Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells

Abstract

Organisms use l-amino acids (l-aa) for most physiological processes. Unlike other organisms, bacteria chiral-convert l-aa to d-configurations as essential components of their cell walls and as signaling molecules in their ecosystems. Mammals recognize microbe-associated molecules to initiate immune responses, but roles of bacterial d-amino acids (d-aa) in mammalian immune systems remain largely unknown. Here, we report that amino acid chirality balanced by bacteria-mammal cross-talk modulates intestinal B cell fate and immunoglobulin A (IgA) production. Bacterial d-aa stimulate M1 macrophages and promote survival of intestinal naïve B cells. Mammalian intestinal d-aa catabolism limits the number of B cells and restricts growth of symbiotic bacteria that activate T cell–dependent IgA class switching of the B cells. Loss of d-aa catabolism results in excessive IgA production and dysbiosis with altered IgA coating on bacteria. Thus, chiral conversion of amino acids is linked to bacterial recognition by mammals to control symbiosis with bacteria.

Profiling of D-alanine production by the microbial isolates of rat gut microbiota

“…While Ala and Glu racemases are ubiquitous in bacterial species for cell wall peptidoglycan synthesis, other AA racemases have been found in different bacterial species (33). Previous research showed that there is a large diversity in the phylogenetic distribution of AA racemases and in the composition and amount of D-AA released by bacteria, mostly on the genus level (23,34). Our results further show that such variation in D-AA secretion exists within the same genus and even the same species.…”

“…In microbial communities, exogenous D-AAs secreted by D-AA producers may be modulators of microbial adaptation to the environment and microbial diversity (23,55). D-AAs can induce host responses via interaction with mucosal or airway surfaces (20,21,34). The gut microbiota-produced free D-AAs can also be absorbed through the gut and potentially regulate host physiology.…”

Mammalian D‐cysteine: A novel regulator of neural progenitor cell proliferation

“…[ 42 ] Catabolic roles for host DAO on D‐amino acids was also shown by Suzuki et al. [ 43 ] This study showed that D‐amino acid catabolism in the mammalian intestine limits the number of B cells and restricts the growth of symbiotic bacteria that activate IgA class switching of B cells by T cells.…”

B cell class switching in intestinal immunity in health and disease

“…Furthermore, B cell responses may be directly or indirectly regulated by microbiotaderived metabolites, such as SCFAs and aryl hydrocarbon receptor (AHR) ligands, which are known to be disrupted in IBD. 145,174,175 The T-box transcription factor family member T-bet has traditionally been associated with initiating and directing effector Th1 responses and controlling IFN-y secretion in viral infection, as well as in dictating Type 1 identity in ILC1s and a subset of mucosal ILC3s. 176,177 More recently, an atypical B cell subset expressing T-bet and secreting IgG has received much attention due to their presence in both mice and humans in a variety of diseases, including autoimmune disorders such as multiple sclerosis and SLE, as well as infectious diseases including Hepatitis C, HIV and rhinovirus.…”