Gut bacteria could drive autoimmune response in genetically predisposed

 

Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.

Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.

In monocolonized and autoimmune-prone mice, the research team reported in Science that E. gallinarum could spontaneously translocate outside of the gut to lymph nodes, the liver, and spleen and initiate the production of autoantibodies and inflammation that led to death.

The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.

 

“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.

The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.

Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.

“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.

 

The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.

“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.

The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.

 

Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.

Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.

In monocolonized and autoimmune-prone mice, the research team reported in Science that E. gallinarum could spontaneously translocate outside of the gut to lymph nodes, the liver, and spleen and initiate the production of autoantibodies and inflammation that led to death.

The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.

 

“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.

The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.

Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.

“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.

 

The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.

“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.

The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.

 

Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.

Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.

In monocolonized and autoimmune-prone mice, the research team reported in Science that E. gallinarum could spontaneously translocate outside of the gut to lymph nodes, the liver, and spleen and initiate the production of autoantibodies and inflammation that led to death.

The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.

 

“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.

The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.

Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.

“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.

 

The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.

“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.

The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.