM ecosystem is present
      also in patients with BS, corresponding to specific changes in the profiles of SCFA
      production. In particular, the GM ecosystem in BS showed a low biodiversity, in line with
      several other chronic disorders. Moreover, a significant depletion of well- known butyrate
      producers, Roseburia and Subdoligranulum, and a corresponding decrease of butyrate production
      in BS patients was demonstrated. Butyrate - which is the preferred fuel for colonocytes - is
      able to induce T regulatory cell differentiation via several mechanisms, so the butyrate
      impairment in BS patients could favor a reduced T regulatory cell- mediated control, thus
      promoting a powerful immuno-pathological T cell responses.

      In this context, over the last years, growing evidence suggested that high-fiber dietary
      patterns are able to promote a more favorable GM profile, and are key mediators of microbial
      diversity. In particular, it has recently been demonstrated that high adherence to a
      lacto-ovo-vegetarian diet - including high intake of non-refined cereals, fruit, vegetables
      and legumes - is associated with a beneficial GM profile, with enrichment in fiber-degrading
      bacteria and increase of fecal SCFA. In a similar way, other dietary patterns have been shown
      to modulate GM dysbiosis, by supporting the recovery of a balanced microbial community of
      health-promoting SCFA-producing members with the decrease of pro-inflammatory groups.
      Furthermore, current evidence indicates that the consumption of certain fibers - such as
      inulin and resistant starch - leads to specific GM rearrangements with the production of more
      butyrate than others in humans.

      All these findings let hypothesize that the adherence to a controlled dietary profile such as
      lacto-ovo-vegetarian diet, possibly enriched in substrates with potential for butyrate
      production may select butyrate-producing bacteria - especially Roseburia spp. (Clostridium
      cluster XIVa) and Faecalibacterium prausnitzii (Clostridium cluster IV)- so reversing the
      pro- inflammatory dysbiosis observed in BS.

      Preliminary Data:

      A recent study by our group showed that a peculiar dysbiosis of the GM ecosystem is present
      in patients with BS, corresponding to specific changes in the profiles of SCFA production. By
      strengthening this dysbiotic GM structure, a significant decrease of fecal butyrate
      production was found in BS patients. More recently, a high percentage of Th1/Th17 cells at
      gut mucosal level in BS patients was observed, thus suggesting a reduced T regulatory
      activity, probably mediated by reduced levels of butyrate (unpublished data).

      Specific Aim 1: To conduct a dietary intervention randomized controlled trial in order to
      investigate whether a lacto-ovo-vegetarian diet enriched in substrates with potential for
      butyrate production or a Mediterranean diet supplemented with 2 g/day of butyrate could be
      beneficial for GM and for the amelioration of the clinical manifestations and disease
      severity of patients with BS.

      Specific Aim 2: To evaluate the effects of these interventions on: inflammatory parameters,
      circulating biomarkers of disease, endogenous butyrate production, and oxidative stress
      markers.

      Specific Aim 3: To validate and extend our preliminary results on GM ecosystem dysbiosis in
      BS patients
    

Intervention name(s): Vegetarian diet; Mediterranean diet with butyrate; Mediterranean diet
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): 7-days dietary profile with a Vegetarian diet (VD), containing inulin and resistant starch-rich foods and including no meat and fish, but containing eggs and dairy, for 3 months; 7-days dietary profile with Mediterranean diet with oral supplementation with butyrate (MD+Bt), 2 g/day, for 3 months; 7-days dietary profile with Mediterranean diet (MD), including 2 portions per week of fish and 3 portions per week of fresh and processed meat (2 of which fresh or processed red meat), for 3 months
Other intervention name(s): VD; MD+Bt; MD
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized crossover open dietary intervention study with 3 arms of intervention
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Gut microbiota; Mediterranean diet; Vegetarian diet; Short chain fatty acids