Gut Microbial Metabolites Fuel Host Antibody Responses

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript comparable to the C3 levels created by HFD (Figure S2A).”

“SCFAs increase colonic FoxP3+ Tregs (Furusawa et al., 2013; Smith et al., 2013).”

“A mounting body of evidence indicates that gut microbiota profoundly influences the host immune system (Alexander et al., 2014; Belkaid and Hand, 2014).”

“For example, germ-free mice are variably impaired in epithelial integrity, gut-associated lymphoid tissue development, innate and adaptive immunity, and immune tolerance (Round and Mazmanian, 2009).”

“SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”

“…and analyzed data and drafted the manuscript with MK. anuscript A uthor M anuscript Keywords Short chain fatty acids; antibody; B cells; metabolism INTRODUCTION Host and gut microbial flora functionally interact in the gut for mutual benefits (Brown et al., 2013; Tremaroli and Backhed, 2012).”

“These genes are linked to B cell differentiation and/or IgA and IgG production (Aldrich et al., 2003; Muramatsu et al., 2000; Turner et al., 1994).”

“The total luminal SCFA concentration in humans reaches ~130 mmol/Kg in the colon and ~15 mmol/Kg in the small intestine (SI) (Cummings et al., 1987).”

“Moreover, SCFAs enhanced the mitochondrial ATP production and maximal respiration rates in B cells (Figure 4C).”

“Short chain fatty acid (SCFAs) are the major microbial metabolites of DF (Macfarlane and Macfarlane, 2003).”

“We observed elevated levels of cellular acetyl-CoA and lipid droplets, which promote B cell differentiation and antibody production. mTOR activation increases glycolytic activity in general (Masui et al., 2013; Shi et al., 2011).”

“Cells that are known to be regulated by SCFAs include T cells, phagocytes, and epithelial cells (Kim et al., 2013; Le Poul et al., 2003; Park et al., 2015; Smith et al., 2013).”

“SCFAs are HDAC inhibitors and, therefore, have the potential to regulate gene expression and cell signaling through regulation of protein acetylation (Davie, 2003).”

“SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”

“Numerous microbial products, including proteins, polysaccharides, and molecules that activate pattern recognition receptors (PRR), such as Toll-like receptors (TLR) and NODlike receptors (NLR), stimulate the mucosal immune system (Abreu, 2010).”

“SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”

“This activation induces the production of cytokines, retinoic acid (RA) and other B cell-activating molecules by various cell types (Gutzeit et al., 2014; Kim, 2013; Mora et al., 2006).”

“While SCFAs are derived from DF, DF and SCFAs are not identical in their effects because DF can generate more than SCFAs and may also affect gut microbiota differently than SCFAs (Lee and Hase, 2014).”

“SCFAs exert their functions through several different mechanisms, including activation of cell surface receptors (GPR41, GPR43 and GPR109A), histone deacetylase (HDAC) inhibition, and metabolic integration (Ganapathy et al., 2013; Kim et al., 2014; Licciardi et al., 2011).”

“SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”

“, 2011), some Tregs can convert to Tfh cells in PP (Tsuji et al., 2009).”

“B cells utilize both glycolysis and mitochondrial energy production for plasma cell differentiation (Caro-Maldonado et al., 2014).”

“…and analyzed data and drafted the manuscript with MK. anuscript A uthor M anuscript Keywords Short chain fatty acids; antibody; B cells; metabolism INTRODUCTION Host and gut microbial flora functionally interact in the gut for mutual benefits (Brown et al., 2013; Tremaroli and Backhed, 2012).”

“The gut microbiota also supports systemic antibody responses (Zeng et al., 2016).”

“We observed elevated levels of cellular acetyl-CoA and lipid droplets, which promote B cell differentiation and antibody production. mTOR activation increases glycolytic activity in general (Masui et al., 2013; Shi et al., 2011).”

“SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”

“This activation induces the production of cytokines, retinoic acid (RA) and other B cell-activating molecules by various cell types (Gutzeit et al., 2014; Kim, 2013; Mora et al., 2006).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Acetyl-CoA, which can be derived from SCFAs, is the main substrate in fatty acid synthesis (FA, more specifically palmitic acid) (Bloch and Vance, 1977).”

“The numbers of IgAcoated and IgA-free bacteria were assessed as described previously (Chu et al., 2014).”

“SCFAs exert their functions through several different mechanisms, including activation of cell surface receptors (GPR41, GPR43 and GPR109A), histone deacetylase (HDAC) inhibition, and metabolic integration (Ganapathy et al., 2013; Kim et al., 2014; Licciardi et al., 2011).”

“While Tregs, particularly follicular Tregs, suppress B cell responses (Chung et al., 2011; Lim et al., 2004; Linterman et al., 2011), some Tregs can convert to Tfh cells in PP (Tsuji et al.”

“Indeed, others observed that C4 or other HDAC inhibitors at such high concentrations can suppress B cells or kill T cells in vitro (White et al., 2014; Zimmerman et al., 2012).”

“DISCUSSION The current paradigm for the function of gut microbiota in supporting antibody responses is mediated through TLR-activating bacterial DNA, proteins, and cell wall components, which directly and/or indirectly promote antibody responses (Kirkland et al., 2012; Teng et al., 2016).”

“Acetyl-CoA carboxylase (ACC) catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA, and fatty acid synthase (FAS) extends the length of fatty acids to make palmitic acid (Girard et al., 1994).”

“It is generally accepted that TLR ligands support antibody responses (Buchta and Bishop, 2014; Pone et al., 2012; Zeng et al., 2016).”

“AMPK activation suppresses the mTOR pathway (Green et al., 2011; Limon and Fruman, 2012).”

“One of the defective components of the adaptive immunity in GF mice is mucosal IgA production (Moreau et al., 1978).”

“A mounting body of evidence indicates that gut microbiota profoundly influences the host immune system (Alexander et al., 2014; Belkaid and Hand, 2014).”

“There is a positive correlation between dietary fiber (DF) intake and intestinal IgA levels (Kudoh et al., 1998; Lim et al., 1997).”

“Because FA synthesis is important for plasma B cell differentiation (Dufort et al., 2014; Fagone et al., 2007) and palmitic acid stimulates antibody production by B cells (Kunisawa et al., 2014), we examined lipid content in B cells treated with SCFAs.”

“For confocal imaging of cellular lipid droplets, B cells were cultured with indicated SCFAs in the IgA-inducing condition for 3 days, fixed, and stained with BODIPY (10 μM, Invitrogen) and DRAQ5 (1 μM) (Gold et al., 2012).”

“SCFAs exert their functions through several different mechanisms, including activation of cell surface receptors (GPR41, GPR43 and GPR109A), histone deacetylase (HDAC) inhibition, and metabolic integration (Ganapathy et al., 2013; Kim et al., 2014; Licciardi et al., 2011).”

“We also found that genes involved in B cell differentiation and function, such as Hepatitis A virus cellular receptor 1 (HAVcr-1)/T-cell immunoglobulin and mucin domain 1 (TIM-1), microphthalmia-associated transcription factor (Mitf), CD27, and LAPTM5 (Lin et al., 2004; Ouchida et al., 2010; Xiao et al., 2015; Xiao et…”

“We also found that genes involved in B cell differentiation and function, such as Hepatitis A virus cellular receptor 1 (HAVcr-1)/T-cell immunoglobulin and mucin domain 1 (TIM-1), microphthalmia-associated transcription factor (Mitf), CD27, and LAPTM5 (Lin et al., 2004; Ouchida et al., 2010; Xiao et al., 2015; Xiao et…”

“Indeed, others observed that C4 or other HDAC inhibitors at such high concentrations can suppress B cells or kill T cells in vitro (White et al., 2014; Zimmerman et al., 2012).”

“AMPK activation suppresses the mTOR pathway (Green et al., 2011; Limon and Fruman, 2012).”

“It is generally accepted that TLR ligands support antibody responses (Buchta and Bishop, 2014; Pone et al., 2012; Zeng et al., 2016).”

“DISCUSSION The current paradigm for the function of gut microbiota in supporting antibody responses is mediated through TLR-activating bacterial DNA, proteins, and cell wall components, which directly and/or indirectly promote antibody responses (Kirkland et al., 2012; Teng et al., 2016).”

“We also found that genes involved in B cell differentiation and function, such as Hepatitis A virus cellular receptor 1 (HAVcr-1)/T-cell immunoglobulin and mucin domain 1 (TIM-1), microphthalmia-associated transcription factor (Mitf), CD27, and LAPTM5 (Lin et al., 2004; Ouchida et al., 2010; Xiao et al., 2015; Xiao et…”

“Because FA synthesis is important for plasma B cell differentiation (Dufort et al., 2014; Fagone et al., 2007) and palmitic acid stimulates antibody production by B cells (Kunisawa et al., 2014), we examined lipid content in B cells treated with SCFAs.”

“Because FA synthesis is important for plasma B cell differentiation (Dufort et al., 2014; Fagone et al., 2007) and palmitic acid stimulates antibody production by B cells (Kunisawa et al., 2014), we examined lipid content in B cells treated with SCFAs.”

“We also found that genes involved in B cell differentiation and function, such as Hepatitis A virus cellular receptor 1 (HAVcr-1)/T-cell immunoglobulin and mucin domain 1 (TIM-1), microphthalmia-associated transcription factor (Mitf), CD27, and LAPTM5 (Lin et al., 2004; Ouchida et al., 2010; Xiao et al., 2015; Xiao et…”

“It was observed many years ago that DF intake potentiates IgA responses in rats (Kudoh et al., 1998).”

“These genes are linked to B cell differentiation and/or IgA and IgG production (Aldrich et al., 2003; Muramatsu et al., 2000; Turner et al., 1994).”

“This activation induces the production of cytokines, retinoic acid (RA) and other B cell-activating molecules by various cell types (Gutzeit et al., 2014; Kim, 2013; Mora et al., 2006).”

“Dietary fibres and SCFA enhance antibody response to bacteria by supporting B cell differentiation into plasma B cells via the increase of histone acetylation and of B cell metabolism((161,162)).”

“…gut The metabolic relationship between commensals and immune cells in the gut is further illustrated by the finding that SCFAs derived from the fermentation of dietary fiber by gut microbiota promote B cell metabolism and boost antibody responses in both mouse and human B cells (Kim et al., 2016).”