Here, we propose the development of Lactobachill, a smart psychobiotic that in addition to its intrinsic probiotic properties, can also aid in the normalization of aberrant gut-brain signaling. For this, we will develop two different strategies aimed at blocking the trans-signaling pathway of the pro-inflammatory cytokine IL-6. Increased levels of this pleiotropic cytokine have been implicated in the pathophysiology and treatment of clinical depression, which in turn is accompanied by an increase in the levels of oxidative and nitrosative stress.

Lactobachill is based on the widely used probiotic strain, Lactobacillus rhamnosus GG, a biosensing component that detects an increase in nitrosative stress, and two different response mechanisms: 1) secretion of the soluble variant of sgp130, the soluble form of the IL-6 signal transducer; and 2) secretion of a mutated variant of sIL-6R that cannot bind to gp130. This smart psychobiotic will be able to sense and respond to alterations in inflammatory and nitrosative stress pathways, which are critical to the pathogenesis of depression. Non-conventional therapies, including psychobiotics such as Lactobachill, could be used as adjuvants to increase the efficacy of existing treatments against these and other mental disorders.

According to the World Health Organization, more than 300 million people suffer from depression and anxiety worldwide1. Despite the wide range of therapeutic approaches available, not all patients receive adequate attention due to incorrect diagnosis, expensive treatment options, and misinformation in general. These issues could lead to additional complications and comorbidities, which difficult treatment and diagnosis and often worsen patient prognosis. For instance, 30% to 70% of suicide victims suffer from major depression or bipolar (manic-depressive) disorder, which is critical since suicide constitutes the second leading cause of death among people between 15 and 29 years of age.

Although psychotherapy and antidepressant medication are widely prescribed, not all patients respond to the treatment and some are averse to pharmacologic intervention3. Furthermore, antidepressants are often associated with several undesirable side effects such as nausea, fatigue, insomnia, irritability, and a severe discontinuation syndrome upon withdrawal.

Psychiatric disorders such as anxiety and depression are of multifactorial origin and may arise from hormonal unbalance, as well as the genetic makeup and the brain biochemistry of each patient. In addition, accumulating evidence has shown that there is a strong relationship between systemic inflammation and psychiatric disorders4. For instance, circulating levels of pro-inflammatory cytokines such as IL-1, TNF-α, and IL-6 have been shown to be increased in patients with depression and anxiety5. In particular, the pro-inflammatory effects of the pleiotropic cytokine IL-6 are predominantly mediated through IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R)6. The formation of the IL-6/sIL-6R complex promotes binding to and dimerization of the ubiquitously expressed gp130, which transduces IL-6 signaling through the Jak/STAT pathway (Figure 1). In this regard, previous works have demonstrated that the soluble variant of gp130 (sgp130) constitutes the natural antagonist of IL-6 trans-signaling7.

Probiotics are live microorganisms that provide different health benefits when ingested. Recent evidence has demonstrated that some probiotic strains could produce and deliver neuroactive compounds, thereby acting as bona fide psychotropic agents. These so-called “psychobiotics” are probiotic microorganisms that confer benefits to the mental health of the host and have been shown to exert anxiolytic and antidepressant effects in animal models 10. The mechanisms through which psychobiotics exert their effects on the neurophysiology of the host include the enteric nervous system and the immune system10. Thus, we hypothesized that probiotic microorganisms could be used to engineer living biosensors, which could detect alterations in inflammatory and O&NS pathways related to anxiety and depression.

In particular, specific strains such as Lactobacillus rhamnosus GG could be ideal candidates for these applications, owing to their intrinsic psychobiotic properties. Therefore, we propose the development of Lactobachill, a smart psychobiotic that detects increases in nitrosative stress via the nitrite-sensitive repressor NsrR11. In addition, we will investigate two different response mechanisms aimed at blocking the IL-6 trans-signaling pathway: 1) Concomitant secretion of soluble sgp13013; and 2) secretion of a mutated variant of sIL-6R that cannot bind to gp13014

Lactobachill could potentially be used as an adjuvant to current treatments against anxiety, depression, and other associated mental disorders. This approach could help minimize the use of antidepressants, as well as the incidence of different mental disorders without the need for pharmacologic intervention. Furthermore, due to the intrinsic probiotic and psychobiotic properties of Lactobacillus rhamnosus, Lactobachill could be integrated into functional foods or supplements to help reduce the risk of several intestinal and extra-intestinal disorders. Therefore, Lactobachill could constitute an attractive alternative for the prevention and treatment of a variety of mental disorders and help improve the quality of life of millions of people worldwide.