Effects of Short-chain Fatty Acids on Inflammatory and Metabolic Parameters in Maintenance Hemodialysis (PLAN)

November 28, 2016 updated by: Dr Biagio Di Iorio, Azienda Sanitaria ASL Avellino 2

Effects of Short-chain Fatty Acids, Here Sodium Propionate, a Metabolism Product of the Human Gut-microbiome, on Inflammatory and Metabolic Parameters in Patients on Maintenance Hemodialysis - a Pilot Study

End-stage renal disease (ESRD) is associated with multiple comorbidities such as cardiovascular disease, anemia, mineral and bone disorders, malnutrition, body wasting, muscle loss (sarcopenia), neurological problems and infections resulting in a poor survival.

In the pathogenesis of the uremic syndrome the altered intestinal function seems to be an important contributor. While the normal gut microbiota plays a prominent role in the maintenance of health and disease prevention, changes of its composition is associated with numerous diseases such as obesity, type 2 diabetes, cardiovascular disturbances and auto-immune diseases.In ESRD metabolic alterations of uremia results in quantitative and qualitative changes of its bacterial flora with an overgrowth of pathobionts (1). Due to concomitant disruption of the intestinal barrier function, noxious luminal products are translocated in the body's internal milieu (2).The accumulation of these compounds correlates with systemic inflammation, protein wasting and accelerated cardiovascular complications in hemodialysis patients (3).

Short-chain fatty acids (SCFA) are produced in the colon and distal small intestine by anaerobic bacteria following fermentation of complex carbohydrates.They have been shown to exert anti-inflammatory, anti-cancer, antibacterial and antidiabetic effects (4). Supplementation of SCFA exerts anti-inflammatory actions both in intestinal epithelial cells (5) and in the cardiovascular system (6). They also positively influence auto- immune reactions /diseases (7,8).

In this study we want to investigate in MHD patients whether a treatment with SCFA in form of sodium propionate (SP) modulates the systemic inflammation, insulin resistance and accumulation of intestinal uremic toxins.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

End-stage renal disease (ESRD) is associated with multiple comorbidities such as cardiovascular disease, anemia, mineral and bone disorders, malnutrition, body wasting, muscle loss (sarcopenia), neurological problems and infections resulting in a poor survival. Important promoters of these obstacles are enhanced generation of reactive oxygen species (ROS), systemic inflammation, acquired immunodeficiency (9, 10) and an impaired glucose and insulin homeostasis (11).

Systemic inflammation and oxidative stress in ESRD are induced by activation of the innate immune system involving monocytes, macrophages, granulocytes and cellular constituents (endothelial cell activation) as well as depletion of natural regulatory T cells that impairs their ability to suppress inflammation .The concomitant reduced humoral immunity is favored by depletion of antigen presenting dendritic cells, a lowered CD44/CD8 T cell ratio, depletion of naïve and central memory T cells, diffuse B cell lymphopenia and an impaired phagocytic ability of monocytes and PMNs (12).

Insulin resistance (IR) participates in the pathogenesis of multiple metabolic and cardiovascular disturbances (13) and is an important factor of the accelerated muscle protein degradation in ESRD (14). Underlying mechanisms of IR are the metabolic inflammation, in particular elevated LPS levels.

In the pathogenesis of the uremic syndrome the altered intestinal function seems to be an important contributor. While the normal gut microbiota plays a prominent role in the maintenance of health and disease prevention, changes of its composition is associated with numerous diseases such as obesity, type 2 diabetes, cardiovascular disturbances and auto-immune diseases. In ESRD metabolic alterations of uremia results in quantitative and qualitative changes of its bacterial flora with an overgrowth of pathobionts (1). Due to concomitant disruption of the intestinal barrier function, noxious luminal products are translocated in the body's internal milieu (Fig.2). The passage includes whole bacteria (going into mesenteric lymph nodes), endotoxins/ lipoproteinlipase (LPS) (cell wall components of the bacteria) and other noxious luminal products which induce a persistent local (gut) and systemic inflammation.The process is intensified by the intestinal generation of several pro-inflammatory uremic toxins such as indoxyl sulfate, p-cresyl sulfate and trimethyamine-N-oxide (2).The accumulation of these compounds correlates with systemic inflammation, protein wasting and accelerated cardiovascular complications in hemodialysis patients (3).

Short-chain fatty acids (SCFA) are produced in the colon and distal small intestine by anaerobic bacteria following fermentation of complex carbohydrates. The 3 major compounds are acetic acid, butyric and propionic acids. SCFA contribute to the health of the gut (microbiome and mucosa) and the host. They have been shown to exert anti-inflammatory, anti-cancer, antibacterial and antidiabetic effects. Lower values and an dysbiotic gut contribute to various diseases such colitis, type 2 diabetes, rheumatoid disease and multiple sclerosis. Supplementation of SCFA exerts anti-inflammatory actions both in intestinal epithelial cells (5) and in the cardiovascular system (6). They also positively influence auto- immune reactions /diseases (7, 8). In particular SCFA enhances formation of regulatory T cells in the colon which are critical for regulating intestinal inflammation (15). Also effector T cells such as Il-10 are implicated (16). Likewise SCFA are involved in the control of body weight and insulin sensitivity (17), cholesterol synthesis (18) and retardation of progressive CKD.

In patients on maintenance hemodialysis (MHD) a diet with a high fiber content, which favors the intestinal SCFA formation (19), lowered the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate (20) and reduced inflammation, cardiovascular diseases and all-cause mortality in CKD/ESRD patients (21). However, in ESRD consumption of a fiber rich diet is limited due to the risk of hyperpotassemia. In addition the frequent antibiotic therapy, application of phosphate binder or iron therapy alters the gut microbiome.

The following mechanisms have been proposed for the actions of SCFA: the G-protein-coupled receptors GPR 41 and GPR 43 (the free fatty acid receptors FFAR 3 and 2 ), GPR 109a, Olfr78 , the inhibition of histone deacetylases (HDAC) and stimulation of histone acetyltransferase (HAT) activity (22, 23).

n this study we want to investigate in MHD patients whether a treatment with SCFA in form of sodium propionate (SP) modulates the systemic inflammation, insulin resistance and accumulation of intestinal uremic toxins. SP is chemically composed by a carboxylic acid moiety and a small hydrocarbon chain with three carbon atoms (black balls), two oxygen (red balls) and the white hydrogen atoms.

SP is involved in most effects of the short chain fatty acids including inhibition of intestinal and hepatocyte lipid synthesis (24), lowering of fasting glycemia (25, 26) and protection against diet-induced obesity ( 27). SP also regulates colonic T-reg cell homeostasis (28) and exerts marked anti-inflammatory actions including intestinal epithelial cells and macrophages (29) as well as in neutrophils, colon cells and colon cultures (30). It improved experimental autoimmune encephalomyelitis (31) and experimental acute renal failure (32). In addition antibacterial effects were documented (33, 34).

The patients under maintenance hemodialysis will receive the food additive sodium propionate with a daily intake of 2 x 500 mg in form of capsules (Propicum) for 12 weeks. The demographic information and the blood chemistry will be collected before the study, after 6, 12 and 16 weeks of drug administration.

The project will last for one year. The planned patient group should comprise of 15 patients on maintenance hemodialysis.

Study Type

Interventional

Enrollment (Anticipated)

15

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Stable hemodialysis patients treated by renal replacement therapy for at least 6 months
  • Written informed consent written

Exclusion Criteria:

  • Patients with malnutrition, infections, carcinoma, previous renal transplant, intestinal diseases (medically diagnosed irritable bowel syndrome, Crohn's disease, ulcerative colitis and diarrhea) and antibiotic treatment within one month of study will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sodium propionate
Sodium propionate will be administered with a daily intake of 2 x 500 mg in form of capsules for 12 weeks.
Other: Sodium Propionate
Sodium propionate is a non-toxic food additive, confirmed and licensed by the European Food Safety Authority (EFSA) sodium propionate E281. We are planning the oral application of 500 mg SP 2x per day. This dose is about 0.014 mg/kg of the body weight. Therefore, no risk of toxicity is expected in the patients.
Other Names:
  • Sodium propionate E281

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Variation from the beginning to the study end of serum inflammatory biomarkers
Time Frame: 16 weeks
endotoxin /lipopolysaccharide levels, high sensitivity C-reactive protein (hs-CRP), fibrinogen, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-10, IL-2, INFγ, TGFβ, IL-4, IL-1β, IL-17a and white blood cell count.
16 weeks
Variation from the beginning to the study end of serum oxidative stress biomarkers
Time Frame: 16 weeks
glutathione peroxidase, malone dialdehyde
16 weeks
Variation from the beginning to the study end of insulin resistance
Time Frame: 16 weeks
Determination of Homa Index (Homeostasis Model Assessment) by measurement fasting blood sugar and insulin level as well as hemoglobin HbA1c. IR appears to be as associated of metabolic disorders including lipid abnormalities, atherosclerotic cardiovascular disease and accelerated muscle protein degradation (Wang et al. 2006). IL is induced in particular by systemic inflammation.
16 weeks
Variation from the beginning to the study end of serum lipid levels
Time Frame: 16 weeks
Triglycerides, total cholesterol, high and low density cholesterol
16 weeks
Variation from the beginning to the study end of hormonal parameter
Time Frame: 16 weeks
Leptin, resistin, adiponectin and glucagon-like peptide -1.
16 weeks
Variation from the beginning to the study end of uremic toxins produced in the intestinal tract
Time Frame: 16 weeks
p-cresyl sulfate, indoxyl sulfate and trimethylamine -N-oxide
16 weeks
Variation from the beginning to the study end of nutritional status
Time Frame: 16 weeks
Serum albumin
16 weeks
Variation from the beginning to the study end of parameters of well-being
Time Frame: 16 weeks
patient reported health (SF-36).
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Sanitaria ASL Avellino 2

Investigators

  • Principal Investigator: Biagio Di Iorio, Chief, PhD, ASL Avellino

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2017

Primary Completion (Anticipated)

July 1, 2017

Study Completion (Anticipated)

December 1, 2017

Study Registration Dates

First Submitted

November 15, 2016

First Submitted That Met QC Criteria

November 28, 2016

First Posted (Estimate)

November 29, 2016

Study Record Updates

Last Update Posted (Estimate)

November 29, 2016

Last Update Submitted That Met QC Criteria

November 28, 2016

Last Verified

November 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ASL AVELLINO

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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