Human microbiota refers to the trillions of microorganisms that inhabit our bodies and have been discovered to have a substantial impact on human health and disease. By sampling the microbiota, it is possible to generate massive quantities of data for analysis using Machine Learning algorithms. In this study, we employed several modern Machine Learning techniques to predict Inflammatory Bowel Disease using raw sequence data. The dataset was obtained from NCBI preprocessed graph representations and converted into a structured form. Seven well-known Machine Learning frameworks, including Random Forest, Support Vector Machines, Extreme Gradient Boosting, Light Gradient Boosting Machine, Gaussian Naïve Bayes, Logistic Regression, and k-Nearest Neighbor, were used. Grid Search was employed for hyperparameter optimization. The performance of the Machine Learning models was evaluated using various metrics such as accuracy, precision, fscore, kappa, and area under the receiver operating characteristic curve. Additionally, Mc Nemar’s test was conducted to assess the statistical significance of the experiment. The data was constructed using k-mer lengths of 3, 4 and 5. The Light Gradient Boosting Machine model overperformed over other models with 67.24%, 74.63% and 76.47% accuracy for k-mer lengths of 3, 4 and 5, respectively. The LightGBM model also demonstrated the best performance in each metric. The study showed promising results predicting disease from raw sequence data. Finally, Mc Nemar’s test results found statistically significant differences between different Machine Learning approaches.