Exploring Crohn’s Disease: Causes, Immune Dysfunction, Microbiome, and Future Therapies
- World Scholars Review
- 3 hours ago
- 14 min read
Authors: Dhiya Moorthy & Sanchi Verma
Mentor: Dr. Liam Barrett. Dr. Barrett received his medical degree from the University of Birmingham. He is a member of the Royal College of Emergency Medicine, and is currently pursuing a DPhil in medical science at the University of Oxford.
Abstract
Crohn’s disease is a long-term inflammatory bowel disease that can affect any part of the gastrointestinal tract. It matters because it causes pain, diarrhea, fatigue, weight loss, and complications such as strictures and fistulas. This review looks at five areas in the literature: what causes Crohn’s, how the microbiome and immune system drive disease, how clinicians make a diagnosis, which immune pathways current and emerging treatments target, and how public health can improve outcomes. We used peer-reviewed reviews, meta-analyses, and clinical studies that are appropriate for a student audience. The main finding is that Crohn’s is not caused by one thing. Genes such as NOD2 and ATG16L1 raise risk. Smoking and some dietary patterns add stress to the gut barrier and shift the microbiome. The immune system then stays active and injures tissue over time. Diagnosis works best when symptoms are combined with fecal calprotectin, C-reactive protein, intestinal ultrasound, and endoscopy when needed. Treatments target TNF-α and IL-12/23, with gut-selective and oral options now available. Public education, earlier recognition, and fair access to care can reduce delays and complications. A layered approach that brings these parts together gives people the best chance to do well.
Introduction
Crohn’s disease is a form of inflammatory bowel disease that causes ongoing inflammation anywhere along the gastrointestinal tract, most often in the end of the small intestine and the colon. It is sometimes confused with ulcerative colitis, which affects only the colon, but Crohn’s can involve any part of the tract and can inflame all layers of the bowel wall. Common symptoms include abdominal pain, diarrhea, weight loss, fatigue, and sometimes bleeding. Over time the inflammation can lead to strictures, fistulas, abscesses, and malnutrition. The condition is often diagnosed in teens and young adults, but it can appear at any age. There is no cure, so treatment focuses on calming inflammation, keeping remission, and preventing complications over the long term (Loddo & Romano, 2015).
At the center of the disease is a loss of immune tolerance to normal gut contents. The immune system reacts as if there were a constant infection. The gut microbiome, which is the community of microbes in the intestine, often shifts toward an imbalanced pattern called dysbiosis. These changes weaken the intestinal barrier and fuel inflammation. Smoking and some dietary patterns can add further stress (Loddo & Romano, 2015). With that frame in mind, this review turns to five research questions in the literature to understand causes, mechanisms, diagnosis, treatment targets, and public health solutions.
Literature Review
Research question 1: What are the main causes of Crohn’s disease, and how do genetic, immune, and environmental factors interact?
Crohn’s develops from a mix of genes, environment, and immune responses. Variants in NOD2, a gene that helps cells detect bacterial cell wall components, are linked with ileal disease, stricturing, and a higher chance of surgery (Kayali et al., 2025). This does not mean NOD2 alone causes Crohn’s, but it raises risk and can shape the type of disease a person gets (Kayali et al., 2025). Genes involved in autophagy, the cell’s recycling and cleanup system, also matter. ATG16L1 variants can weaken this process in the gut lining and in immune cells. That makes it harder to clear microbes and damaged parts, which can keep inflammation going (Hampe et al., 2007).
Environment and behavior influence that genetic background. Smoking increases intestinal permeability and is linked to worse outcomes in people who already have Crohn’s (Alzahrani et al., 2024). Diets high in processed foods and low in fiber are tied to changes in the microbiome and to inflammation (Hu et al., 2022). Early-life microbial exposures may shape immune tolerance later on (Hu et al., 2022). A simple way to see this is that a susceptible host with a NOD2 or ATG16L1 variant who also smokes or follows a pro-inflammatory diet is more likely to develop a strong, persistent immune response in the gut (Hampe et al., 2007; Loddo & Romano, 2015). Once that response starts, it does not switch off well, which leads to tissue injury and ongoing inflammation (Hampe et al., 2007; Kayali et al., 2025; Loddo & Romano, 2015).
The idea that Crohn’s is multifactorial helps explain why no single intervention prevents it. Genes set the baseline, the environment supplies triggers, and the immune system and microbiome determine how the gut responds. That is why prevention advice focuses on modifiable factors like avoiding smoking and building a fiber-rich diet, and why treatment aims to calm immune pathways that are already overactive.
Research question 2: What is the pathophysiology of Crohn’s disease, and how does the microbiome influence development and progression?
Both innate and adaptive immunity drive disease. Innate cells such as macrophages and dendritic cells respond to microbes and injured tissue and present antigens to T cells. Th1 and Th17 responses then release cytokines that amplify inflammation and disrupt the epithelial barrier. A weaker barrier lets more microbial products enter the tissue, which feeds the loop and keeps inflammation going (Chandwaskar et al., 2024).
The microbiome sits in the middle of this loop. People with Crohn’s often have fewer beneficial, short-chain fatty acid producers such as Faecalibacterium prausnitzii and more pathobionts like adherent-invasive Escherichia coli. The shift reduces protective metabolites like butyrate that normally support barrier function and help keep the immune system balanced (Hu et al., 2022). Mesenteric adipose tissue, sometimes called creeping fat, also takes part. Creeping fat can wall off infection yet at the same time send signals that promote fibrosis and strictures. It interacts with both the microbiome and the immune system (He et al., 2021; Wu et al., 2024).
Attempts to restore balance show promise in some settings. Diet changes that raise fiber and lower ultra-processed foods, targeted probiotics, and fecal microbiota transplantation have improved inflammation in selected studies, although cause and effect are not always clear and not everyone responds (Alzahrani et al., 2024; Wu et al., 2024). Disease course varies. Observational data suggest that a sizable minority progress within a few years of diagnosis, often with stricturing, while others remain stable for longer (Fan et al., 2024). These differences hint that early control of inflammation and support for the barrier may change the path of disease over time.
Research question 3: What decision-making tools are there to aid clinicians in the diagnosis of Crohn’s disease?
Because Crohn’s can look like many other conditions, no single test is enough. Doctors combine symptoms, biomarkers, imaging, and endoscopy. Fecal calprotectin is a non-invasive stool test that reflects intestinal inflammation and helps distinguish inflammatory bowel disease from irritable bowel syndrome. A recent meta-analysis supports its use as a rule-out test, with better sensitivity around a cut-off of 50 μg/g or lower (Dajti et al., 2023). C-reactive protein is a blood marker of systemic inflammation that can help, but it may be normal in localized disease.
Intestinal ultrasound is popular because it is non-invasive, quick, and repeatable. A 2024 review reported pooled sensitivity near 85 percent and specificity near 92 percent for detecting intestinal inflammation when compared with reference standards, especially when combined with biomarkers (Huynh et al., 2024). Endoscopy remains important for direct visualization and biopsy. Capsule endoscopy helps evaluate the small bowel when other tests are inconclusive, although the risk of capsule retention must be considered when strictures are suspected (Calabrese et al., 2022; Choi et al., 2017). New decision-support tools that use machine learning to segment bowel on imaging and assist scores like the magnetic resonance index of activity are promising, but most are not yet part of routine care (Holland et al., 2019).
In practice, clinicians often start with symptoms and exam, order fecal calprotectin and C-reactive protein, add intestinal ultrasound or cross-sectional imaging, and then use targeted endoscopy with biopsy when needed. This layered approach improves accuracy and helps people start treatment sooner (Calabrese et al., 2022; Dajti et al., 2023; Huynh et al., 2024).
Research question 4: What immune pathways are involved in Crohn’s disease, and how are they being targeted by current or emerging treatments?
Crohn’s is sustained by cytokine networks and cell-trafficking signals that keep inflammation active. TNF-α is a key cytokine produced by macrophages and T cells. Monoclonal antibodies such as infliximab and adalimumab neutralize TNF-α, reduce inflammation, and can promote healing, though some people do not respond at first or lose response over time. Drug-level monitoring and switching classes are common in practice (Roda et al., 2016; Vulliemoz et al., 2020). IL-12/23 signalling shapes Th1 and Th17 responses. Ustekinumab blocks the shared p40 subunit and is effective, including in people who did not respond to anti-TNF therapy (Honap et al., 2022). Newer, selective IL-23 blockers are also in use and study (Cherry et al., 2015). Gut-selective trafficking is another strategy. Vedolizumab blocks the α4β7 integrin and limits T-cell homing to the gut. It has a favorable safety profile with real-world support (Cherry et al., 2015; Dotti et al., 2023; Qiu et al., 2022). JAK inhibitors are oral small molecules that dampen multiple cytokine signals inside cells. They are established in ulcerative colitis, and evidence in Crohn’s is growing (Dell'Avalle et al., 2022; Honap et al., 2024).
Treatment choice depends on disease location, complications, prior drugs, safety, and preference. The overall trend is toward treat-to-target care that aims for deep remission rather than symptom relief alone. That means aiming not just for fewer symptoms but also for endoscopic healing and, where possible, preventing structural damage. Because response varies and loss of response can occur, close follow-up and timely adjustment are a big part of care (Roda et al., 2016; Vulliemoz et al., 2020).
Research question 5: How can public health education, early diagnosis, and access to treatment improve outcomes for people living with Crohn’s disease?
Early recognition is critical because delays in diagnosis and treatment increase the risk of complications. Training and simple pathways for primary care can help clinicians spot likely inflammatory bowel disease sooner and refer for testing. Clear symptom education for the public also directs people to seek care earlier (Angelberger et al., 2009; Kim et al., 2018).
A practical way to support earlier action is to pay attention to less obvious clues. Oral findings such as aphthous ulcers, gingival inflammation, or swelling of the lips and cheeks can precede intestinal symptoms, especially in younger patients. Dentists, school nurses, and primary care clinicians can prompt timely evaluation if they recognize these signs (Pecci-Lloret et al., 2023). Access to simple, non-invasive tests speeds the process. Wider use of fecal calprotectin in primary care can help rule out inflammatory bowel disease and reduce unnecessary referrals, while still identifying those who need urgent workup. Adding intestinal ultrasound in centers that have the skill, and equipment gives a quick view of bowel wall inflammation, which can guide who needs endoscopy (Dajti et al., 2023; Huynh et al., 2024). Alongside these steps, basic public information about Crohn’s and ulcerative colitis reduces confusion with common, short-lived stomach illnesses and may shorten time to diagnosis (Angelberger et al., 2009; Kim et al., 2018).
Discussion
Looked at together, the five areas point to a loop rather than a single cause. Genetics create susceptibility, with NOD2 and ATG16L1 pointing to problems in microbial sensing and cellular housekeeping. Environment and behavior, especially smoking and some dietary patterns, add stress to the intestinal barrier and shape the microbiome. The immune system then responds as if there were a persistent threat and does not stand down, so inflammation becomes chronic. The microbiome runs through the whole story. Loss of short-chain fatty acid producers and an increase in pathobionts correlate with worse inflammation and weaker barrier function. Mesenteric adipose tissue adds to the picture by interacting with immune and microbial signals and may contribute to fibrosis (He et al., 2021; Hu et al., 2022; Wu et al., 2024).
The research suggests that this loop can be nudged at multiple points. On the prevention side, avoiding smoking and eating a higher-fiber diet are practical ways to reduce some of the environmental pressure (Alzahrani et al., 2024). On the clinical side, early recognition and a clear diagnostic pathway that uses fecal calprotectin, C-reactive protein, intestinal ultrasound, and targeted endoscopy can shorten delays and start treatment sooner (Calabrese et al., 2022; Dajti et al., 2023; Huynh et al., 2024). Treatment itself has shifted from broad suppression to pathway-specific strategies. Anti-TNF agents were an early step. IL-12/23 blockade, gut-selective trafficking inhibitors, and JAK inhibitors have expanded choices. These options make it possible to move toward treat-to-target care that aims for deeper remission, including mucosal healing, not only symptom relief (Dell'Avalle et al., 2022; Honap et al., 2022; Qiu et al., 2022; Vulliemoz et al., 2020).
There are gaps that matter. Diagnostics still focus more on detecting inflammation than on predicting who will progress. Standardized non-invasive markers tied to longer-term outcomes would help move care from reaction to prevention. Machine-learning tools that score imaging and integrate biomarkers are promising, but most remain research tools rather than standard practice (Holland et al., 2019). In treatment, response varies widely, and many lose response over time (Roda et al., 2016). We lack strong tools to match a person to the right drug early. This is why immune profiling, genetic risk panels, and microbiome signatures are active areas of study. If those profiles can be linked to drug response, care could become more personal and more efficient. Practical system steps matter too: making fecal calprotectin and intestinal ultrasound easier to access outside specialty centers, and giving primary care clear referral routes, can reduce time to diagnosis and treatment (Dajti et al., 2023; Huynh et al., 2024).
The main message is that Crohn’s is a set of linked problems, which is why the best results come from combining earlier diagnosis, targeted therapy, healthy lifestyle changes, and steady follow-up. This is also why one plan does not fit everyone. People bring different mixes of genes, exposures, and microbiome patterns. A layered, patient-centered approach that adjusts over time is the most realistic way to improve long-term outcomes.
Conclusion
Crohn’s disease develops from the interaction of genetic risk, immune dysregulation, environmental triggers, and the gut microbiome. NOD2 and ATG16L1 signal problems with microbial sensing and cellular cleanup. Smoking and certain dietary patterns add barrier stress and shift the microbiome toward dysbiosis. The immune system stays active and injures tissue over time. Diagnosis works best when symptoms are combined with fecal calprotectin, C-reactive protein, intestinal ultrasound, and endoscopy when indicated. Treatments target major pathways such as TNF-α and IL-12/23, while gut-selective and oral options expand choices. Public steps that focus on recognition of early signs, easier non-invasive testing, and timely referral can reduce delays and complications. No single factor explains Crohn’s, so a layered, patient-centered approach offers the most practical way to better outcomes.
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