Psychophysiological Effects of Lactobacillus Plantarum PS128 in Patients With Major Depressive Disorder and High Level of Inflammation: a Pilot Study of 8-week Open Trial

1. Background Major depressive disorder (MDD) is a complex and long-term illness that involves marked disabilities in affected patients. It has been one of the leading causes of global burden of disease, especially in the middle-age groups (GBD Lancet 2016; 388:1603-58). It is also a common comorbidity in patients with irritable bowel syndrome, cardiovascular disease and cancer (Musselman et al. 1998; Spiegel et al. 2003; Whitehead et al. 2002). The mechanisms responsible for depression and its comorbidity are not clear, but inflammatory processes may be implicated. Meta-analysis has shown that patients with depression have higher levels of inflammatory markers, such as C-Reactive Protein (CRP), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-alpha (Dowlati et al. 2010; Howren et al. 2009). Microbiota-gut-brain axis may explain higher inflammatory cytokines in patients with MDD. Accumulating data now indicate that the gut microbiota can communicate with the CNS--possibly through immune, neural, and endocrine pathways--and thereby influences brain function and behavior (Cryan et al. 2012; Forsythe et al. 2016; Rogers et al. 2016). Probiotics, which are defined as a live organism that when ingested in adequate amount exerts a health benefit, can affect gut microbiota, brain neurochemistry, HPA axis, and inflammation, and may be a novel class of psychotropics (Dinan et al. 2013).

1.1 Microbiota-gut-brain axis The lower gastrointestinal tract contains almost 100 trillion microorganisms, most of which are bacteria. The microbiota collectively encodes more than 3.3 million non-redundant genes, exceeding the number encoded by the human host genome by 150-fold (Qin et al. 2010). Many microbial gene products have important effects on metabolism and the health of the host.

There have been numerous studies supporting the communications between gut microbiota and brain. Study using germ free (GF) animal is a good model to show the relationship between microbiota and brain. Compared to specific pathogen free (SPF) mice with a normal gut microbiota, GF mice display increased motor activity and reduced anxiety behavior. An increased turnover of dopaminergic and serotonergic neurotransmitters in striatum was observed in GF mice (Diaz Heijtz et al. 2011). In addition, GF mice exhibited higher adrenocorticotropic hormone (ACTH) and corticosterone elevation in response to restraint stimulus than SPF mice did (Sudo et al. 2004). It suggests that gut microbiota can affect host's response to stress.

Several studies have shown that manipulation of gut microbiota can affect the presentation of host's psychophysiology. For example, consumption of high fat diet (HFD) is associated with altered microbial diversity (Daniel et al. 2014) and reduced synaptic plasticity (Liu et al. 2015). HFD also increased anxiety-like behavior (Sharma et al. 2013). Adult male C57BL/6 mice given HFD microbiota had significant and selective disruptions in exploratory, cognitive, and stereotypical behavior compared with mice with control diet microbiota. No significant differences in body weight were noted. The difference in composition of gut microbiota between HFD and normal-diet groups was noted (Bruce-Keller et al. 2015).

Administration of antibiotics is another way to affect gut microbiota composition and change host's psychophysiology. Oral administration of non-absorbable antimicrobials transiently altered gut microbiota composition and increased exploratory behavior and hippocampal expression of BDNF mRNA in mice, but intraperitoneal administration had no effect on behavior (Bercik et al. 2011). Increased antibiotic exposures were associated with the risk of depression and anxiety in a population study (Lurie et al. 2015). Therefore, administration of probiotics may be a direct way to change the environment and composition of gut microbiota, and observe its physiological effects on host.