Intestinal Microbiota as a Necessary Basis for Homeostasis, General Pathology, and Ageing, or Back to Elia Metchnikov

Introduction

Elia Metchnikoff’s (1845-1916) genius ideas [1] started to be rejuvenated from the mid-1980s. At that time, the ability of both intestinal microflora (lipopolysaccharides LPS) and stress to induce inflammation was postulated [2], the central receptor for innate immunity (TLR4) was approved to be an endotoxin receptor (2011 Nobel Prize in Physiology and Medicine) [3], and the endotoxin theory of human physiology and pathology being formulated [4, 5].

Systemic Endotoxinemia and Endotoxin Aggression

The methodology for studying the LPS biological role under clinical conditions created by Russian scientists is based on the ability of LPS blood level reducing tools (introduction of intestinal sorbents, hepatoprotectors, bifid bacterium, intravenous laser blood irradiation as well, etc.) to increase the patient treatment efficacy [5]. These efforts and works resulted in and allowed following events and discoveries, in particular: i) to formulate of the LPS and stress involvement to the induction of general adaptation syndrome (basing on the models of psycho-emotional stress and physical overtraining) [6, 7] or disseminated intravascular coagulation (DIC) condition (postsurgical complications being considered) [8], which represent starting points for the development of multiple organ failure syndrome; ii) to establish the LPS involvement to pathogenesis (possibly even to induction) of broncho-obstructive syndrome [9], of chronic hepatitis C, AIDS and SARS-COV-2 as well [10, 11, 12, 13], of atherosclerosis and acute myocardial infarction [14, 15, 16], of alimentary obesity and/or type 1 diabetes [13, 17, 18], of female infertility [19], of endogenous iridocyclitis and endophthalmitis [20] of autoimmune diseases [21] and endogenous psychoses as well [22]; iii) to create interdisciplinary definitions of inflammation and sepsis, to introduce into scientific semantics new definitions such as “Systemic Endotoxinemia” (SEE) [5] as an obligate homeostasis factor and “Endotoxin Aggression” (EA) as a pre-disease and/or universal factor of disease pathogenesis (Figure 1) [4, 5, 23].

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Figure1: Illustrative presentation of the role of SEE and EA phenomena in the treatment and preventive medicine.

Triangle (right up) represents: HMC – high-technological medical care; Hospital and Polyclinic where current “drug” medicine hosts now. “Systemic endotoxinemia” SEE phenomenon is a process of controlling the activity of adaptive systems (including immune system) by intestinal endotoxin with the participation of the hypothalamic-pituitary-adrenal system whose activity determines the LPS level entry into the general bloodstream from the depot (intestine, and adipose tissue). The LPS excess in the blood circulation (increased intestinal permeability, stress, and renal failure) results in the development of “endotoxin aggression” EA (inducing systemic inflammation). The EA phenomenon represents a pre-disease and/or universal factor of general pathology, manifested by one or another form of disease due to genetic and/or acquired predisposition.

Intestinal Permeability towards Endotoxin

The results of experimental and model-based studies played a very important key role in understanding the position of the microbiota (and LPS) phenomenon in general pathology. Cani, et al. [24] proposed an alimentary model of chronic EA (CEA), which they called “metabolic endotoxemia” ME (which is not the best term, in our opinion). Using the model the authors discovered a direct relationship between the LPS level in general blood circulation (i.e., CEA), obesity, and insulin resistance [24]. They established an entirely new direction in the prevention of type 2 diabetes and other metabolic disorders associated with decreasing intestinal permeability [24]. In terms of the endotoxin theory of human physiology and pathology [4, 5], obesity and insulin resistance are also a direct consequence of CEA phenomenon, due to several circumstances at once. There are among them: 1) Such as transport of the LPS hydrophobic form (a recirculating molecule pool along the gut-blood-liver- gut-blood pathway) via the intestinal wall occurs due to its involvement into chylomicron-”fatty food” composition and increases intestinal permeability and body weight (probably LPS activate lipogenesis); 2) The obesity patients are characterized by a tendency to flaccid inflammatory diseases, increased pro- inflammatory background, and enhanced LPS blood levels; 3) Due to the adipose tissue represents the LPS depot therapeutic fasting and use of a gastrointestinal lipase inhibitor in nutrition reduces body weight, the integral indices of systemic endotoxinemia (SE) being returned to the normal values [17].

The first successful attempt to reduce intestinal permeability with a probiotic preparation (live bifidobacteria culture) was made in 2004 to reduce the LPS patient blood level and decrease the frequency of chronic disease exacerbation [23]. Furthermore, it was found that Akkermansia muciniphila-based preparation has even greater ability to strengthen the intestinal barrier [25], which, in our opinion, appeared to be one of the most significant achievements of current clinical microbiology. It happens due to the EA prevention and/or elimination should become a mandatory component of the treatment and preventive medicine, including delaying aging.

Aging: Burning of Human Organism in the Flame of Inflammation

In our opinion, inflammaging phenomenon discovered by Dr. Claudio Franceschi and colleagues (University of Bologna, Italy) - “Inflammation as a driving force of aging” - should be considered as one of the most outstanding clinical achievements of the century [26, 27] (which couldn’t be probably noted on the term “inflammaging” itself). They defined accelerated aging of the organism as a result of the accumulation of chronic inflammation factors [26]. Autoimmune inflammation is predetermined by the nature of the immunity function itself, which protects and destroys simultaneously the host, ensures self-renewal of the population and species evolution [5]. It accompanies us from the birth and increases under aging, without acquiring new qualities. The main trend in the maintaining health and longevity would be decreasing the activity of adaptive immunity (controlled by innate immunity and its ligands), since life itself and aging represent “a process of organism combustion in the fire of chronic inflammation” including, perhaps primarily, autoimmune one [4, 5]. Of principal importance is the fact that the LPS blood level, the number and severity of age-associated chronic diseases (including those of atherosclerotic nature) are increased progressively under aging (Figure 2) [5]. These phenomena are accompanied by a decrease in the activity of anti-endotoxin immunity and the organism ability to respond to the excessive LPS level in the bloodstream by increasing body temperature. In other words, there is a growing tolerance to intestinal endotoxins under aging (age-related endotoxin tolerance). The phenomenon is probably required as individual purposes for the short term to block excessive activity (aggression) of the immune system in extreme situations (sepsis, shock), and for the long term - to ensure the aging self-renewal pool as a part of species evolution. The gut microbiota plays a key role in this process as a source of innate immunity ligands [5].

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The LPS blood level (red curve 1) and the number of chronic diseases are increased permanently, atherosclerosis being in progress (yellow curve 3). The ability of human organism to increase body temperature and the activity of anti-endotoxin immunity are decreasing (blue curve 2).

Intestinal Microbiota: Either Friend or Enemy?

At the first glance, the interaction of the intestinal microbiota with the host is contradictory. On the one hand, it provides digestive processes, synthesis of compounds vital for homeostasis (including vitamins, signaling molecules, ligands of innate immunity, etc.). On the other hand, the microbiota is the first enemy of its host due to the aging and self-destruction processes are realized with its participation, which is predetermined by innate immune system itself and the interaction with LPS. At the same time, it has become clear that endotoxin is not only a marker, but also serves as an aging inducer [5, 28]. Thus, the statement that aging looks, and it is not far from the truth, like combustion process in which the human body burns in a fire of chronic (low-intensity) inflammation with periods of exacerbation, induced respectively by CEA and acute EA [5].

Specific Anti-endotoxin Therapy or Novel Medicine?

At present, there is a question of concern: could a specific anti-endotoxin therapy exist to combat the pathogenesis of chronic and acute diseases, especially septic shock [5, 23, 28, 29, 30, 31]? There are several approaches to reduce the level and activity of endotoxins in human body, namely: 1) The use of intestinal sorbents to eliminate endotoxins from the bloodstream, hence acute or chronic endotoxin aggression (e.g., ToxipacTM device, U.S.A.) [29, 32]; 2) Extra-corporal plasma purification by therapeutic plasmapheresis using appropriate membranes/sorbents with immobilized antibodies against endotoxins; 3) Correction of the profile of Gram-negative intestinal microorganisms by microbial preparations such as bifid bacteria administered to patients with chronic disease under remission [23]; 4) Impact onto endotoxins’ level and the profile of Gram- negative intestinal microorganisms using nutritional diets and natural bioantioxidant complexes (onion, garlic, ginger) [33, 34]; 5) Strengthening of natural anti-endotoxin immunity in various ways including usage of chaotropic agents [35]; and selective enterosorption of sources of endotoxin aggression development basing on finding out an EA etiology [36].

The World-Wide Discussion on Role of Intestinal Microbiota in Homeostasis, Inflammation, and Aging is Needed

The First International Congress “Microbiota: Homeostasis, Inflammation, and Aging”, which planned to be held at City-of-Naberezhnye Chelny, Republic of Tatarstan Russian Federation (not far from City-of-Kazan), from 6-8 September 2024 [37], may become the first worldwide discussion of the questions and problems raised in the present mini-review article, as well as a generalization of ideas on the role of intestinal endotoxins and stress in adaptation processes and induction of inflammation [4, 5, 36], inflammaging [26, 27], and aging [28], which have already become classical. Over the past 35 years, there has been a major breakthrough in the understanding of the mechanisms of interaction between the microbiota and the host, and a number of interesting findings have been published that have not yet been fully systematized and, therefore, not properly understood. We are convinced that the time has come for such an International Congress to be held with the participation of leading researchers from a wide range of biological, biomedical, and medical disciplines.

The following issues and problems are proposed for discussion at the Congress: consensus on the terminology and definitions used; establishment of scientific contacts between clinicians and basic scientists; creation of a unified database on the problems studied and the possibility for publication in open (not engaged) Internet publications; determination of directions for the search of means for normalization of systemic endotoxinemia indicators as the basis for preventive medicine [36], among them: probiotics and prebiotics, intestinal sorbents, hepatoprotectors, immune drugs, chaotropic effects (plasmapheresis, blood irradiation, and other); clinical and experimental models for disease study; prospects for dynamic monitoring of systemic endotoxinemia indicators; creation a research protocol to establish the range of integral indicators of systemic endotoxinemia (LPS level and activity of anti- endotoxin immunity); discussion of information on the study of LPS-factor pathogenesis of diseases and ways to learn the mechanism of development of endotoxin tolerance and its overcoming; the need to include new information in the curricula of doctors’ training; and finding financial resources to conduct “independent research”.

Conclusions

1. The LPS factor is involved to pathogenesis: of broncho- obstructive syndrome, of chronic hepatitis C, AIDS and SARS-COV-2, of atherogenesis and acute myocardial infarction, of alimentary obesity and/or type 1 diabetes, of autoimmune diseases;

2. New definitions are introduced into scientific semantics: such as “Systemic Endotoxinemia” (SEE) as an obligate homeostasis factor and “Endotoxin Aggression” (EA) as a pre-disease and/or universal factor of disease pathogenesis; 3. The EA prevention and/or elimination would become a mandatory component of the treatment and preventive medicine, including delaying aging. Human life and aging look like “burning of human organism in the flame of chronic inflammation” with periods of exacerbation; 4. A specific anti-endotoxin therapy could be developed to combat the pathogenesis of chronic and acute diseases (especially septic shock) which surely represents a basis for creation of novel direction in current medicine;

The Worldwide discussion of the topics and problems is needed in sense of LPS-centered medicine, as well as a generalization of ideas on the role of intestinal endotoxins and stress in adaptation processes and induction of inflammation, inflammaging, and aging.