Clostridium as microbial cell factory to enable the sustainable utilization of three generations of feedstocks.

The sustainable production of chemicals and biofuels from non-fossil carbon sources is considered key to reducing greenhouse gas (GHG) emissions. Clostridium sp. can convert various substrates, including the 1st-generation (biomass crops), the 2nd-generation (lignocellulosic biomass), and the 3rd-generation (C1 gases) feedstocks, into high-value products, which makes Clostridia attractive for biorefinery applications. However, the complexity of lignocellulosic catabolism and C1 gas utilization make it difficult to construct efficient production routes. Accordingly, this review highlights the advances in the development of three generations of feedstocks with Clostridia as cell factories. At the same time, more attention was given to using agro-industrial wastes (lignocelluloses and C1 gases) as the feedstocks, for which metabolic and process engineering efforts were comprehensively analyzed. In addition, the challenges of using agro-industrial wastes are also discussed. Lastly, several new synthetic biology tools and regulatory strategies are emphasized as promising technologies to be developed to address the aforementioned challenges in Clostridia and realize the efficient utilization of agro-industrial wastes.