The role of intestinal bacterial microbiota has been described as key in the pathophysiology of Crohn’s disease (CD). CD is characterized by frequent relapses after periods of remission which are not entirely understood. In this paper, we investigate whether the heterogeneity in microbiota profiles in CD patients could be a suitable predictor for these relapses. This prospective observational study involved 259 CD patients, in which 41 provided an additional total of 62 consecutive fecal samples, with an average interval of 25 weeks in between each of these samples. Fecal microbiota was analyzed by massive genomic sequencing through 16 S rRNA amplicon sampling. We found that our 259 CD patients could be split into three distinct subgroups of microbiota (G1, G2, G3). From G1 to G3, we noticed a progressive decrease in alpha diversity (p ≤ 0.0001) but no change in the fecal calprotectin (FC) level. Focusing on the 103 consecutive samples from 41 CD patients, we showed that the patients microbiota profiles were remarkably stable over time and associated with increasing symptom severity. Investigating further this microbiota/severity association revealed that the first signs of aggravation are (1) a loss of the main anti-inflammatory Short-Chain Fatty Acids (SCFAs) Roseburia, Eubacterium , Subdoligranumum , Ruminococcus (P < 0.05), (2) an increase in pro-inflammatory pathogens Proteus , Finegoldia (P < 0.05) while (3) an increase of other minor SCFA producers such as Ezakiella , Anaerococcus , Megasphaera , Anaeroglobus , Fenollaria (P < 0.05). Further aggravation of clinical signs is significantly linked to the subsequent loss of these minor SCFAs species and to an increase in other proinflammatory Proteobacteria such as Klebsiella, Pseudomonas, Salmonella, Acinetobacter, Hafnia and proinflammatory Firmicutes such as Staphylococcus, Enterococcus, Streptococcus. (P < 0.05). To our knowledge, this is the first study (1) specifically identifying subgroups of microbiota profiles in CD patients, (2) relating these groups to the evolution of symptoms over time and (3) showing a two-step process in CD symptoms’ worsening. This paves the way towards a better understanding of patient-to-patient heterogeneity, as well as providing early warning signals of future aggravation of the symptoms and eventually adapting empirically treatments.