Background: Various noninvasive biomarkers have been used in the diagnosis, prognosis, and treatment of different gastrointestinal (GI) diseases for years. Novel technological developments and profound perception of molecular processes related to GI diseases over the last decade have allowed researchers to evaluate genetic, epigenetic, and many other potential molecular biomarkers in different diseases and clinical settings. Here, we present a review of recent and most relevant articles in order to summarize major findings on novel biomarkers in the diagnosis of benign and malignant GI diseases. Summary: Genetic variations, noncoding RNAs (ncRNAs), cell-free DNA (cfDNA), and microbiome-based biomarkers have been extensively analyzed as potential biomarkers in benign and malignant GI diseases. Multiple single-nucleotide polymorphisms have been linked with a number of GI diseases, and these observations are further being used to build up disease-specific genetic risk scores. Micro-RNAs and long ncRNAs have a large potential as noninvasive biomarkers in the management of inflammatory bowel diseases and GI tumors. Altered microbiome profiles were observed in multiple GI diseases, but most of the findings still lack translational clinical application. As of today, cfDNA appears to be the most potent biomarker for early detection and screening of GI cancers. Key Messages: Novel noninvasive molecular biomarkers show huge potential as useful tools in the diagnostics and management of different GI diseases. However, the use of these biomarkers in real-life clinical practice still remains limited, and further large studies are needed to elucidate the ultimate role of these potential noninvasive clinical tools.

Various biomarkers have been used in the diagnosis, prognosis, and treatment of different diseases [1, 2]. Identification of high-risk individuals or early diagnosis of a disease is not only a part of primary prevention but also one of the main approaches in order to properly treat various conditions and increase overall survival (OS) [3, 4]. Combination of benchmark diagnostic methods, such as evaluation of signs and symptoms, blood and other biomarkers, various medical imaging techniques, histopathology, microbiology, and surgical procedures, still remains the gold standard in the diagnostics of most pathologies. However, novel diagnostic approaches allow scientists to examine and evaluate each individual’s genetic and epigenetic information in order to analyze disease susceptibility and tailor proper treatment for each patient [5, 6]. This method is known as personalized medicine, which is expected to become the main therapeutic approach in the near future [7, 8]. Various genetic variations are being investigated or are already used in the management of different diseases, such as type 1 diabetes [9-11], breast cancer [12-14], and Alzheimer’s disease [15, 16]. Gastroenterology is a field of medicine with a broad spectrum of disorders that have a big potential to be involved in genetic testing. A lot of effort is being put into research in order to discover these new biomarkers; however, the results are still controversial. Therefore, the aim of this review article is to summarize the findings of the most recent publications, studies, and information on the potential novel biomarkers (shown in Fig. 1) in the diagnosis of benign and malignant gastrointestinal (GI) diseases. All of the findings that are reviewed in this article are briefly summarized in Table 1.

Table 1.

Summary of investigated novel biomarkers in GI diseases

Summary of investigated novel biomarkers in GI diseases
Summary of investigated novel biomarkers in GI diseases
Fig. 1.

Promising novel groups of biomarkers in gastrointestinal diseases.

Fig. 1.

Promising novel groups of biomarkers in gastrointestinal diseases.

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Latest advances in genomics allowed scientists to identify single-nucleotide polymorphisms (SNPs), which are the most frequent type of genetic variations in humans [17-19]. SNPs result from the variations of a single nucleotide in a DNA strand [20, 21]. SNPs in genes that are responsible for cell cycle regulation, repair processes, and metabolism are associated with increased susceptibility to various types of cancer [22, 23]. SNPs have also been linked with numerous benign and malignant GI diseases. Genome-wide association studies (GWASs) try to focus on associations between hundreds or thousands of SNPs and various diseases [24, 25].

One of the diseases that studies focus on is gastric cancer (GC). Some investigations found no relation between GC and multiple SNPs in various genes: polymorphisms of ACE, NOD1, TRL4, FAS/FASL [26] or IL1B, and IL1RN [27] genes and SNPs of micro-RNAs (miRNAs) -27a, -146a, -196a-2, -492, -492a, and -608 [28] were not linked with higher risk of GC. However, other studies found some relations between gene polymorphisms and GC or premalignant gastric conditions. A study by Kupcinskas et al. [29] found out that polymorphisms of PSCA gene (rs2976392 allele A; rs2294008 allele T) were associated with higher risk of GC and high-risk atrophic gastritis, while genetic variation of MUC1 (rs4072037 allele G) gene was protective. Another study discovered that rs1051690 SNP in the INSR gene was associated with increased risk of GC, while polymorphisms in IL12B, CCND1, and IL10 genes were not linked with the presence of the disease [30]. A study by Dargiene et al. [31] concluded that TLR1 rs4833095 SNP was associated with an increased risk of GC, while genetic variant rs13361707 of PRKAA1 gene had no connection with GC.

Another large group of diseases that genetic studies focus on is liver disease. A study released in the year 2017 focused on 4 genes; it was concluded that SNPs in PNPLA3 and RNF7 genes were associated with higher risk of developing liver fibrosis or liver cirrhosis (LC), while MERTK and PCSK7 SNPs had no connection with both conditions [32]. A meta-analysis by Wang et al. [33] came to a conclusion that SNP rs2596542G>A in the MICA gene is associated with HCV-induced hepatocellular carcinoma (HCC) susceptibility in Asian, Caucasian, and African populations. Even though some studies showed that TM6SF2 rs58542926 and MBOAT7 rs641738 might be risk factors for alcoholic LC and nonalcoholic fatty liver disease, a study by Basyte-Bacevice et al. [34] in the year 2019 concluded that these genetic variations were not linked to the mentioned conditions in eastern European population. Another research by the same authors revealed that SERPINA1 (Pi*S rs17580 variant) conferred an increased risk of developing liver fibrosis, while SERPINA1 (Pi*Z rs28929474 variant) and HSD17B13 rs10433937 were not associated with the disease [35]. A few studies have shown associations between SNP rs738409 of PNPLA3 gene and nonalcoholic fatty liver disease [36-38].

Some studies focus on associations between genetic variations and survival of cancer patients. A study by Rizzato et al. [39] analyzed effects of various SNPs on OS of pancreatic ductal adenocarcinoma patients; the research concluded that 3 SNPs (2p12-rs1567532, 10q26-rs10764826, and 2p11-rs13431245) had statistically significantly worse and 2 SNPs (9p33-rs10818020 and 6p21-rs12209785) had a longer OS . Pancreatic cancer risk was investigated by Campa et al. [40] in the year 2016; the study found a strong association between the A allele of rs3217992 SNP (CDKN2B gene) and increased risk of pancreatic ductal adenocarcinoma in Caucasian populations. Another research found 3 novel pancreatic cancer susceptibility signals marked by SNPs rs2816938 at chromosome 1q32.1 (NR5A2), rs10094872 at 8q24.21 (MYC), and rs35226131 at 5p15.33 (CLPTM1L-TERT) [41].

In recent years, genetic variations in various intestinal diseases have also been a subject of interest by multiple studies. An investigation in the year 2014 found no associations between gene polymorphisms of multiple miRNAs and the presence of colorectal cancer (CRC) in European patients [42]. Barontini et al. [43] did not discover any statistically significant association between risk of developing CRC and selected 6 SNPs (rs860170, rs978739, rs1357949, rs1525489, rs6466849, and rs10268496) in TAS2R16 gene. Interestingly, one study found out that a variant of COL3A1 (rs3134646) was associated with an increased risk of developing colonic diverticulosis in white men, while SNPs rs1800255 (COL3A1) and rs1800012 (COL1A1) were not associated with the disease [44]. Some GWAS have identified SNP rs17810546 in a noncoding region on chromosome 3 as a risk factor for celiac disease [45]. A wide systematic review and meta-analysis by Zhu et al. [46] concluded that SNPs rs4263839 and rs6478108 of TNFSF15 gene were associated with an increased risk of irritable bowel syndrome (IBS), while rs1800896 GG genotype (IL10 gene) was linked to a decreased risk of IBS. SNPs might even be useful in prediction of inflammatory bowel disease (IBD) progression [47]. Recent analysis revealed that in Japanese populations, the IL23R rs76418789 was a susceptibility locus for ulcerative colitis (UC) and had a genome-wide significant association [48]. Some GWASs have identified novel biomarkers significantly associated with CRC risk in Japanese (IRF8-FOXF1 rs847208 and TOX2 rs6065668) [49] and African-American populations (SYMPK rs56848936) [50]. Some centers used polymorphisms of thiopurine methyltransferase and inosine triphosphate pyrophosphatase for predicting the side effects of thiopurines (azathioprine) in management of IBD [51], but the decreasing use of this group of medications, especially among IBD patients, does not make this approach significantly useful in everyday GI clinical practice.

The new approach that has been more recently used to estimate an individual’s genetic liability to various diseases is the genetic risk score (GRS), which takes into account multiple SNPs [52, 53]. This is quite a new approach, and there is still a lack of studies in regard to GI diseases. A study by Zupančič et al. [54] combined 33 SNPs and found out that Slovenian individuals with the highest risk (GRS > 5.54) showed significantly increased odds of developing Crohn’s disease compared to the study subjects with the lowest risk (GRS < 4.57). Another study by Xin et al. [55] concluded that a simple count GRS model might be optimal for predicting the genetic risk of CRC. A German CRC screening study derived a GRS based on 48 SNPs associated with the disease and concluded that increased GRS was associated with an increased prevalence of advanced neoplasms [56].

One of the major problems associated with clinical use of SNPs is linked to the fact that most of the significant associations between certain genetic variations and GI diseases have an odds ratio in the range of 1.2–2.0; thus, their ability to be used for screening purposes and identify individuals at risk of certain conditions remains very limited [57, 58]. More advanced research of genetic variations is expected to come from the novel whole-exome sequencing (WES) studies, which are even more focused on personalized medicine and should cover a much larger range of human genome as compared to the GWAS approach. Some scientists have already used WES in order to examine CRC [59-61] or liver diseases [62, 63].

Over the last few decades, a great deal of effort has been put into researching ncRNAs as biomarkers for various disorders from autoimmune diseases to cancer. Examples of these RNAs include miRNAs, long ncRNAs, circular RNAs, small nuclear RNAs, ribosomal RNAs, and transfer RNAs. ncRNAs are not translated into proteins but play an important role in a variety of physiological functions [64, 65].

There is a distinct lack of accurate noninvasive markers for the diagnosis of IBD, and ncRNAs were identified as candidates to fill this gap. In 2008, deregulated miRNAs have been identified in the colonic tissues of patients with UC [66]. Since then, there have been several reports stating correlation of ncRNA expression between colonic tissues and peripheral blood or feces [67, 68], and ncRNA expression is continuously investigated in feces or peripheral blood and its components. Several studies have reported distinct ncRNA expression in feces of IBD patients and healthy controls [69-72], and many studies have reported altered ncRNA expression in the peripheral blood of IBD patients [67, 68, 71, 73-92], although there are differences in the amount of deregulated ncRNAs and their diagnostic accuracy being reported. While some studies show unremarkable accuracy of ncRNAs in distinguishing between patients and healthy controls with receiver operating characteristics analysis showing an area under the curve (AUC) of 0.65–0.79 [80, 84, 86], others report really promising results with an AUC of 0.97–0.99 for miRNA pairs of miR-215/miR-30e-3p, miR-215/miR-145, and miR-203/miR-145 [81]; 0.94 for serum miR-372 [67]; 0.88 for fecal miR-223 [71]; and 0.91 for miR-874-3p in distinguishing between colonic Crohn’s disease and UC. However, when comparing different studies, the results are varied and sometimes inconsistent. This may be due to different methodologies employed by researchers; the methods of RNA extraction, normalization, sequencing, and even the source (whole blood, plasma, serum, or cells like mononuclear cells or platelets) may create bias, and this makes comparing data difficult.

Despite declining incidence [93], GC still provides great challenges for clinicians. Therefore, a lot of effort is being put into finding novel noninvasive biomarkers to aid in the early diagnosis of this disease, with ncRNAs being prime candidates for this role. An overwhelming amount of studies have been published during the last decade, and some of them report very promising results in distinguishing GC patients from controls, with an AUC 0.96 for plasma miR-940 [94], 0.94 for plasma miR-139 [95], 0.90 for serum miR-16 [96], 0.912 for serum miR-21 [97], and 0.96 for plasma miR-451 [98]. However, most ncRNAs show lower AUC values of 0.6–0.8 [96, 99-111]. The studies also display significant methodological differences and sometimes report conflicting results, where one miRNA is upregulated in one study and downregulated in another [112-114].

Esophageal cancer is one of the most common oncologic disorders in the world, and its 5-year survival rate is generally poor [115]. Like in many other conditions, ncRNAs are being investigated to fill the gap of noninvasive biomarkers for the early diagnosis of this condition [116-125]. Several studies show good diagnostic accuracy with an AUC of 0.95–0.96 for serum miR-18a [125], 0.9 for serum miR-31 [120], and 0.95 for serum miR-22 [119]. That being said, most studies showed less impressive results, with an AUC around 0.8, and once again, the same problem of heterogeneous reports is present.

CRC is the third most common malignant disorder in the world, and despite screening programs, the morality rate remains high [126]. Therefore, ncRNAs are being investigated as possible noninvasive biomarkers to facilitate early diagnosis of this pathology, and the AUC for distinguishing various stages of CRC from controls usually varies between 0.7 and 0.8, up to 0.95 [127-134]. Furthermore, several meta-analysis reports have indicated that several ncRNA panels might be more accurate for cancer diagnosis than single ncRNAs [135-137].

In conclusion, a great number of proof-of-principle studies have been published, showing that ncRNAs show a lot of potential as noninvasive biomarkers for both malignant and autoimmune GI disorders, but we are still a long way from clinical practice. While some reports state excellent diagnostic accuracy, the heterogeneity of results in different studies leaves us with doubts and suggests that improvement and standardization of research protocols, as previously stated [138], are necessary. Furthermore, all these results still need to be confirmed in prospective cohort studies.

Blood-based testing and the potential of liquid biopsies have led to much research into noninvasive blood biomarkers. Circulating cell-free DNA (cfDNA) has emerged as a novel potential molecular analyte for various conditions including cancer, while the molecular profile of tumor material is typically assessed by invasive techniques such as biopsies. Circulating tumor DNA (ctDNA) shed by primary tumors or metastatic tumor sites and harboring genetic alterations of tissues of origin could serve as a powerful tool for the disease state, relapse, and response to therapy monitoring [139, 140].

Investigation of cfDNA first implements analysis of total cfDNA yield and integrity. It was observed in numerous studies that the yield of total cfDNA is dramatically increased in plasma of patients with GI cancers [141-147]. It was also showed that cfDNA could be more sensitive than classical oncoproteins in early screening of GC [143] and may be associated with various clinical features such as tumor relapse [144], progression-free, and OS time [142].

Moreover, a minor fraction of cfDNA-ctDNA could carry more relevant information. High-throughput and sensitive techniques such as new-generation sequencing or digital droplet PCR led to numerous studies, analyzing tumor tissue-derived alterations. Majority of studies analyzed alterations of single genes, associated with cancerous processes. TP53 gene alterations are still considered responsible for around half of esophageal and GC cases [148, 149], and analysis of tumors harboring TP53 mutations revealed that ctDNA could be used for monitoring of esophageal [150-152] and gastric [153] tumor status. Studies also showed that ctDNA could serve as an effective tool for evaluating treatment effectiveness, while KRAS mutations associated with acquired resistance were detected in esophageal cancer patients’ blood [154]. Tumor reoccurrence or minimal residual disease risk was also successfully assessed by analyzing variant allele frequencies of mutated genes such as TP53, ERBB2, FAT3, and HER2 [151, 155-158] in case of esophageal, GC, and HCC. In addition to single gene mutational analysis, MYC2 and HER2 gene amplification analysis could be applied as a screening target for GC [159, 160]. On the other hand, the most investigated ct-DNA marker in CRC and pancreatic cancers is KRAS gene, and studies show promising results for applying this gene for the purposes of prognosis, detection of metastases, and determination of response to immunotherapy [161-164]. Other genes that have been investigated through ctDNA in the case of CRC are APC, BRAF, and TP53. All 3 of these genes have shown a high specificity for CRC detection similar to that of KRAS [164, 165]. Although studies report low amounts of cfDNA in pancreatic cancer cases [166, 167], in the study conducted by Sausen et al. [166], it was observed that using mutations in cfDNA, pancreatic cancer recurrences could be detected approximately 6 months before the detection by imaging tests.

Gene panels, WES, or whole-genome sequencing allows to evaluate wide mutational profile, concordance of mutational profiles between cfDNA and tissue, and novel potential targets. Taking into consideration the heterogeneous nature of GI tumors, especially GC and HCC, the concordance rate varies greatly and usually does not reach 50% [156, 168-170]. Interestingly, in the case of CRC, the concordance rate of mutations in plasma with corresponding tumor tissue was generally high with over 85% [171-173]. A low concordance rate could be explained by tumoral heterogeneity as the plasma cfDNA mutational profile is usually compared with a single-site biopsy sample. In that case, plasma cfDNA or liquid biopsies could reflect an even more accurate genetic profile and have advantage over single-site biopsy.

The application of ctDNA analysis as a noninvasive biomarker in GI malignancies is promising, while the research reveals that it could be related to a tumor state, prognosis, and disease recurrence rate. Although ctDNA analysis is highly diverse and could include various approaches (from estimation of the total cfDNA yield to whole-genome sequencing), evaluation of cancer-related alterations during the course of a disease in a noninvasive manner would undoubtedly improve diagnostics, prognostics, and even treatment of GI cancer patients.

The human microbiota is extremely diverse and complex. Unique profiles of microbiome have been identified in nearly all human body parts. Bacteria, viruses, archaea, fungi, and protozoa inhabit surfaces of the skin and urogenital system; however, the richest microbiome is found in the GI tract: the large intestine accounts for around 70% of all the human bacteria. Microbiome is a crucial part for a healthy state of an individual as it plays an important role in fermentation, metabolism, and immunity training [174].

Disruption of microbiome homeostasis has been linked with numerous diseases. A classic example of dysbiosis-related disease is Clostridium difficile colitis, which, even if treated successfully, has significant reoccurrence rates due to persistent dysbiosis. Therefore, the re-establishment of the microbiome equilibrium via fecal microbiota transplantation shows tremendous success in treatment of this disease [175].

Gut microbiome is thought to be one of the key players in IBD pathogenesis as most of genetic mutations in these patients have been linked to interactions of the immune system and microbiome [176]. Decreased diversity, lower levels of Firmicutes, higher levels of Proteobacteria, increased microbiome instability, and reduced anti-inflammatory taxa are common findings in microbiome studies of IBD patients [177]. There are studies that identified bacterial families like Enterobacteriaceae, Veillonellaceae, and Fusobacteriaceae to be enriched and members of Bacteroidales and Clostridiales to be depleted in patients as compared to controls. Faecalibacterium prausnitzii has been suggested as a potentially protective and beneficial species [178-181]. Fecal and mucosal microbiome markers were shown to be efficient predictors of treatment response, disease relapse, progression or postoperative recurrence, and a promising diagnostic biomarker with an accuracy of >80% [179, 182-189].

Microbiome studies have been of interest in IBS cases as well. Series of studies described fecal microbiome alterations related to IBS; however, results are inconsistent [190-192]. A recent population study of IBS microbiome showed no proof for altered microbiome in either stool or mucosa [193].

It is assumed that up to 20% of cancers might be related to infectious agents [194]. Probably, the best-known pathogen related to cancer is Helicobacter pylori, which is associated with >90% of GCs. For its inflammatory, direct genotoxic effect, as well as effect and capacity of transforming benign lesions to premalignant and malignant state, it has been classified as a class I carcinogen by the World Health Organization [195].

Recent publications revealed that gastric carcinogenesis is associated with dysbiosis. Oral bacteria and other microbes like Prevotella intermedia, Prevotella oris, and Fusobacterium nucleatum might also play a role in development and progression of this malignancy [196]. The incidence of colon cancer can be related to genetic alterations in only a fraction of patients. Uninterrupted contact with colonizing bugs in the colon led to hypothesis that microbiome might be involved. Studies show that CRC could be associated with species such as Streptococcus bovis, Helicobacter pylori, Clostridium septicum, Bacteroides fragilis, adherent Escherichia coli, Enterococcus faecalis, and its toxins [197, 198]. Recently, more attention has been paid to Fusobacterium nucleatum, which has been found in tumor tissue, metastatic lymph nodes, and even liver metastasis. It is thought to play a role in development and progression of CRC by causing alterations in signaling pathways related to carcinogenesis [199, 200]. Intratumoral load of these bacteria in cancer tissue is related to poor prognosis [201]. F. nucleatum alone or in combination with other bacteria has been proposed as noninvasive diagnostic biomarkers with even higher accuracy than the fecal immunochemical test [202-206].

Recently, progresses have been made in determining the structure of previously stated sterile compartments. Studies have showed that patients with LC, acute or chronic hepatitis B, and alcoholic hepatitis have altered microbiome composition [207-209]. Moreover, using a blood-derived microbiome signature showed diagnostic accuracy of around 80% when identifying patients with HCC [210]. Even more fascinating diagnostic capabilities of circulating microbiome were investigated by Poore et al. [211]. Using machine-learning trained classifier, authors correlated blood microbial signatures with cancer detection and were able to detect cancer patients at stages as early as Ia or IIc and be cancer type-specific.

Microbiome analysis in various body parts and fluids shows great potential as a novel noninvasive biomarker for diagnostics and monitoring of various diseases. However, substantial effort is needed to standardize the process of specimen collection, preparation and analysis for interpretation, and reproducibility of the results.

Most of the currently researched potential biomarkers have not yet been validated and approved to be used in real-life clinical practice for screening purposes or diagnostics of specific GI diseases; however, the future of biomarkers looks promising. Even though some studies show excellent diagnostic accuracy of various biomarkers, the heterogeneity of the results leaves us with doubts. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As already mentioned in the article, most modern diagnostic approaches, such as WES studies, should cover a much larger range of human genome. One of the currently researched and most promising diagnostic methods is single cell sequencing, which measures gene expression at the single-cell level and has the advantage of detecting heterogeneity among individual cell groups or even individual cells [212-215]. Constant development of novel molecular diagnostic approaches and validation of currently researched biomarkers should lead to a faster and more accurate data processing as well as the cost reduction of these diagnostic methods, which would result in increased availability and better implementation in real-life clinical setting. As of today, diagnostic biomarkers seem to be a significant part of personalized medicine, which could become one of the main therapeutic approaches in the near future.

The recent progress in modern diagnostic methods leads to a conclusion that personalized medicine might become the main diagnostic and therapeutic approach in the near future for different GI diseases. Various novel biomarkers, such as genetic variations, miRNAs, cfDNA, or microbiome-based biomarkers, are currently among the main translational research targets. Some of these biomarkers have strong associations with various disorders and have the potential to be used as one of the tools in the diagnostics, prognosis, and treatment of different GI diseases. However, the use of these biomarkers in real-life clinical practice is still very limited as most of investigated molecular biomarkers still lack required specificity and sensitivity for real life clinical applications. Further large-scale studies are needed to elucidate the ultimate role of the abovementioned potential noninvasive biomarkers in management of benign and malignant GI diseases.

No ethical approval is required.

The authors have no conflicts of interest to declare.

The authors did not receive any funding.

J.K. and J.S. were the supervisors of the manuscript and reviewed and finalized the final version of the manuscript. P.J. prepared and designed the first draft of the manuscript and contributed to the part about SNPs. V.K. contributed to the part about miRNAs and ncRNAs. G.S. contributed to the part about exome sequencing and cfDNA and created the illustration of the manuscript. R.G. contributed to the part about microbiome-based biomarkers. All authors approved for the final manuscript.

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