Although defining what constitutes a normal or healthy microbiota remains a current challenge in the field, scientists have suggested that the human-gut microbiota relationship is in a stable state of homeostasis that when perturbed moves towards another pre-disease or disease stable state that is more susceptible to the development of chronic diseases.
New proof-of-concept findings suggest the combined targeting of host inflammation and the state of the gut microbiota could be an approach worth considering for increasing remission in patients with ulcerative colitis
Such observations resemble the behavior of other complex ecosystems such as lakes, oceans and tropical forests with alternative stable states. That is, different stable configurations of the whole ecosystem that can exist under identical external conditions.
For instance, individuals with a Western lifestyle may represent a pre-disease state that can increase the likelihood of inflammatory diseases, including inflammatory bowel disease. This approach implies that combined therapeutic approaches addressing both host processes and microbiota should be used to treat disease.
However, until now the extent to which alternative states can be used to affect remission from debilitating ulcerative colitis in humans, which is characterized by a deregulated innate immune system and a modified gut microbiota, is unknown.
New proof-of-concept findings from INRAE scientists suggest the combined targeting of host inflammation and the state of the gut microbiota could be an approach worth considering for increasing remission in patients with ulcerative colitis.
While previous findings from the same authors provided proof of concept for the existence of alternative stable states of the intestinal ecosystem in a rat model of colitis, this study analyzed data on the inflammatory status—assessed by fecal calprotectin—and the gut microbiota of 353 pediatric patients with new-onset ulcerative colitis, who were longitudinally followed for 1 year.
Four classes of gut microbiota composition were identified—representing alternative stable states that were independent of host inflammatory status or artifacts related to sampling—coupled with four levels of inflammation, from 1 (the lowest level) to 4 (the highest level).
Both the four classes of gut microbiota and the four levels of inflammation were closely connected and possible mutually aggravating. For instance, gut microbiota state 1 was found to disappear when inflammation assessed by fecal calprotectin was reduced to a low level. The authors acknowledged that the findings could explain why usual UC treatments that suppress inflammation do not always lead to a remission rate and prevent relapses. For instance, only 36% of patients reached a non-pathological state of inflammation after one year of personalized anti-inflammatory treatments and only 19% of patients had reached the least inflammation-prone gut microbiota state at the end of the study, highlighting that individual patients’ trajectories could rely on what scientists called “alternative state barriers”.
According to Maarten Van de Guchte, director of research at Micalis Institute at INRAE: “Our data strongly suggest that the stability of alternative states of the intestinal ecosystem interferes with remission from UC under standard of care (i.e., anti-inflammatory treatments). These new insights call for innovative therapeutic strategies to favor remission from UC. We identify microbiota management as an additional lever to be considered in UC treatment, in combination with the management of inflammation. The results provide a strong rationale for the application of such combinatorial therapeutic strategies.”
The longitudinal follow up of treatment-naïve patients for whom remission was evaluated at 52 weeks revealed that alternative state properties may prevent or delay remission of ulcerative colitis when patients received an anti-inflammatory treatment, which suggests that the gut microbiota and host inflammatory states described in the study may influence treatment efficacy.
One caveat of the study is that it did not consider the role of external factors, such as diet, in driving the alternative stable states described above. Van de Guchte explained to the GMFH editors via email that his team will now investigate if a Western diet can induce a transition to an alternative ecosystem state (a “pre-disease state”, more prone to disease development).
Van de Guchte M, Blottière HM, Doré J. Humans as holobionts: implications for prevention and therapy. Microbiome. 2018; 8:81. doi: 10.1186/s40168-018-0466-8.
Van de Guchte M, Mondot S, Doré J. Dynamic properties of the intestinal ecosystem call for combination therapies, targeting inflammation and microbiota, in ulcerative colitis. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.057.
Van de Guchte, Burz SD, Cadiou J, et al. Alternative stable states in the intestinal ecosystem: proof of concept in a rat model and a perspective of therapeutic implications. Microbiome. 2020; 8(1):153. doi: 10.1186/s40168-020-00933-7.