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There is increasing evidence that a number of people experience moderate milk intolerance characterised by increased gas production, bloating and abdominal cramp, which can neither be attributed to lactose intolerance, nor to milk protein allergy. Milk digestion can lead to the formation of bioactive peptides, one of which derived from a mutated gene variant (A1) coding for milk beta-casein has been associated with increased gastrointestinal inflammation and poor gastrointestinal function. In this study, we hypothesise that consumption of non-mutated A2 milk will improve gastrointestinal symptoms in non-lactose milk intolerant individuals.
Non-lactose milk intolerance is a condition that has not been defined clinically yet but the current literature reports existence of subjects who are moderately milk intolerant and whose intolerance can neither be attributed to a defect in lactose intolerance, nor to milk protein allergy. Yet, they experience at least one or two of the following symptoms following milk consumption: gases, bloating, abdominal cramp. It is known that the A1gene variant coding for beta-casein leads to the production of a bioactive peptide with opioid activity named betacasomorphin 7 (BCM7). This peptide has been associated with several metabolic health disorders including diabetes, elevated cardiovascular risk and stimulation of pro-inflammatory signals. Recently, it was reported that non-lactose milk intolerant subjects did not experience such symptoms when consuming milk containing the non-mutated A2 gene variant coding for beta-casein. In this study, we hypothesise that consumption of A2 milk will improve gastrointestinal symptoms in non-lactose milk intolerant individuals. The primary outcome of this study will be the reduction of gastrointestinal inflammation following a course of A2 milk consumption.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A1/A2 milk | Sham Comparator | Commercial conventional A1/A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows:
|
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| A2 milk | Active Comparator | Commercial A2 semi-skimmed fresh pasteurised cow milk. Progressive intake of intervention milk as follows:
|
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| A2 milk 100 | Dietary Supplement | Days 1 and 2: 100 mL A2 milk twice a day |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change in gastrointestinal inflammation indicated by fecal calprotectin | Measurement of fecal calprotectin (ug/g feces) | baseline, 14 days, 28 days, 42 days and 56 days |
| Measure | Description | Time Frame |
|---|---|---|
| Change in NMR-based urinary metabolic profiles | Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit) | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in NMR-based plasma metabolic profiles |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sandrine P Claus, PhD | University of Reading | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Food and Nutritional Sciences | Reading | Berkshire | RG6 6AP | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24166511 | Background | Ul Haq MR, Kapila R, Sharma R, Saliganti V, Kapila S. Comparative evaluation of cow beta-casein variants (A1/A2) consumption on Th2-mediated inflammatory response in mouse gut. Eur J Nutr. 2014 Jun;53(4):1039-49. doi: 10.1007/s00394-013-0606-7. Epub 2013 Oct 29. | |
| 24986816 | Background | Ho S, Woodford K, Kukuljan S, Pal S. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994-1000. doi: 10.1038/ejcn.2014.127. Epub 2014 Jul 2. |
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We do not plan to share IPD with other researchers outside the University of Reading. Anonymous data may be made available upon publication of the study outcome in appropriate repositories (e.g. metabolomic profiles).
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| ID | Term |
|---|---|
| D007787 | Lactose Intolerance |
| ID | Term |
|---|---|
| D008286 | Malabsorption Syndromes |
| D007410 | Intestinal Diseases |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
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| A2 milk 150 |
| Dietary Supplement |
Days 3 and 4: 150 mL A2 milk twice a day |
|
| A2 milk 200 | Dietary Supplement | Days 5 and 6: 200 mL A2 milk twice a day |
|
| A2 milk 250 | Dietary Supplement | Days 7 to 14: 250 mL A2 milk twice a day |
|
| A1/A2 milk 100 | Dietary Supplement | Days 1 and 2: 100 mL A1/A2 milk twice a day |
|
| A1/A2 milk 150 | Dietary Supplement | Days 3 and 4: 150 mL A1/A2 milk twice a day |
|
| A1/A2 milk 200 | Dietary Supplement | Days 5 and 6: 200 mL A1/A2 milk twice a day |
|
| A1/A2 milk 250 | Dietary Supplement | Days 7 to14: 250 mL A1/A2 milk twice a day |
|
Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit)
| baseline, 14 days, 28 days, 42 days and 56 days |
| Change in NMR-based fecal metabolic profiles | Measured using High Resolution 700MHz proton NMR spectroscopy (Bruker) (no unit) | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in gut microbiota ecosystem assessed by sequencing the 16S rDNA extracted from feces | Measures relative abundance of bacterial taxa | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in systemic inflammation indicated by circulating levels of high sensitivity C-reactive protein | hs-CRP in mg/L | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in gastrointestinal function assessed using visual analogue scale for GI symptoms | Measures gases, bloating, abdominal cramps, diarrhoea, headache, constipation, nausea and rash | 14 days |
| Height (in m) used to detect change in BMI (kg/m^2) | baseline |
| Weight (in kg) used to detect change in BMI (kg/m^2) | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in systolic blood pressure in mmHg | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in diastolic blood pressure in mmHg | baseline, 14 days, 28 days, 42 days and 56 days |
| Diagnostic of lactose intolerance by breath hydrogen concentration following ingestion of 25g lactose in 250 mL water | screening visit, 14 days, 42 days and 56 days |
| Diagnostic of lactose intolerance by breath methane concentration following ingestion of 25g lactose in 250 mL water | screening visit, 14 days, 42 days and 56 days |
| Self-reported change in gut transit time | 14 days, 42 days and 56 days |
| Monitoring of changes in psychological behaviour assessed by TMT | baseline, 14 days, 28 days, 42 days and 56 days |
| Monitoring of changes in psychological behaviour assessed by Letter Memory Test | baseline, 14 days, 28 days, 42 days and 56 days |
| Monitoring of changes in psychological behaviour assessed by Flanger Test | baseline, 14 days, 28 days, 42 days and 56 days |
| Monitoring of changes in mood measured by PANAS questionnaire | baseline, 14 days, 28 days, 42 days and 56 days |
| Change in stool consistency using the Bristol stool chart | baseline, 14 days, 28 days, 42 days and 56 days |
| 27039383 | Background | Jianqin S, Leiming X, Lu X, Yelland GW, Ni J, Clarke AJ. Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows' milk. Nutr J. 2016 Apr 2;15:35. doi: 10.1186/s12937-016-0147-z. |
| 8438774 | Background | Johnson AO, Semenya JG, Buchowski MS, Enwonwu CO, Scrimshaw NS. Correlation of lactose maldigestion, lactose intolerance, and milk intolerance. Am J Clin Nutr. 1993 Mar;57(3):399-401. doi: 10.1093/ajcn/57.3.399. |
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |