An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients
Abstract
:1. Introduction
2. Results
2.1. Clinical Trial, Baseline Characteristics and Clinical Results
2.2. NATUREN G® Reduces Serum Concentration of Free IS Only in CKD Patients
2.3. Whole Gut Permeability in Healthy Subjects and in CKD Patients
2.4. NATUREN G® Ameliorates Gastrointestinal Symptoms in the CKD Group
2.5. Total and Free IS Directly Correlate with Azotemia in Synbiotic-Treated CKD Patients
3. Discussion
4. Materials and Methods
4.1. Study Design, Clinical Parameters and GSRS/Bristol Scores
4.2. Liquid Chromatography/Electrospray Ionization–Mass Spectrometry/Mass Spectrometry (LC/ESI–MS/MS) for Quantification of pCS and IS
4.3. Measurement of Gut Permeability
4.4. IL6 ELISA
4.5. Statistical Analysis and Correlations
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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P | S | Difference at Baseline (p Value) | |
---|---|---|---|
Gender | 7 M, 3 F | 7 M, 6 F | - |
Age | 51.5 ± 2.8 | 51 ± 4.3 | 0.6 |
BMI | 25.8 ± 0.9 | 27.2 ± 1 | 0.4 |
eGFR mL/min | 23.9 ± 3.6 | 31.5 ± 2.8 | 0.1 |
Serum creatinine mg/dl | 3.2 ± 0.4 | 2.3 ± 0.2 | 0.04 |
sys BP (mmHg) | 126.5 ± 3.6 | 124.2 ± 3.6 | 0.7 |
dia BP (mmHg) | 82.5 ± 2.5 | 82.7 ± 2.5 | 1.0 |
Serum albumin (g/dL) | 3.9 ± 0.1 | 3.9 ± 0.1 | 0.8 |
Azotemia (mg/dL) | 97 ± 16 | 94.9 ± 7.2 | 0.9 |
BUN (mg/dL) | 45.3 ± 7.5 | 44.3 ± 3.3 | 0.9 |
Blood glucose (mg/dL) | 76.4 ± 2.8 | 78.1 ± 3.4 | 0.7 |
HbA1c % | 36.8 ± 1.3 | 35.8 ± 1.1 | 0.6 |
Serum tryglicerides (mg/dL) | 149.4 ± 22.1 | 134.7 ± 20.6 | 0.6 |
HDL cholesterol (mg/dL) | 53.9 ± 3.9 | 58 ± 5.2 | 0.6 |
LDL cholesterol (mg/dL) | 101.7 ± 6.6 | 97.5 ± 10.4 | 0.8 |
Total cholesterol mg/dL | 174.4 ± 8.4 | 184.4 ± 11.2 | 0.5 |
Serum calcium (mg/dL) | 9.2 ± 0.2 | 9.2 ± 0.1 | 1.0 |
Serum phosphorus (mg/dL) | 3.4 ± 0.3 | 3.5 ± 0.1 | 0.8 |
Serum potassium (mEq/L) | 4.7 ± 0.1 | 4.5 ± 0.1 | 0.3 |
Serum sodium (mEq/L) | 141 ± 0.6 | 142.1 ± 0.6 | 0.2 |
CaxP (mg2/dL2) | 31.6 ± 2.7 | 32.3 ± 1.4 | 0.8 |
Total serum proteins (g/dL) | 7.2 ± 0.1 | 7.2 ± 0.1 | 1.0 |
CRP (mg/L) | 4.1 ± 1.1 | 3 ± 0.1 | 0.3 |
Rrinary creatinine (mg/dL) | 66.7 ± 9.5 | 53.7 ± 3.6 | 0.2 |
Proteinuria (mg/dL) | 577 ± 211 | 500.9 ± 117.9 | 0.8 |
P | S | Difference at Baseline (p Value) | |
---|---|---|---|
Gender | 4 M, 10 F | 5 M, 5 F | - |
Age | 42.7 ± 2.7 | 41.6 ± 3.0 | 0.8 |
BMI | 23.5 ± 0.8 | 26 ± 1.6 | 0.1 |
Serum creatinine mg/dl | 0.79 ± 0.0 | 0.83 ± 0.0 | 0.5 |
sys BP (mmHg) | 109.2 ± 2.6 | 115.6 ± 3.5 | 0.2 |
dia BP (mmHg) | 68.8 ± 2.1 | 78.3 ± 2.2 | 0.01 |
Serum albumin (g/dL) | 4.2 ± 0.1 | 4.1 ± 0.1 | 0.4 |
Azotemia (mg/dL) | 32.6 ± 1.1 | 36.4 ± 3.1 | 0.2 |
BUN (mg/dL) | 15.3 ± 0.3 | 17.0 ± 1.4 | 0.2 |
Blood glucose (mg/dL) | 71.5 ± 2.5 | 75.2 ± 3.2 | 0.4 |
HbA1c % | 33.3 ± 1.3 | 34.6 ± 1.0 | 0.5 |
Serum tryglicerides (mg/dL) | 65.8 ± 6.8 | 91 ± 9.8 | 0.04 |
HDL cholesterol (mg/dL) | 72.7 ± 4.1 | 72.2 ± 7.4 | 1.0 |
LDL cholesterol (mg/dL) | 100.2 ± 5.1 | 113.4 ± 8.5 | 0.2 |
Total cholesterol mg/dL | 186.8 ± 6.3 | 204 ± 10.0 | 0.1 |
Serum calcium (mg/dL) | 9.3 ± 0.1 | 9.2 ± 0.1 | 0.1 |
Serum phosphorus (mg/dL) | 3.4 ± 0.1 | 3.2 ± 0.2 | 0.4 |
Serum potassium (mEq/L) | 4.1 ± 0.1 | 4.1 ± 0.1 | 1.0 |
CaxP (mg2/dL2) | 31.9 ± 1.4 | 29.6 ± 1.9 | 0.3 |
Total serum proteins (g/dL) | 7.5 ± 0.2 | 7.4 ± 0.1 | 0.8 |
CRP (mg/L) | 2.9 ± 0.0 | 4.2 ± 1.3 | 0.3 |
Urinary creatinine (mg/dL) | 103.2 ± 11.0 | 157.1 ± 29.4 | 0.1 |
Proteinuria (mg/dL) | 89 ± 10.6 | 125.9 ± 17.9 | 0.1 |
Treatment | T0 | T2 | T3 | Difference Between Time Points (p-Value) | Difference Between Arms (p-Value) | |
---|---|---|---|---|---|---|
BMI | P | 25.8 ± 0.9 | 26.0 ± 0.9 | 26.0 ± 0.9 | - | - |
S | 27.2 ± 1.0 | 27.0 ± 1.1 | 27.4 ± 1.0 | - | ||
eGFR (mL/min) | P | 23.9 ± 3.6 | 22.7 ± 3.0 | 23.3 ± 3.3 | - | - |
S | 31.5 ± 2.8 | 31.1 ± 2.4 | 31.4 ± 2.5 | - | ||
Serum creatinine (mg/dL) | P | 3.2 ± 0.4 | 3.1 ± 0.3 | 3.1 ± 0.3 | - | p = 0.02 |
S | 2.3 ± 0.2 $ | 2.3 ± 0.2 $ | 2.3 ± 0.2 $ | - | ||
Serum albumin (g/dL) | P | 3.9 ± 0.1 | 3.9 ± 0.1 | 3.8 ± 0.1 | - | - |
S | 3.9 ± 0.1 | 4.0 ± 0.1 | 4.0 ± 0.1 | - | ||
Azotemia (mg/dL) | P | 97.0 ± 16.0 | 95.2 ± 16.4 | 97.5 ± 15.2 | - | - |
S | 94.9 ± 7.2 | 94.1 ± 7.0 | 87.1 ± 6.2 § | 0.01 | ||
Serum calcium (mg/dL) | P | 9.2 ± 0.1 | 9.2 ± 0.2 | 9.0 ± 0.1 | - | - |
S | 9.2 ± 0.1 | 9.2 ± 0.1 | 9.1 ± 0.2 | - | ||
Serum phosphorus (mg/dL) | P | 3.4 ± 0.3 | 3.42 ± 0.2 | 3.2 ± 0.2 | - | - |
S | 3.5 ± 0.1 | 3.4 ± 0.1 | 3.3 ± 0.1 | - | ||
Serum potassium (mEq/L) | P | 4.7 ± 0.1 | 4.5 ± 0.1 | 4.5 ± 0.1 | - | - |
S | 4.5 ± 0.1 | 4.5 ± 0.1 | 4.5 ± 0.1 | - | ||
Serum sodium (mEq/L) | P | 141.0 ± 0.6 | 140.5 ± 0.5 | 138.4 ± 0.8 *§ | p < 0.02 | p = 0.001 |
S | 142.1 ± 0.6 | 142.7 ± 0.4 $ | 140.7 ± 0.8 | |||
CaxP (mg2/dL2) | P | 31.6 ± 2.7 | 31.6 ± 2.5 | 19.7 ± 4.2 | - | - |
S | 32.3 ± 1.4 | 31.8 ± 1.1 | 23.7 ± 3.2 § | 0.03 | ||
Total serum proteins (g/dL) | P | 7.2 ± 0.1 | 7.2 ± 0.2 | 7.1 ± 0.1 | - | - |
S | 7.2 ± 0.1 | 7.1 ± 0.1 | 7.1 ± 0.1 | - | ||
CRP (mg/L) | P | 4.1 ± 1.1 | 3.1 ± 0.1 | 3.0 ± 0.1 | - | - |
S | 3.0 ± 0.1 | 4.2 ± 1.2 | 3.3 ± 0.4 | - | ||
Urinary creatinine (mg/dL) | P | 66.7 ± 9.5 | 59.4 ± 8.7 | 58.3 ± 7.6 | - | - |
S | 53.7 ± 3.6 | 51.8 ± 4.5 | 48.9 ± 3.7 | - | ||
Urinary proteins (mg/dL) | P | 577.0 ± 211.0 | 414.2 ± 139.6 | 431.8 ± 135.4 | - | - |
S | 500.9 ± 117.9 | 497.8 ± 108.8 | 502.1 ± 116.3 | - |
Treatment | T0 | T2 | T3 | Difference Between Time Points (p-Value) | Difference Between Arms (p-Value) | |
---|---|---|---|---|---|---|
BMI | P | 23.5 ± 0.8 | 23.3 ± 0.8 | 23.4 ± 0.8 | - | - |
S | 26.0 ± 1.6 | 26.0 ± 1.6 | 26.3 ± 1.6 | - | ||
Serum creatinine (mg/dL) | P | 0.79 ± 0.03 | 0.83 ± 0.04 | 0.77 ± 0.03 | - | - |
S | 0.83 ± 0.05 | 0.90 ± 0.06 | 0.84 ± 0.05 | - | ||
Serum albumin (g/dL) | P | 4.2 ± 0.1 | 4.1 ± 0.1 | 4.1 ± 0.1 | - | - |
S | 4.1 ± 0.1 | 3.6 ± 0.4 | 4.0 ± 0.1 | - | ||
Azotemia (mg/dL) | P | 32.6 ± 1.1 | 33.4 ± 2.1 | 31.2 ± 1.7 | - | - |
S | 36.4 ± 3.1 | 33.3 ± 3.1 | 33.8 ± 3.0 | - | ||
Serum calcium (mg/dL) | P | 9.4 ± 0.1 | 9.3 ± 0.2 | 7.1 ± 1.1 | - | - |
S | 9.2 ± 0.1 | 9.1 ± 0.1 | 8.0 ± 1.0 | - | ||
Serum phosphorus (mg/dL) | P | 3.4 ± 0.1 | 3.4 ± 0.2 | 3.4 ± 0.1 | - | - |
S | 3.2 ± 0.2 | 3.3 ± 0.2 | 3.4 ± 0.2 | - | ||
Serum potassium (mEq/L) | P | 4.1 ± 0.1 | 4.0 ± 0.1 | 4.1 ± 0.1 | - | - |
S | 4.1 ± 0.1 | 4.0 ± 0.1 | 4.1 ± 0.1 | - | ||
CaxP (mg2/dL2) | P | 31.9 ± 1.4 | 31.8 ± 1.5 | 23.8 ± 3.9 | - | - |
S | 29.6 ± 1.9 | 29.9 ± 1.9 | 26.4 ± 3.9 | - | ||
Total serum proteins (g/dL) | P | 7.5 ± 0.2 | 7.2 ± 0.1 | 7.3 ± 0.1 | - | |
S | 7.4 ± 0.1 | 6.9 ± 0.4 | 7.2 ± 0.1 | - | ||
CRP (mg/L) | P | 2.90 ± 0.04 | 2.9 ± 0.04 | 2.9 ± 0.00 | - | - |
S | 4.2 ± 1.3 | 3.5 ± 0.4 | 3.2 ± 0.2 | - | ||
Urinary creatinine (mg/dL) | P | 103.2 ± 11.0 | 112.2 ± 13.7 | 101.1 ± 17.5 | - | - |
S | 157.1 ± 29.4 | 154.0 ± 43.8 | 136.2 ± 20.5 | - | ||
Urinary proteins (mg/dL) | P | 89.0 ± 10.6 | 85.1 ± 9.0 | 76.2 ± 8.1 | - | - |
S | 125.9 ± 17.9 | 109.2 ± 23.8 | 103.2 ± 13.1 | - |
Healthy Subjects | CKD III B | CKD IV | p | |
---|---|---|---|---|
Number | 27 | 11 | 11 | |
Stomach (sucrose recovery, %) | 0.031 ± 0.006 | 0.019 ± 0.007 | 0.021 ± 0.007 | ns |
Median | 0.02 | 0.02 | 0.02 | |
Range | 0.01–0.16 | 0.01–0.03 | 0.01–0.05 | |
Small intestine (lactulose/mannitol, ratio) | 0.029 ± 0.01 | 0.019 ± 0.01 | 0.03 ± 0.01 | ns |
Median | 0.017 | 0.018 | 0.017 | |
Range | 0.005–0.31 | 0.012–0.032 | 0.01–0.1 | |
Colon (sucralose recovery, %) | 1.03 ± 0.08 | 0.40 ± 0.09 * | 0.30 ± 0.09 * | <0.00001 |
Median | 0.97 | 0.4 | 0.31 | |
Range | 0.01–1.95 | 0.25–0.65 | 0.16–0.51 |
Placebo | Baseline | T2 | T3 | p-Value |
Number | 9 | 9 | 9 | |
Stomach (sucrose recovery, %) | 0.02 ± 0.003 | 0.018 ± 0.003 | 0.021 ± 0.003 | ns |
Median | 0.02 | 0.02 | 0.02 | |
Range | 0.01–0.05 | 0.01–0.03 | 0.01–0.04 | |
Small intestine (lactulose/mannitol, ratio) | 0.027 ± 0.006 | 0.022 ± 0.006 | 0.02 ± 0.006 | ns |
Median | 0.018 | 0.02 | 0.02 | |
Range | 0.012–0.10 | 0.014–0.035 | 0.01–0.035 | |
Colon (sucralose recovery, %) | 0.36 ± 0.06 | 0.37 ± 0.07 | 0.34 ± 0.06 | ns |
Median | 0.32 | 0.37 | 0.36 | |
Range | 0.16–0.56 | 0–0.08 | 0.14–0.57 | |
Synbiotic | Baseline | T2 | T3 | p-Value |
Number | 12 | 12 | 12 | |
Stomach (sucrose recovery, %) | 0.017 ± 0.002 | 0.017 ± 0.002 | 0.015 ± 0.002 | ns |
Median | 0.02 | 0.015 | 0.01 | |
Range | 0.01–0.03 | 0.01–0.03 | 0.01–0.03 | |
Small intestine (lactulose/mannitol, ratio) | 0.019 ± 0.01 | 0.015 ± 0.001 * | 0.015 ± 0.001 * | 0.040 |
Median | 0.017 | 0.015 | 0.014 | |
Range | 0.01–0.032 | 0.008–0.022 | 0.01–0.023 | |
Colon (sucralose recovery, %) | 0.35 ± 0.04 | 0.41 ± 0.05 | 0.36 ± 0.05 | ns |
Median | 0.34 | 0.4 | 0.31 | |
Range | 0.2–0.65 | 0.2–0.7 | 0–0.82 |
Placebo | Baseline | T2 | T3 | p-Value |
Number | 14 | 14 | 14 | |
Stomach (sucrose recovery, %) | 0.027 ± 0.004 | 0.028 ± 0.004 | 0.025 ± 0.002 | ns |
Median | 0.02 | 0.025 | 0.03 | |
Range | 0.01–0.06 | 0.01–0.06 | 0.01–0.04 | |
Small intestine (lactulose/mannitol, ratio) | 0.018 ± 0.003 | 0.18 ± 0.002 | 0.016 ± 0.001 | ns |
Median | 0.016 | 0.016 | 0.017 | |
Range | 0.009–0.047 | 0.01–0.05 | 0.009–0.025 | |
Colon (sucralose recovery, %) | 1.03 ± 0.07 | 1.14 ± 0.09 | 1.04 ± 0.1 | ns |
Median | 1.04 | 1.12 | 0.98 | |
Range | 0.64–1.45 | 0.63–1.64 | 0.58–2.15 | |
Synbiotic | Baseline | T2 | T3 | p-Value |
Number | 10 | 10 | 10 | |
Stomach (sucrose recovery, %) | 0.037 ± 0.012 | 0.035 ± 0.007 | 0.045 ± 0.016 | ns |
Median | 0.02 | 0.02 | 0.02 | |
Range | 0.01–0.16 | 0.02–0.07 | 0.01–0.17 | |
Small intestine (lactulose/mannitol, ratio) | 0.042 ± 0.025 | 0.015 ± 0.002 | 0.017 ± 0.002 | ns |
Median | 0.018 | 0.015 | 0.015 | |
Range | 0.005–0.31 | 0–0.022 | 0.011–0.031 | |
Colon (sucralose recovery, %) | 1.04 ± 0.17 | 0.98 ± 0.07 | 1.13 ± 0.13 | ns |
Median | 0.94 | 0.92 | 1.17 | |
Range | 0.01–1.95 | 0.76–1.44 | 0.45–1.68 |
T0 | T2 | T3 | p-Value Between Time Points | ||
---|---|---|---|---|---|
GSRS 6 | P | 2.40 ± 0.41 | 2.20 ± 0.51 | 2.00 ± 0.32 | - |
S | 2.38 ± 0.34 | 2.08 ± 0.41 | 1.46 ± 0.23 * | 0.04 | |
GSRS 13 | P | 2.20 ± 0.76 | 1.40 ± 0.38 | 1.40 ± 0.38 | - |
S | 2.23 ± 0.27 | 1.15 ± 0.15 * | 1.31 ± 0.20 * | <0.004 | |
Abdominal pain | P | 4.00 ± 0.58 | 4.40 ± 0.75 | 3.40 ± 0.25 | - |
S | 4.85 ± 0.51 | 3.54 ± 0.28 * | 3.62 ± 0.34 | 0.03 * | |
Constipation syndrome | P | 5.00 ± 0.69 | 4.00 ± 0.58 | 4.40 ± 0.64 | - |
S | 6.08 ± 0.80 | 3.77 ± 0.41* | 4.23 ± 0.71 | 0.02 * |
T0 | T2 | T3 | p-Value Between Time Points | ||
---|---|---|---|---|---|
GSRS 3 | P | 2.08 ± 0.28 | 1.15 ± 0.15 * | 1.15 ± 0.15 | 0.01 |
S | 1.67 ± 0.32 | 1.00 ± 0.00 | 1.44 ± 0.28 | - | |
GSRS 9 | P | 3.15 ± 0.26 | 1.77 ± 0.27 * | 2.08 ± 0.35 | 0.01 |
S | 2.33 ± 0.32 | 3.00 ± 0.55 | 2.11 ± 0.46 | - | |
Abdominal pain | P | 8.69 ± 0.81 | 5.92 ± 0.42 * | 6.23 ± 0.51 * | <0.01 |
S | 7.33 ± 0.98 | 5.33 ± 0.22 | 6.56 ± 1.26 | - | |
Indigestion syndrome | P | 9.69 ± 0.95 | 6.31 ± 0.53 * | 6.46 ± 0.66 * | <0.01 |
S | 7.56 ± 0.99 | 8.44 ± 1.17 | 6.89 ± 1.15 | - |
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Cosola, C.; Rocchetti, M.T.; di Bari, I.; Acquaviva, P.M.; Maranzano, V.; Corciulo, S.; Di Ciaula, A.; Di Palo, D.M.; La Forgia, F.M.; Fontana, S.; et al. An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients. Toxins 2021, 13, 334. https://doi.org/10.3390/toxins13050334
Cosola C, Rocchetti MT, di Bari I, Acquaviva PM, Maranzano V, Corciulo S, Di Ciaula A, Di Palo DM, La Forgia FM, Fontana S, et al. An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients. Toxins. 2021; 13(5):334. https://doi.org/10.3390/toxins13050334
Chicago/Turabian StyleCosola, Carmela, Maria Teresa Rocchetti, Ighli di Bari, Paola Maria Acquaviva, Valentina Maranzano, Simone Corciulo, Agostino Di Ciaula, Domenica Maria Di Palo, Flavia Maria La Forgia, Sergio Fontana, and et al. 2021. "An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients" Toxins 13, no. 5: 334. https://doi.org/10.3390/toxins13050334
APA StyleCosola, C., Rocchetti, M. T., di Bari, I., Acquaviva, P. M., Maranzano, V., Corciulo, S., Di Ciaula, A., Di Palo, D. M., La Forgia, F. M., Fontana, S., De Angelis, M., Portincasa, P., & Gesualdo, L. (2021). An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients. Toxins, 13(5), 334. https://doi.org/10.3390/toxins13050334