Inulin Supplementation for Reducing Inflammation and Knee Pain in Older Adults With Osteoarthritis

Knee osteoarthritis (OA) is a leading cause of pain and disability among older adults. Low-grade systemic inflammation has been implicated in OA pathogenesis, and bacterial products such as lipopolysaccharide (LPS) translocated from the gut microbiome may contribute to joint inflammation. Inulin-type fructans are non-digestible carbohydrates classified as prebiotic fibers. By modulating the gut microbiome, inulin has been shown to promote the growth of beneficial bacteria and to increase short-chain fatty acid (SCFA) production, which may help reduce systemic LPS levels and inflammation.

This is a single-center, randomized, double-blind, placebo-controlled clinical trial of participants aged 40 years or older with radiographically confirmed knee OA and significant knee pain. Participants will be randomized in a 1:1:1 ratio to receive 10 g/day inulin, 15 g/day inulin, or placebo (maltodextrin) for 8 weeks. The primary outcome is change in serum LPS from baseline to 8 weeks in the combined inulin groups compared to placebo.

The study hypothesis is that inulin supplementation will reduce circulating LPS and improve knee pain outcomes, supporting the role of gut microbiome modulation in the management of OA-related inflammation.

• inulin (Drug), also known as Orafti® Inulin, BENEO-Orafti: Inulin is a fermentable prebiotic fiber derived from chicory root. For this study, inulin is packaged into single-dose sachets containing 5 g, 10 g, or 15 g of powder. Participants in the 10 g arm escalate from 5 g/day for 3 days to 10 g/day, then continue with sachets containing a 2:1 blend of inulin and maltodextrin to provide a daily 10 g inulin dose. Participants in the 15 g arm escalate from 5 g/day for 3 days, 10 g/day for 4 days, then 15 g/day for the remaining 8 weeks. Sachets are mixed with food or beverage and taken once daily with the largest meal.
• Maltodextrin (Placebo) (Drug), also known as Placebo: Maltodextrin is a carbohydrate powder widely used as a food additive. For this study, maltodextrin is used as the placebo comparator. It is packaged into single-dose sachets identical in appearance and taste to inulin sachets. Participants receive escalating doses (5 g/day for 3 days, 10 g/day for 4 days, then 15 g/day) for a total of 8 weeks. Sachets are mixed with food or beverage and taken once daily with the largest meal.

Primary outcomes

• Change in serum lipopolysaccharide (LPS) concentration from baseline to 8 weeks [Baseline and 8 weeks]: Serum LPS levels will be measured at baseline and at 8 weeks to evaluate the effect of inulin supplementation compared to placebo.

Secondary outcomes

• Change in serum LPS concentration between 10 g and 15 g inulin groups [Baseline and 8 weeks]: Dose-response effect of inulin supplementation on serum LPS levels.
• Change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [Baseline and 8 weeks]: Self-reported knee pain and function will be measured using the WOMAC scale. Higher scores indicate worse pain, stiffness, and functional limitations. Total possible score of 0-96.

Other outcomes

• Change in systemic inflammatory biomarkers [Baseline and 8 weeks]: Changes in circulating CRP, IL-6, TNF-α, and LBP concentrations will be measured.
• Change in synovial fluid LPS concentration [Baseline and 8 weeks]: Synovial fluid will be collected at baseline and 8 weeks to assess changes in LPS levels.
• Change in knee pain [Baseline and 8 weeks]: Knee pain will be assessed using the Numeric Rating Scale (NRS). Total score range 0-10 with higher scores indicating more severe pain.
• Adherence rate (% sachets taken) [Baseline through Week 8]: Adherence to the assigned intervention will be assessed by calculating the percentage of study sachets taken during the 8-week intervention period. Participants will be asked to return unused sachets at each visit. Adherence will be expressed as the number of sachets consumed divided by the total number expected.

Sex: All, ages: 40 Years to any

Inclusion Criteria:

* Provision of signed and dated informed consent form.
* Stated willingness to comply with all study procedures and availability for the duration of the study (8 weeks).
* Male or female, aged ≥ 40 years.
* Established patient in the VA Connecticut Healthcare System
* At least one knee with pain severity in the past week ≥ 4/10 on numerical rating scale (NRS)
* Self-reported knee pain on most days of the prior month.
* Diagnosed with knee osteoarthritis (Kellgren-Lawrence grade 2-4 on radiographic imaging within the past 2 years).
* Ability to take oral powder supplements and willingness to adhere to the inulin/placebo daily regimen.
* Agreement to adhere to lifestyle considerations (see Section 5.3) throughout study duration, including maintenance of current diet, physical activity, and avoidance of new dietary supplements or complementary therapies.
* English-speaking and able to provide informed consent.
* For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to continue such method during study participation.

Exclusion Criteria:

* Current diagnosis of pre-diabetes (impaired glucose tolerance) or diabetes mellitus (Type 1 or Type 2).
* Use of antibiotics within the past 6 months.
* Current use of medications known to significantly impact the gut microbiome (e.g., proton pump inhibitors, disease-modifying antirheumatic drugs, GLP-1 receptor agonists).
* Use of anti-inflammatory dietary supplements (e.g., turmeric, omega-3 fatty acids) within the past 30 days.
* Participation in another interventional study or use of an investigational drug within the past 30 days.
* Current use of complementary or integrative therapies for knee OA including tai chi, acupuncture or yoga.
* Known allergy or intolerance to components of the study intervention, including inulin or maltodextrin.
* The presence of significant gastrointestinal disease that may interfere with the intervention or outcomes, such as inflammatory bowel disease or active peptic ulcer disease.
* Any medical, psychological, or behavioral condition that, in the opinion of the investigators, would place the participant at undue risk, interfere with study participation or adherence, or compromise data integrity.
* Current diagnosis of alcohol use disorder
* Pregnancy

• Evelyn Hsieh, MD, PhD, Principal investigator, Yale University

NIH grants: R61AT013472