New Biomarkers for Crohn’s Disease

See “Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth,” by Nair N, Austin C, Curtin P, et al, on page 383; and “Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis,” by Torres J, Petralia F, Sato T, et al, on page 96.Case control studies of patients with inflammatory bowel disease (IBD) may facilitate the identification of factors present to a greater extent in those with the disease compared with those without the disease. If these factors are present before disease expression, they might be considered as risk factors. This can lead to further exploration of the biology of the factor in relation to IBD pathogenesis, or alternatively, as a biomarker identifying that the disease may be diagnosed at some future time. It is more difficult to prove that an antedating factor is a true risk factor. One reason is that it is very difficult to determine exactly when IBD starts in an individual patient. The first clinical presentation of disease might in fact be long after the biology of the disease has been set in motion. Prediagnosis factors have not necessarily emerged before disease onset, but rather before clinical manifestation of disease. They may in fact be sequelae of the disease pathogenesis unfolding. Postoperative Crohn’s disease is a good model of preclinical disease. Asymptomatic endoscopic recurrences are quite common.Finding environmental risk factors that might unravel disease etiology in IBD has been the holy grail of IBD researchers for decades.1Bernstein CN (on behalf of organizing committee)Assessing environmental risk factors affecting the inflammatory bowel diseases: a joint workshop of the Crohn's & Colitis Foundations of Canada and the USA.Inflamm Bowel Dis. 2008; 14: 1139-1146Crossref PubMed Scopus (18) Google Scholar Measurable factors strongly associated with a disease can serve as biomarkers which can aid in diagnosis regardless of the timing at which they are found in relation to disease presentation. Anti-Sacccharomyces cerivisiae (ASCA) is one such marker.2McKenzie H. Main J. Pennington C.R. Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease.Gut. 1990; 31: 536-538Crossref PubMed Scopus (138) Google Scholar ASCA is also underexplored; the antibody and its fungal antigen present interesting opportunities for etiologic hypotheses. Newly identified biomarkers may be valuable diagnostic aids, but can also represent an entrance to an important pathogenetic pathway; or alternatively, an off-ramp to a misleading coincidence. It is on this complex background that 2 studies published in Gastroenterology this month point us in different directions along the etiologic and diagnostic hunt.3Nair N. Austin C. Curtin P. et al.Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth.Gastroenterology. 2020; 159: 383-385Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarIn the article by Nair et al,3Nair N. Austin C. Curtin P. et al.Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth.Gastroenterology. 2020; 159: 383-385Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar the authors relate the presence of heavy metals in baby teeth to the later development of Crohn’s disease. They lead off their discussion by suggesting that this finding is a key link to urbanization associated with Crohn’s disease. Theirs is a fascinating finding, but recent data have suggested that the disease does not necessarily favor urban areas.5Amarapurkar A.D. Amarapurkar D.N. Rathi P. et al.Risk factors for inflammatory bowel disease: a prospective multi-center study.Ind J Gastroenterol. 2018; 37: 189-195Crossref PubMed Scopus (33) Google Scholar,6Benchimol E.I. Kaplan G.G. Otley A.R. et al.Rural and urban residence during early life is associated with a lower risk of inflammatory bowel disease: a population-based inception and birth cohort study.Am J Gastroenterol. 2017; 112: 1412-1422Crossref PubMed Scopus (48) Google Scholar Wherever the metals are coming from, this study strengthens the connection of IBD risk with the mothers of affected individuals. The finding of metals that can be tracked to the in utero state suggests that the offspring who will ultimately present with IBD and have high values of these metals are likely acquiring these metals from their mothers. Mothers may have accessed these metals in their cookware, in their cosmetics, in the packaged food they have eaten, or in the homegrown food they have consumed that has been affected by the metal-laden soil in which it was grown. The authors propose that the metals found in increased amounts may be important for the development of IBD. However, having not reported any metals that were not in excess in the affected individuals’ baby teeth argues against the 4 specific metals having unique roles in IBD pathogenesis. Nonetheless, the authors have identified that persons with IBD have associated markers that can be traced to early in life. Whatever ultimately leads to IBD may be experienced in the developing child. Our mothers are even more important to our health than we even previously considered! What and when they feed us during early childhood, and even what mothers ingest themselves may impact our future health.Recently, our study from Manitoba, published in Gastroenterology, reported that the strongest risk factor for a child ultimately developing IBD was the presence of IBD in their mothers.7Bernstein C.N. Burchill C. Targownik L.E. et al.Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases.Gastroenterology. 2019; 156: 2190-2197Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar This factor may be genetic—the mother passing on genes that modulate how metals are handled, genes that modulate the developing gut microbiome, or both. Alternatively, this factor may be environmental—the mother passing on to the child what she is ingesting. In the Manitoba study, the second most significant risk factor for developing IBD was having an infection in the first year of life—an infection in the child independent of his or her mother. Hence, an infection that may alter a developing gut microbiome, an infection that may be treated with antibiotics which may alter the developing gut microbiome or an infection the response to which may be impacted by the presence of excess heavy metals8Lopez C.A. Skaar E.P. The impact of dietary transition metals on host-bacterial interactions.Cell Host Microbe. 2018; 23: 737-748Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar may be a critical inciting event in the pathogenesis of IBD.In the study by Torres et al,4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar a serum bank of Department of Defense recruits was accessed to study for microbial antibodies and immune-inflammatory markers for ≤5 years antedating diagnoses of either Crohn’s disease or ulcerative colitis. Anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease. A Somologic panel of 1100 potential proteins led to a handful that collectively formed a moderately good predictive model of later diagnosis of Crohn’s disease. These included C-reactive protein, complement C5, PRSS2 (trypsin 2), serum amyloid-P, osteomodulin, and aggrecan core protein. Four additional factors, complement factor I, IL-11 receptor subunit alpha, macrophage mannose receptor 1, and protein SET II were commonly selected at timepoints 1–4 years before diagnosis.It is not surprising that anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease since they have been associated with it previously. In fact, ASCA IgA has also been a strong predictor of aggressive disease behavior in Crohn’s disease.9Siegel C.A. Horton H. Siegel L.S. et al.A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables.Aliment Pharmacol Ther. 2016; 43: 262-271Crossref PubMed Scopus (69) Google Scholar,10Ryan J.D. Silverberg M.S. Xu W. et al.Predicting complicated Crohn’s disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population based cohort.Aliment Pharmacol Ther. 2013; 38 (274–083)Crossref Scopus (56) Google Scholar The significantly associated proteins are all involved in immune response, cytokine-mediated signaling pathway and apoptosis. Again, not surprising. Flagellin X is a bacterial product and ASCA is a response to a yeast. ASCA has been popping up as a disease marker for 30 years.2McKenzie H. Main J. Pennington C.R. Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease.Gut. 1990; 31: 536-538Crossref PubMed Scopus (138) Google Scholar Is this the Helicobacter pylori-equivalent that has been staring at researchers? Of note Saccharomyces cerivisae may have an important role to play in heavy metal biosorption.11Wang J. Chen C. Biosorption of heavy metals by Saccharomyces cerevisiae: a review.Biotechnol Adv. 2006; 24: 427-451Crossref PubMed Scopus (1066) Google Scholar The authors have convincingly showed that these microbial antibodies and immune-inflammatory mediators are present years before the first clinical manifestation of Crohn’s disease. These phenomena very likely are early biological manifestations of Crohn’s disease. They may not be risk factors that Crohn’s disease is coming, but rather that it is already present. If the value in identifying these markers in asymptomatic persons is so that they can be acted upon to prevent Crohn’s disease, it may be an unfulfilled hope, analogous to identifying NOD2 mutations. There are more people in the general population who have NOD2 mutations who will never get Crohn’s disease, but without question, persons who have NOD2 mutations are more likely to get Crohn’s disease.12Brant S. Wang M.-H. Rawsthorne P. et al.A population-based case control study of CARD15 and other risk factors in Crohn's disease and ulcerative colitis.Am J Gastroenterol. 2007; 102: 313-323Crossref PubMed Scopus (57) Google Scholar Will the predictive package reported by Torres et al be stronger than ASCA alone or NOD-2 mutations?Regardless, there remains little to offer to avoid the full expression of Crohn’s disease, even when it is believed to be in the offing. Some might say knowledge of a biomarker antedating Crohn’s disease presentation could lead to advice, for example, against smoking, for example, because smoking is associated, with Crohn’s disease in Western populations. There are surely better reasons not to smoke. Regardless, smoking does not even seem to be associated with Crohn’s disease in China or India where IBD is on the rise, likely in the absence of NOD2 mutations.5Amarapurkar A.D. Amarapurkar D.N. Rathi P. et al.Risk factors for inflammatory bowel disease: a prospective multi-center study.Ind J Gastroenterol. 2018; 37: 189-195Crossref PubMed Scopus (33) Google Scholar,13Wang P. Hu J. Ghadermarzi S. et al.Smoking and inflammatory bowel disease: a comparison of China, India, and the USA.Dig Dis Sci. 2018; 63: 2703-2713Crossref PubMed Scopus (20) Google Scholar Torres et al4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar present the premise that “biomarkers are needed to identify persons at risk for developing inflammatory bowel diseases.” Until the tools are available to truly prevent Crohn’s disease evolution, at best we can say that biomarkers are needed to help expand our diagnostic armamentarium.These 2 groups of investigators should be congratulated for harnessing extraordinary resources (long-held baby teeth and a long-held serum bank) and for challenging the research community to make sense of their findings. From many years (in utero) to a few years before being diagnosed with Crohn’s disease, affected individuals are harboring increased levels of heavy metals and subclinical inflammation and antibody responses to microbial proteins. These 2 studies may be linked through the gut microbiome (including the fungome); being altered early in its development by exposure to heavy metals and ultimately establishing a proinflammatory microbiome that stimulates inflammatory proteins and antibodies to its constituents. To understand the biology of Crohn’s disease rather than studying those newly diagnosed in search of clues, a concerted effort should be undertaken to study a large cohort of pregnant women and their children. An expanded version of the Canadian Healthy Infant Longitudinal Development (CHILD) study14Persaud R.P. Azad M.B. Chari R.S. et al.Perinatal antibiotic exposure of neonates in Canada and associated risk factors: a population-based cross sectional study.J Matern Fetal Neonatal Med. 2015; 28: 1190-1195Crossref PubMed Scopus (45) Google Scholar could facilitate an understanding of early life changes that lead to chronic immune diseases some time later. See “Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth,” by Nair N, Austin C, Curtin P, et al, on page 383; and “Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis,” by Torres J, Petralia F, Sato T, et al, on page 96. See “Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth,” by Nair N, Austin C, Curtin P, et al, on page 383; and “Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis,” by Torres J, Petralia F, Sato T, et al, on page 96. See “Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth,” by Nair N, Austin C, Curtin P, et al, on page 383; and “Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis,” by Torres J, Petralia F, Sato T, et al, on page 96. Case control studies of patients with inflammatory bowel disease (IBD) may facilitate the identification of factors present to a greater extent in those with the disease compared with those without the disease. If these factors are present before disease expression, they might be considered as risk factors. This can lead to further exploration of the biology of the factor in relation to IBD pathogenesis, or alternatively, as a biomarker identifying that the disease may be diagnosed at some future time. It is more difficult to prove that an antedating factor is a true risk factor. One reason is that it is very difficult to determine exactly when IBD starts in an individual patient. The first clinical presentation of disease might in fact be long after the biology of the disease has been set in motion. Prediagnosis factors have not necessarily emerged before disease onset, but rather before clinical manifestation of disease. They may in fact be sequelae of the disease pathogenesis unfolding. Postoperative Crohn’s disease is a good model of preclinical disease. Asymptomatic endoscopic recurrences are quite common. Finding environmental risk factors that might unravel disease etiology in IBD has been the holy grail of IBD researchers for decades.1Bernstein CN (on behalf of organizing committee)Assessing environmental risk factors affecting the inflammatory bowel diseases: a joint workshop of the Crohn's & Colitis Foundations of Canada and the USA.Inflamm Bowel Dis. 2008; 14: 1139-1146Crossref PubMed Scopus (18) Google Scholar Measurable factors strongly associated with a disease can serve as biomarkers which can aid in diagnosis regardless of the timing at which they are found in relation to disease presentation. Anti-Sacccharomyces cerivisiae (ASCA) is one such marker.2McKenzie H. Main J. Pennington C.R. Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease.Gut. 1990; 31: 536-538Crossref PubMed Scopus (138) Google Scholar ASCA is also underexplored; the antibody and its fungal antigen present interesting opportunities for etiologic hypotheses. Newly identified biomarkers may be valuable diagnostic aids, but can also represent an entrance to an important pathogenetic pathway; or alternatively, an off-ramp to a misleading coincidence. It is on this complex background that 2 studies published in Gastroenterology this month point us in different directions along the etiologic and diagnostic hunt.3Nair N. Austin C. Curtin P. et al.Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth.Gastroenterology. 2020; 159: 383-385Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar In the article by Nair et al,3Nair N. Austin C. Curtin P. et al.Association between early-life exposures and inflammatory bowel diseases, based on analyses of deciduous teeth.Gastroenterology. 2020; 159: 383-385Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar the authors relate the presence of heavy metals in baby teeth to the later development of Crohn’s disease. They lead off their discussion by suggesting that this finding is a key link to urbanization associated with Crohn’s disease. Theirs is a fascinating finding, but recent data have suggested that the disease does not necessarily favor urban areas.5Amarapurkar A.D. Amarapurkar D.N. Rathi P. et al.Risk factors for inflammatory bowel disease: a prospective multi-center study.Ind J Gastroenterol. 2018; 37: 189-195Crossref PubMed Scopus (33) Google Scholar,6Benchimol E.I. Kaplan G.G. Otley A.R. et al.Rural and urban residence during early life is associated with a lower risk of inflammatory bowel disease: a population-based inception and birth cohort study.Am J Gastroenterol. 2017; 112: 1412-1422Crossref PubMed Scopus (48) Google Scholar Wherever the metals are coming from, this study strengthens the connection of IBD risk with the mothers of affected individuals. The finding of metals that can be tracked to the in utero state suggests that the offspring who will ultimately present with IBD and have high values of these metals are likely acquiring these metals from their mothers. Mothers may have accessed these metals in their cookware, in their cosmetics, in the packaged food they have eaten, or in the homegrown food they have consumed that has been affected by the metal-laden soil in which it was grown. The authors propose that the metals found in increased amounts may be important for the development of IBD. However, having not reported any metals that were not in excess in the affected individuals’ baby teeth argues against the 4 specific metals having unique roles in IBD pathogenesis. Nonetheless, the authors have identified that persons with IBD have associated markers that can be traced to early in life. Whatever ultimately leads to IBD may be experienced in the developing child. Our mothers are even more important to our health than we even previously considered! What and when they feed us during early childhood, and even what mothers ingest themselves may impact our future health. Recently, our study from Manitoba, published in Gastroenterology, reported that the strongest risk factor for a child ultimately developing IBD was the presence of IBD in their mothers.7Bernstein C.N. Burchill C. Targownik L.E. et al.Events within the first year of life, but not the neonatal period, affect risk for later development of inflammatory bowel diseases.Gastroenterology. 2019; 156: 2190-2197Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar This factor may be genetic—the mother passing on genes that modulate how metals are handled, genes that modulate the developing gut microbiome, or both. Alternatively, this factor may be environmental—the mother passing on to the child what she is ingesting. In the Manitoba study, the second most significant risk factor for developing IBD was having an infection in the first year of life—an infection in the child independent of his or her mother. Hence, an infection that may alter a developing gut microbiome, an infection that may be treated with antibiotics which may alter the developing gut microbiome or an infection the response to which may be impacted by the presence of excess heavy metals8Lopez C.A. Skaar E.P. The impact of dietary transition metals on host-bacterial interactions.Cell Host Microbe. 2018; 23: 737-748Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar may be a critical inciting event in the pathogenesis of IBD. In the study by Torres et al,4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar a serum bank of Department of Defense recruits was accessed to study for microbial antibodies and immune-inflammatory markers for ≤5 years antedating diagnoses of either Crohn’s disease or ulcerative colitis. Anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease. A Somologic panel of 1100 potential proteins led to a handful that collectively formed a moderately good predictive model of later diagnosis of Crohn’s disease. These included C-reactive protein, complement C5, PRSS2 (trypsin 2), serum amyloid-P, osteomodulin, and aggrecan core protein. Four additional factors, complement factor I, IL-11 receptor subunit alpha, macrophage mannose receptor 1, and protein SET II were commonly selected at timepoints 1–4 years before diagnosis. It is not surprising that anti-Flagellin X and ASCA-IgA were predictive of Crohn’s disease since they have been associated with it previously. In fact, ASCA IgA has also been a strong predictor of aggressive disease behavior in Crohn’s disease.9Siegel C.A. Horton H. Siegel L.S. et al.A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables.Aliment Pharmacol Ther. 2016; 43: 262-271Crossref PubMed Scopus (69) Google Scholar,10Ryan J.D. Silverberg M.S. Xu W. et al.Predicting complicated Crohn’s disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population based cohort.Aliment Pharmacol Ther. 2013; 38 (274–083)Crossref Scopus (56) Google Scholar The significantly associated proteins are all involved in immune response, cytokine-mediated signaling pathway and apoptosis. Again, not surprising. Flagellin X is a bacterial product and ASCA is a response to a yeast. ASCA has been popping up as a disease marker for 30 years.2McKenzie H. Main J. Pennington C.R. Parratt D. Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease.Gut. 1990; 31: 536-538Crossref PubMed Scopus (138) Google Scholar Is this the Helicobacter pylori-equivalent that has been staring at researchers? Of note Saccharomyces cerivisae may have an important role to play in heavy metal biosorption.11Wang J. Chen C. Biosorption of heavy metals by Saccharomyces cerevisiae: a review.Biotechnol Adv. 2006; 24: 427-451Crossref PubMed Scopus (1066) Google Scholar The authors have convincingly showed that these microbial antibodies and immune-inflammatory mediators are present years before the first clinical manifestation of Crohn’s disease. These phenomena very likely are early biological manifestations of Crohn’s disease. They may not be risk factors that Crohn’s disease is coming, but rather that it is already present. If the value in identifying these markers in asymptomatic persons is so that they can be acted upon to prevent Crohn’s disease, it may be an unfulfilled hope, analogous to identifying NOD2 mutations. There are more people in the general population who have NOD2 mutations who will never get Crohn’s disease, but without question, persons who have NOD2 mutations are more likely to get Crohn’s disease.12Brant S. Wang M.-H. Rawsthorne P. et al.A population-based case control study of CARD15 and other risk factors in Crohn's disease and ulcerative colitis.Am J Gastroenterol. 2007; 102: 313-323Crossref PubMed Scopus (57) Google Scholar Will the predictive package reported by Torres et al be stronger than ASCA alone or NOD-2 mutations? Regardless, there remains little to offer to avoid the full expression of Crohn’s disease, even when it is believed to be in the offing. Some might say knowledge of a biomarker antedating Crohn’s disease presentation could lead to advice, for example, against smoking, for example, because smoking is associated, with Crohn’s disease in Western populations. There are surely better reasons not to smoke. Regardless, smoking does not even seem to be associated with Crohn’s disease in China or India where IBD is on the rise, likely in the absence of NOD2 mutations.5Amarapurkar A.D. Amarapurkar D.N. Rathi P. et al.Risk factors for inflammatory bowel disease: a prospective multi-center study.Ind J Gastroenterol. 2018; 37: 189-195Crossref PubMed Scopus (33) Google Scholar,13Wang P. Hu J. Ghadermarzi S. et al.Smoking and inflammatory bowel disease: a comparison of China, India, and the USA.Dig Dis Sci. 2018; 63: 2703-2713Crossref PubMed Scopus (20) Google Scholar Torres et al4Torres J. Petralia F. Sato T. et al.Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis.Gastroenterology. 2020; 159: 96-104Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar present the premise that “biomarkers are needed to identify persons at risk for developing inflammatory bowel diseases.” Until the tools are available to truly prevent Crohn’s disease evolution, at best we can say that biomarkers are needed to help expand our diagnostic armamentarium. These 2 groups of investigators should be congratulated for harnessing extraordinary resources (long-held baby teeth and a long-held serum bank) and for challenging the research community to make sense of their findings. From many years (in utero) to a few years before being diagnosed with Crohn’s disease, affected individuals are harboring increased levels of heavy metals and subclinical inflammation and antibody responses to microbial proteins. These 2 studies may be linked through the gut microbiome (including the fungome); being altered early in its development by exposure to heavy metals and ultimately establishing a proinflammatory microbiome that stimulates inflammatory proteins and antibodies to its constituents. To understand the biology of Crohn’s disease rather than studying those newly diagnosed in search of clues, a concerted effort should be undertaken to study a large cohort of pregnant women and their children. An expanded version of the Canadian Healthy Infant Longitudinal Development (CHILD) study14Persaud R.P. Azad M.B. Chari R.S. et al.Perinatal antibiotic exposure of neonates in Canada and associated risk factors: a population-based cross sectional study.J Matern Fetal Neonatal Med. 2015; 28: 1190-1195Crossref PubMed Scopus (45) Google Scholar could facilitate an understanding of early life changes that lead to chronic immune diseases some time later. Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before DiagnosisGastroenterologyVol. 159Issue 1PreviewBiomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn’s disease and ulcerative colitis that can be detected and quantified before diagnosis. Full-Text PDF