Intestine, microbiome and osteoarthritis

Rationale: Three major aspects of functioning of the intestine, intestinal barrier (1), intestinal associated immune tolerance (2) and intestinal microbiome (3) interact closely in a very controlled way. A deviant homeostasis contributes to endotoxemia, low chronic systemic inflammation, often with constipation. This deviant homeostasis is often associated with elevated systemic inflammation and localized chronic inflammatory diseases like osteoarthritis (OA) and cardiovascular diseases. Short chain fatty acids, acetate, propionate and especially butyrate, formed by fermentation of non-digestible dietary fibres by the intestinal microbiome are essential for the mentioned aspects of the functioning of the intestine. The association between impaired intestinal barrier function and OA have been described in various studies and it was postulated that amelioration of the impaired barrier function would ameliorate OA. Several studies suggest that the low-grade chronic systemic inflammation in OA is associated with local inflammation in the intestine and impaired intestinal barrier function. We hypothesize that treatment with Sustained Release Calcium Butyrate (SRCaBu) will ameliorate: 1) the intestinal microbiome, intestinal barrier function and immune tolerance: 2) lower systemic inflammation of OA of the hand.
The primary objectives of this study:
This proof of concept study is to estimate the effects of SRCaBu (600 mg daily for four weeks compared with placebo) on compositional and functional characteristics of the microbiome for future sample size calculation.

The secondary objectives:
1) To evaluate the short-term effects (i.e. 4 weeks) of SRCaBu (600 mg dd) compared with placebo on pain and functioning of the hands in hand OA patients.
2) To evaluate whether SRCaBu (600 mg dd) lowers systemic inflammation in hand OA.
3) To evaluate whether immune tolerance will improve as mediating factor for lowering inflammation by characterizing the phenotype of T-cells and monocytes and determining the response of activated peripheral blood mononuclear cells (PBMCs) of patients before and after intake of 600 mg dd SRCaBu.
4) To examine the preliminary safety profile of (600 mg dd) SRCaBu in patients with hand OA over 4 weeks.
5) To examine the association between intestine functioning and pain and functioning of the hands in hand OA patients.
6) To examine the effect of SRCaBu intake on stool behaviour.
Study design: proof of concept, randomized, (double-)blinded, placebo-controlled trial design with follow-up of 4 weeks.
Study population: People with OA of the hand (both hands), aged 50 to 75 years,
BMI ≥20 and ≤30 kg/m2, fulfilling ACR criteria for hand OA, OA in other joints will be allowed.
Assessments: Physical examination 2x (blood pressure, waist circumference, weight, length, number of tender and swollen joint hands (2x). clinical hallmarks (1x)), X-ray of the hands, (1x), vena puncture (2x), faecal sampling (at home) (2x). Questionnaires (2x): hand functioning (MHQ) , quality of life (SF12) patient’s global assessment. Electronic daily questionnaires on pain (NRS) and stool behaviour (Bristol stool behaviour questionnaire). Medication adherence (pill count at 4 weeks).
Intervention and control group: treatment with placebo or SRCaBu (600mg dd) for a period of 4 weeks;
Main study parameters/endpoints: compositional and functional characteristics of the microbiome.
Secondary endpoints: change in intestinal barrier function, change in systemic inflammation parameters, immune tolerance and inflammatory response, tender and swollen joint count, pain, functioning of hands, patient’s global assessment, quality of life, stool behaviour.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Burden; 2 visits to Sint Maartenskliniek (consultation and physical examination; blood pressure, blood sampling (2x 53 mL), faecal sampling (at home 2x)). Online questionnaires (daily). Daily intake of 4x 150 mg SRCaBu or placebo for four weeks.
Group relatedness:
There is no disease modifying agent available for OA. The now used medicines, non-steroidal anti-inflammatory agents and corticosteroids can have unwanted side effects. New is the treatment with Tanezumab, a humanized murine monoclonal antibody to nerve growth factor. Tanezumab is a completely new approach for the treatment of pain, but has drawbacks that it sometimes accelerates the process of joint degradation, and is expensive.

We hypothesize that treatment with Sustained Release Calcium Butyrate (SRCaBu) will ameliorate: 1) the intestinal microbiome, intestinal barrier function and immune tolerance: 2) lower systemic inflammation of OA of the hand.

Assessments will be performed at baseline and after 4 weeks of follow-up.

Sustained Release Calcium Butyrate (SRCaBu)