Recently, the Dai Lei Research Group of the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, and the Dai Lei Research Group of the Shenzhen Institute of Synthetic Biology Innovation published an article entitled "Establishment and resilience of transplanted gut microbiota in aged mice" in the Cell sub-journal iScience. The study transplanted fecal flora from autologous or allogeneic hosts in elderly mice, and followed up observations found that the intestinal flora was successfully colonized and established a steady-state microbiota structure similar to that of the host after transplantation, which had a long-term impact on the host colon transcriptome. In addition, the mice after transplantation were chemically induced to induce intestinal inflammation, and it was found that the flora established by the allogeneic transplant could not maintain a homeostasis similar to that of the donor after being re-perturbed, but returned to the initial state before the transplantation of the elderly host. The study suggests that allogeneic intestinal flora transplantation should be followed by long-term attention to the stability of older hosts and repeat transplantation when needed.
The intestinal flora symbiosis with the host has established a highly adaptable state under long-term interaction, with strong stability. Maintaining a healthy gut microbiome is important for the quality of life and healthy life expectancy of the elderly. Many gastrointestinal disorders, including Clostridium difficile infection (CDI), inflammatory bowel disease (IBD), and irritable bowel syndrome, are associated with dysbacteriosis and are more prevalent in older adults.
Fecal microbiota transplantation (FMT), a means of transferring fecal substances from healthy donors to patients with damaged gut flora, is currently being used to treat a variety of diseases. Two important indicators to assess the success and protective effect of FMT treatment are: (1) whether a new homeostasis can be established in the host, and (2) whether the newly established homeostasis remains rehabilitated after re-disturbance. Especially in the case of allogeneic FMT, the original highly compatible with the host of the microflora state is replaced by a new state with different compositions from the donor, it may be in a metastable state, the newly established flora balance may be more easily destroyed by environmental changes, so it is important to study the stability and resilience of the microbiota after transplantation.
Can older people, as a population with a high incidence of gastrointestinal diseases, benefit from FMT treatment? Previous studies have shown that FMT is safe and effective in treating CDI in elderly patients, but within 6 months after FMT, the recurrence rate in elderly patients is significantly higher than in younger patients. A mouse-mode animal study compared the long-term state of the post-FMT microbiota in juvenile (3-week-old) and adult (8-week-old) mice and found that flora colonization was superior to adult SPF mice in juvenile SPF mice, suggesting that the establishment of the transplanted flora may be influenced by host age. There are currently no studies on the long-term stability and resilience of autologous and allogeneic FMT post-transplanted microbiota in elderly hosts. How to rationally design treatment strategies for the use of FMT in elderly hosts? Do specific precautions need to be taken to prevent the disease from recurring? The study explored this using an older mouse model.
The researchers used naturally aging mice (20 months old) as FMT receptors to study the establishment of the transplanted gut microbiota and its resilience. First, older mice are treated with a mixture of antibiotics to disrupt the gut microbiota and monitor their spontaneous recovery (SR) processes. The study found that the effect of antibiotic treatment on intestinal flora diversity and composition persisted up to 8 weeks after treatment. The researchers then performed autologous (FMT-A) or heterogeneous (FMT-H) FMT on the antibiotic-treated elderly mice to compare their role in promoting homeostasis recovery of the intestinal flora (Figure 1A). The donors for allogeneic transplants are 2-month-old young mice from another supplier whose initial gut flora differs significantly from the composition of older recipients. The study found that both autologous and allogeneic FMT accelerated the recovery time of intestinal flora diversity from 8 weeks to 3 weeks compared with the self-recovery (SR) group (Figures 1B, C). On day 21 after antibiotic treatment, autologous and allogeneic microbiota transplantation established a new flora state in the new host, respectively, and the starting composition was close to the donor's flora composition (Figures 1D-F). This result shows that at the level of transplantation, the allogeneic bacteria are as effective as autologous microflora transplantation, and the newly established microflora is similar in composition to the donor.
FMT may cause significant changes in the composition of functional genes in the gut microbiota (characterized by metagenomic sequencing) and host intestinal gene expression levels (characterized by colonic transcriptome sequencing) and affect the success of FMT treatment. The researchers followed the changes in the metagenomic and colonic transcriptomes of three treatment groups (SR, FMT-A, and FMT-H) of older mice from pre-treatment to 56 days after fecal transplantation, and found that FMT-A was more effective at promoting microbiota function recovery than in the SR and FMT-H groups. Colonic transcriptome sequencing showed that both allogeneic and autologous FMT promoted recovery of the host transcriptome compared to the SR group, and that FMT and different donor options had long-term effects on the host transcriptome.
Finally, the researchers used a chemical (sodium dextran sulfate, DSS) on mice after receiving autologous or allogeneic FMT to induce colon inflammation, causing re-disturbance of the newly established intestinal flora homeostasis (Figure 2A). For older mice receiving autologous transplantation, the recovery process of the intestinal flora is only briefly perturbed by induced inflammation, and after 53 days, both the recipient mice that induce enteritis (FMT-A-DSS group) and the recipient mice that do not induce enteritis after transplantation (FMT-A group) have similar intestinal flora composition (Figure 2B) and no significant difference in distance from older donors (Figure 2D). In contrast, the intestinal flora established by allogeneic transplantation was unable to maintain its composition after perturbation, and the microbiota composition of the enteritis-induced mice (FMT-H-DSS) after allogeneic transplantation gradually returned to the original homeostasis of the older mice before transplantation (Figure 2C), and their flora composition deviated significantly from their donors compared with mice that received only allogeneic fecal transplantation (FMT-H group) (Figure 2D).
Studies have shown that as a widely used intestinal flora intervention in clinical practice, allogeneic FMT should not only focus on its safety and efficacy, but also pay attention to its long-term stability. Although FMT has become an effective treatment for recurrent CDI, about 20% of patients will still develop recurrent CDI after initial FMT treatment. Previous studies of FMT treatment of patients with IBD have also shown that multiple FMT interventions are required to obtain better clinical outcomes. In addition, studies have shown that age differences between donors and patients significantly affect long-term maintenance after FMT. The study found that the selection of donors not only had long-term effects on the metagenomic of the post-FMT intestinal flora and the transcriptome of the host, but also determined the resilience of the transplant flora to subsequent re-disturbances. Therefore, for elderly patients, especially those receiving allogeneic fecal transplantation, monitoring the long-term stability of FMT and subsequent disturbances (e.g., disease recurrence) is important for the effects of newly established homeostasis, and multiple FMT may be required in the case of complex perturbations or more reasonable treatment strategies.
Figure 1: Schematic diagram of Fecal Microbiota Transplantation
Figure 2. Both autologous and allogeneic FMT can promote the establishment of intestinal flora after antibiotic treatment in older mice
Fig. 3.Compared with autologous FMT, the transplant flora established after allogeneic FMT has poor resilience after re-disturbance
Source: Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences