Ignite Creation Date:
2024-05-06 @ 7:57 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06191432
Status:
RECRUITING
Last Update Posted:
2024-05-09
First Post:
2023-12-20
Brief Title:
Tolerability of an Ancient Grain in Patients With Non-Celiac Wheat Sensitivity
Sponsor:
University of Palermo
Organization:
University of Palermo
Study Overview
Official Title:
Tolerability of an Ancient Grain in Patients With Non-Celiac Wheat Sensitivity A Clinical Study and a Search for Diagnostic Biomarkers
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Patients suffering from wheat-related troubles in absence of celiac disease or wheat allergy diagnosis can suffer from non-celiac wheat sensitivity NCWS This is characterized by both gastrointestinal GI and extra-intestinal symptoms which improve with the elimination of wheat intake To date no definitive explanation of pathogenetic mechanisms of NCWS has been proved and similarly no specific non-invasive diagnostic biomarker has been recognized A real need of strict adherence to wheat-free diet WFD in NCWS has never been demonstrated In this context research is actively trying to find wheat varieties with absent or low immune-reactivity to be used for the treatment of NCWS patients Preliminary evidence supports the assumption that diploid wheat species as Triticum monococcum TM compared to common ones Triticum aestivum TA could possess a lower immunogenic potential in NCWS patients The first objective of our project is to verify whether the use of a diploid wheat TM with a lower concentrations and bioactivity of Amylase-Trypsin-Inhibitors ATIs and with gliadin proteins with a better digestibility compared to a hexaploid one TA could improve both symptoms and quality of life QoL of NCWS subjects The second objective is the identification of non-invasive serological biomarkers for NCWS diagnosis The third objective is to identify T cell lymphocytes able to recognize cognate peptides from wheat proteins to better classify and monitor patients affected by NCWS To achieve these results we planned a prospective double-blind clinical trial with crossover in which patients already diagnosed with NCWS according to international criteria and with a double-blind placebo-controlled wheat challenge following a strict WFD will be exposed in double-blind to both TM and TA All the patients will be evaluated clinically at the different timepoints with validated scales to assess tolerability of TM Moreover their intestinal permeability immunological activation and gut microbiota patterns will be studied by both in vitro and in vivo techniques Finally a randomly chosen subset of patients will be studied through single cell transcriptome and T-cell receptor TCR sequencing on rectoscopy biopsy specimens to identify T cell lymphocytes able to recognize cognate peptides from wheat proteins
Detailed Description:
State of the art The association between wheat intake and wheat-related disorders WRDs has been known for a long time including pathologies as celiac disease CD and wheat allergy WA Recently a new non-allergic and non-autoimmune condition has been identified non-celiac gluten sensitivity NCGS This is characterized by both gastrointestinal GI symptoms very similar to those of irritable bowel syndrome IBS eg abdominal pain diarrhea etc and extra-intestinal ones eg arthromyalgias anemia etc which improve on a wheat-free diet WFD
NCGS prevalence rates range from 06 to 13 in the general population and given the lack of a biomarker its diagnosis is based on 1 exclusion of CD and WA 2 symptoms regression on a WFD 3 recurrence of symptoms on a double-blind placebo-controlled challenge DBPCC with wheat
Physicians recognize a significant overlap between NCGS and IBS and it is known that IBS affects about 25 of the general population So if a percentage of IBS patients could have benefit from a WFD this would have a paramount impact on its social health costs being estimated that its indirect costs eg loss of work and reduced productivity are up to 20 billionyears in the US with an annual cost of 9933 per patient Furthermore many patients with IBS-like or upper gastro-esophageal functional-like manifestations self-report a relationship between symptoms onset and wheat ingestion wheat-intolerance Nevertheless a clinical approach with a WFD for all IBS patients would be unmotivated and dangerous determining also a great economic burden
In most IBS patients visceral hypersensitivity may contribute to GI symptoms Immune activation due to mucosal mast cells MCs in close vicinity to gut nerves appears to play a role in IBS symptoms onset A possible neuro-immune interaction in the duodenal submucosa of NCGS patients involving MCs has been described in order to explain GI symptoms Other findings in NCGS include an increased infiltration of eosinophils in GI tract which might produce several inflammatory ie eosinophil cationic protein ECP and tryptase and neuromodulatory substances eg substance P and VIP
Several studies have investigated the performance of serum biomarkers panels in differentiating IBS from NCGS and healthy subjects These included inflammatory cytokines chemokines neurotransmitters and antibodies associated with CD Therefore it is critically important to investigate the performance of serum biomarkers panels to differentiate real NCGS from other conditions
Having not definitively established whether gluten or some other wheats component is responsible for symptoms triggering NCGS has been renamed as non-coeliac wheat sensitivity NCWS which would exclude other relevant cereals such as barley and rye Some components of wheat other than gluten proteins could be potentially deleterious for NCWS patients which include fermentable short-chain carbohydrates FODMAPs and amylase trypsin inhibitors ATIs the latter activating toll-like receptor 4 complex in monocytes macrophages and dendritic cells of the intestinal mucosa might induce innate immunity in both CD and healthy subjects Finally some authors have focused on the activation of innate andor acquired immunity or gut microbiota modifications
Research is actively trying to find wheat varieties with absent or low immune reactivity to be used to treat patients with NCWS Preliminary evidence showed that diploid wheat species as Triticum monococcum TM compared to common ones Triticum aestivum TA and Triticum durum could possess a lower immunogenic potential in NCWS and IBS patients It seems that modern wheats contain higher concentrations and bioactivity of ATIs compared with diploid ones and that gliadin from TM retain a reduced number of immunogenic peptides for CD patients due to a high in vitro digestibility We found that ATIs from TM are sufficiently different than those from TA so to determine lack of immune toxicity in CD after proteolytic digestion Moreover some data showed that in IBS the consumption of ancient wheat can reduce symptoms and proinflammatory cytokines and improves intestinal dysbiosis In this context we have recently shown that NCWS patients who consume ancient grains may receive a late diagnosis due to the possible clinical benefit tolerability obtained with these grains
All these data however must be considered preliminary and the pathogenetic mechanisms and the real clinical tolerability of the ancient wheats remain to be confirmed Thus it is very important to evaluate the hypothesis that specific ancient wheat varieties could be tolerated and safe for NCWS patients trying to identify at the same time possible non-invasive biomarkers to diagnose and differentiate NCWS from IBS patients
Hypotheses and objectives Our hypothesis is that a dietary therapeutic approach based on the use of a diploid wheat TM with a lower concentrations and bioactivity of ATIs and with gliadin proteins with a better digestibility could improve symptoms and quality of life QoL of NCWS patients
We planned to perform a Double-Blind Wheat Challenge DBWC with crossover of 2 wheat varieties TM vs TA in patient diagnosed with NCWS according to Salerno criteria 6 to assess the putative clinical tolerability of TM and analyze the immunological intestinal permeability and microbial differences trying to identify both the pathogenetic mechanisms and potential diagnostic biomarkers of NCWS helping in distinguishing NCWS from IBS patients
If confirmed a dietary regimen with TM would be a more suitable and a less expensive alternative to a WFD and the identification of a biomarker for NCWS will reduce the number of medical visits and examinations with substantial economic savings for the national health systems Furthermore the putative beneficial effect of a diet based on a regional ancient wheat variety will contribute to the regional agriculture and food economy
The overarching objective of the study is to investigate in NCWS patients if a challenge with an ancient wheat TM compared to a modern one TA have a lower symptoms response reflecting visceral hypersensitivity immune activation and distinct microbial profiles in order to guarantee these patients a consistent alternative to WFD and increase their QoL
The second objective is the identification of non-invasive serological biomarkers for NCWS diagnosis
The third objective is to identify through single cell sc transcriptome and T-cell receptor TCR sequencing T cell lymphocytes able to recognize cognate peptides from wheat proteins to better classify patients affected by NCWS with a translational relevance for future tailored therapies
The experimental plan is divided into 4 work packages WPs Within each WP a series of tasks have been defined
WP1 evaluation of clinical response to TM compared to TA in NCWS patients by a DBWC with crossover
Task 11 evaluation of GI symptoms evoked by dietary exposition to TM and TA by a validated GI symptoms rating scale
Task 12 evaluation of extraintestinal symptoms evoked by dietary exposition to TM and TA by an extraintestinal symptoms rating scale
Task 13 evaluation of QoL modifications determined by dietary exposition to TM and TA by a QoL validated scale
WP2 evaluation of intestinal permeability and damage biomarkers in NCWS patients under 3 dietary regimens WFD TM and TA challenge
Task 21 in vivo evaluation of intestinal permeability by the LactuloseMannitol LaMa ratio test
Task 22 analysis of serological indexes of intestinal damage and permeability by ELISA assays
WP 3 Evaluation of immunological inflammatory and visceral hypersensitivity response in NCWS patients under 3 dietary regimens WFD TM and TA challenge
Task 31 analysis of fecal and plasmatic biomarkers of visceral hypersensitivity by ELISA assays
Task 32 analysis of the humoral immune response to gluten by ELISA assays Task 33 analysis of serological inflammatory biomarkers by simultaneous high sensitivity microsphere-based Luminex technology and ELISA assays
Task 34 immunophenotyping of whole blood for quantification of immune cell IC subpopulations and their activation status evaluation of gut homing biomarkers and identification of specific cell population involved in the systemic immune response to wheat
Task 35 Identification through single cell sc transcriptome and TCR sequencing of T cell lymphocytes able to recognize cognate peptides from wheat proteins in the rectal mucosa of NCWS subjects
WP4 evaluation of gut microbiota in NCWS patients under 3 different dietary regimens WFD TM and TA challenge
Task 41 in vitro amplification of bacterial genetic materials from fecal samples by polymerase chain reaction PCR methods and identification of gut microbiota composition
NCGS prevalence rates range from 06 to 13 in the general population and given the lack of a biomarker its diagnosis is based on 1 exclusion of CD and WA 2 symptoms regression on a WFD 3 recurrence of symptoms on a double-blind placebo-controlled challenge DBPCC with wheat
Physicians recognize a significant overlap between NCGS and IBS and it is known that IBS affects about 25 of the general population So if a percentage of IBS patients could have benefit from a WFD this would have a paramount impact on its social health costs being estimated that its indirect costs eg loss of work and reduced productivity are up to 20 billionyears in the US with an annual cost of 9933 per patient Furthermore many patients with IBS-like or upper gastro-esophageal functional-like manifestations self-report a relationship between symptoms onset and wheat ingestion wheat-intolerance Nevertheless a clinical approach with a WFD for all IBS patients would be unmotivated and dangerous determining also a great economic burden
In most IBS patients visceral hypersensitivity may contribute to GI symptoms Immune activation due to mucosal mast cells MCs in close vicinity to gut nerves appears to play a role in IBS symptoms onset A possible neuro-immune interaction in the duodenal submucosa of NCGS patients involving MCs has been described in order to explain GI symptoms Other findings in NCGS include an increased infiltration of eosinophils in GI tract which might produce several inflammatory ie eosinophil cationic protein ECP and tryptase and neuromodulatory substances eg substance P and VIP
Several studies have investigated the performance of serum biomarkers panels in differentiating IBS from NCGS and healthy subjects These included inflammatory cytokines chemokines neurotransmitters and antibodies associated with CD Therefore it is critically important to investigate the performance of serum biomarkers panels to differentiate real NCGS from other conditions
Having not definitively established whether gluten or some other wheats component is responsible for symptoms triggering NCGS has been renamed as non-coeliac wheat sensitivity NCWS which would exclude other relevant cereals such as barley and rye Some components of wheat other than gluten proteins could be potentially deleterious for NCWS patients which include fermentable short-chain carbohydrates FODMAPs and amylase trypsin inhibitors ATIs the latter activating toll-like receptor 4 complex in monocytes macrophages and dendritic cells of the intestinal mucosa might induce innate immunity in both CD and healthy subjects Finally some authors have focused on the activation of innate andor acquired immunity or gut microbiota modifications
Research is actively trying to find wheat varieties with absent or low immune reactivity to be used to treat patients with NCWS Preliminary evidence showed that diploid wheat species as Triticum monococcum TM compared to common ones Triticum aestivum TA and Triticum durum could possess a lower immunogenic potential in NCWS and IBS patients It seems that modern wheats contain higher concentrations and bioactivity of ATIs compared with diploid ones and that gliadin from TM retain a reduced number of immunogenic peptides for CD patients due to a high in vitro digestibility We found that ATIs from TM are sufficiently different than those from TA so to determine lack of immune toxicity in CD after proteolytic digestion Moreover some data showed that in IBS the consumption of ancient wheat can reduce symptoms and proinflammatory cytokines and improves intestinal dysbiosis In this context we have recently shown that NCWS patients who consume ancient grains may receive a late diagnosis due to the possible clinical benefit tolerability obtained with these grains
All these data however must be considered preliminary and the pathogenetic mechanisms and the real clinical tolerability of the ancient wheats remain to be confirmed Thus it is very important to evaluate the hypothesis that specific ancient wheat varieties could be tolerated and safe for NCWS patients trying to identify at the same time possible non-invasive biomarkers to diagnose and differentiate NCWS from IBS patients
Hypotheses and objectives Our hypothesis is that a dietary therapeutic approach based on the use of a diploid wheat TM with a lower concentrations and bioactivity of ATIs and with gliadin proteins with a better digestibility could improve symptoms and quality of life QoL of NCWS patients
We planned to perform a Double-Blind Wheat Challenge DBWC with crossover of 2 wheat varieties TM vs TA in patient diagnosed with NCWS according to Salerno criteria 6 to assess the putative clinical tolerability of TM and analyze the immunological intestinal permeability and microbial differences trying to identify both the pathogenetic mechanisms and potential diagnostic biomarkers of NCWS helping in distinguishing NCWS from IBS patients
If confirmed a dietary regimen with TM would be a more suitable and a less expensive alternative to a WFD and the identification of a biomarker for NCWS will reduce the number of medical visits and examinations with substantial economic savings for the national health systems Furthermore the putative beneficial effect of a diet based on a regional ancient wheat variety will contribute to the regional agriculture and food economy
The overarching objective of the study is to investigate in NCWS patients if a challenge with an ancient wheat TM compared to a modern one TA have a lower symptoms response reflecting visceral hypersensitivity immune activation and distinct microbial profiles in order to guarantee these patients a consistent alternative to WFD and increase their QoL
The second objective is the identification of non-invasive serological biomarkers for NCWS diagnosis
The third objective is to identify through single cell sc transcriptome and T-cell receptor TCR sequencing T cell lymphocytes able to recognize cognate peptides from wheat proteins to better classify patients affected by NCWS with a translational relevance for future tailored therapies
The experimental plan is divided into 4 work packages WPs Within each WP a series of tasks have been defined
WP1 evaluation of clinical response to TM compared to TA in NCWS patients by a DBWC with crossover
Task 11 evaluation of GI symptoms evoked by dietary exposition to TM and TA by a validated GI symptoms rating scale
Task 12 evaluation of extraintestinal symptoms evoked by dietary exposition to TM and TA by an extraintestinal symptoms rating scale
Task 13 evaluation of QoL modifications determined by dietary exposition to TM and TA by a QoL validated scale
WP2 evaluation of intestinal permeability and damage biomarkers in NCWS patients under 3 dietary regimens WFD TM and TA challenge
Task 21 in vivo evaluation of intestinal permeability by the LactuloseMannitol LaMa ratio test
Task 22 analysis of serological indexes of intestinal damage and permeability by ELISA assays
WP 3 Evaluation of immunological inflammatory and visceral hypersensitivity response in NCWS patients under 3 dietary regimens WFD TM and TA challenge
Task 31 analysis of fecal and plasmatic biomarkers of visceral hypersensitivity by ELISA assays
Task 32 analysis of the humoral immune response to gluten by ELISA assays Task 33 analysis of serological inflammatory biomarkers by simultaneous high sensitivity microsphere-based Luminex technology and ELISA assays
Task 34 immunophenotyping of whole blood for quantification of immune cell IC subpopulations and their activation status evaluation of gut homing biomarkers and identification of specific cell population involved in the systemic immune response to wheat
Task 35 Identification through single cell sc transcriptome and TCR sequencing of T cell lymphocytes able to recognize cognate peptides from wheat proteins in the rectal mucosa of NCWS subjects
WP4 evaluation of gut microbiota in NCWS patients under 3 different dietary regimens WFD TM and TA challenge
Task 41 in vitro amplification of bacterial genetic materials from fecal samples by polymerase chain reaction PCR methods and identification of gut microbiota composition
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None