In our study, the median SLE disease activity score among patients with anxiety was higher than in patients without anxiety. High disease activity might be a physical stressor for patients with SLE, which can cause anxiety.17 In addition, we found lower food intake among patients with anxiety, which seems to contradict the theory of emotional eating in anxiety. This difference might be explained by the higher comorbidity of depression in the anxiety group than in patients without anxiety. Depression can cause anhedonia, which results in decreased food intake.18
We found a negative correlation between the disease duration and the depression score. This may be explained by Kübler-Ross’ theory, which states that there are five stages of grieving: denial, anger, bargaining, depression, and acceptance.19 Thus, it is likely that patients with longer disease duration had reached the stage of acceptance.
SLE has a two-way relationship with gut dysbiosis. Gut dysbiosis can worsen the pathology of autoimmunity, and SLE can change gut microbiome patterns (dysbiosis). Pro-inflammatory conditions in SLE can also disrupt intestinal integrity. In dysbiosis, which is caused by various factors such as infection, drugs, and dietary patterns, pathogens are more dominant than normal intestinal flora and activate intestinal lymphoid tissue. This response results in the overactivation of lymphocytes and the transregulation of regulatory T cells to Th17 cells. Interleukin-17 (IL-17) released by Th17 cells amplifies the immune response and activates B cells to produce autoantibodies.13 Thus, intestinal dysbiosis can cause loss of self-tolerance in SLE in the preclinical stage.
A study by Hevia et al. had shown that SLE patients have lower Firmicutes/Bacteroidetes ratios (median ratio 1.97) than healthy subjects (median ratio 4.86).20 A low Firmicutes/Bacteroidetes ratio is one of the parameters of gut dysbiosis.11 The median Firmicutes/Bacteroidetes ratio in our subjects was 0.56 (min‒max 0.18‒3.6). In this study, we also found a significant correlation between some gut microbiota parameters (Bacteroides proportion and diversity indices) and disease activity. A higher proportion of Bacteroides and lower diversity of gut microbiota correlated with higher SLE disease activity.
Pathobionts are potentially pathogenic microbes that can release toxins.21 The predominant phylum in the gut is Bacteroidetes, a pathobiont.12 Bacteroidetes are microbes that tend to be pathogenic and disrupt the integrity of the intestinal epithelium to cause inflammation.22 These conditions can result in changes in synapse architecture, synapse deficits, immune system defects, and progressive inflammation.23 In our study, Bacteroidetes counts were found to be higher among SLE patients with anxiety than in those without anxiety. A similar finding was also found in SLE patients with depression. Bacteroides, the main genus in the phylum Bacteroidetes, are pathogenic, highly virulent microbes in the intestine that trigger inflammatory reactions in the intestine.12,24
Bacteroides fragilis is a facultative, gram-negative, anaerobic bacterium, which comprises a large proportion of the gut microbiota. It secretes various neurotoxins, including the highly pro-inflammatory B. fragilis lipopolysaccharide (BF-LPS).23 BF-LPS can trigger the production of nuclear factor-κB, which causes the transcription of a group of proinflammatory microRNAs. In addition to Bacteroides in the gastrointestinal tract, Bacteroidetes also play a role in the secretion of glycoproteins, SCFA imbalance, and the production of toxins.25
Inflammation causes the conversion of tryptophan—the precursor of serotonin—to kynurenine, which causes serotonin deficiency. The increased levels of kynurenine cause neurotoxicity and neurodegeneration.14 In addition, inflammation is associated with high cortisol levels, which can cause neurotoxicity and decrease GABA production.15 The deficiency of GABA and serotonin can also occur because GABA-producing microbes and serotonin-producing microbes are suppressed by pathobionts.16 GABA deficiency plays a role in the pathogenesis of anxiety,16 whereas serotonin deficiency plays a role in depression.10
Other contributors to dysbiosis are low diversity indices.26 In this study, lower diversity indices were found in SLE patients with anxiety than in those without anxiety and in SLE patients with depression than in those without depression. Loss of microbial diversity is the most constant finding of gut dysbiosis, which may affect the function of the microbial community. High biodiversity helps to maintain a stable ecosystem so that the gut becomes more resilient to many insults.27
In this study, there was a lower proportion of Firmicutes and Firmicutes/Bacteroidetes ratio among SLE patients with depression. Firmicutes are the main gut microbiota that produce SCFAs12 and also produce a number of neurotransmitters.16 A lower proportion of Firmicutes may cause inflammation and deficiency of many neurotransmitters, which may result in depression. Our finding was consistent with that of a study by Jiang et al., which showed a decrease in Firmicutes levels and an increase in Bacteroidetes levels in subjects with depression.28
Patients who experienced both anxiety and depression showed the most severe gut dysbiosis compared to the other groups. In this group, we found the highest proportion of Bacteroidetes and the lowest proportion of Firmicutes, Firmicutes/Bacteroidetes ratio, and diversity indices. Severe dysbiosis can result in a deficiency of neurotransmitters and inflammation, which might worsen psychosomatic disorders.16
The gut microbiome-brain axis is a complex multidirectional system involving the gut microbiota, the enteric nervous system, and the brain. Gut dysbiosis can cause psychosomatic disorders, and psychosomatic disorders can cause gut dysbiosis by affecting dietary patterns.8 In our study, we found lower food intake (carbohydrate, fat, protein, and fiber) in SLE patients with anxiety than in those without anxiety and also in SLE patients with depression than in patients without depression. Lower carbohydrate and fiber intake are risk factors for intestinal dysbiosis.29 In addition, psychosomatic disorders activate the hypotalamus-pituitary-adrenal axis, which can increase the level of cortisol and disrupt the integrity of the intestinal epithelium.8
This is the first study to report the gut microbiota profiles of SLE patients with anxiety or depression, which can give new insight in the pathogenesis and management of psychosomatic problems in SLE patients. However, this study also had limitation. The sample size was small. This study only assessed anxiety and depressive symptoms based on a questionnaire, not based on interviews. In addition, psychosomatic disorders have various influencing factors, including educational background, social and economic factors.