As the years go by, the gut microbiota tends to become less efficient: it loses diversity, metabolic functionality, and the integrity of the intestinal barrier. Factors and changes that expose us to dysbiosis, gastrointestinal issues, and other diseases—even far from the gut site—include cardiovascular and metabolic diseases such as diabetes, and neurological conditions like autism, as well as neurodegenerative disorders such as Parkinson’s disease. These are the latest frontiers of scientific research, which has highlighted that the common thread uniting all these states is chronic low-grade inflammation (inflammaging), responsible for immunosenescence, metabolic alterations, cognitive decline and neuroinflammation, frailty, and other age-related conditions.
Gastrointestinal Diseases
The clinical-functional relationship of these three factors forms an “alliance,” both positive and negative, that is becoming increasingly tight in the literature. “Evidence is growing,” states Alessandra Zilli, a gastroenterologist at the Unit of Gastroenterology and Digestive Endoscopy of San Raffaele Hospital in Milan, “showing that an alteration of the intestinal microbiota impacts gastrointestinal symptoms and some specific diseases. The functions of the intestinal microbiota are well known, including its important barrier role and its education of the immune system, which must be highly performant in proactively responding to attacks from a multitude of external antigens, thereby protecting the entire body and certain sites in particular. Among these, the intestinal epithelial cells are constantly exposed to contaminants of various kinds. Moreover, the metabolic function of the microbiota—influencing nutrient absorption and glycemic index—is of extreme importance. If the microbiota is healthy and performing well, it ensures an eubiotic state in which certain beneficial strains predominate, especially butyrate producers like Faecalibacterium prausnitzii. Conversely, in a state of dysbiosis, characterized by a significant reduction in the alpha diversity of bacterial strains, with a predominance of anaerobes, including enterobacteria, there is evidence of a correlation with several gastrointestinal diseases. Among the most frequent are pouchitis, i.e., inflammation of the pouch—the small reservoir created surgically with the small intestine in patients who have undergone colectomy for ulcerative colitis—wherealters the gut flora triggers acute and chronic inflammation, and recurrent infection by Clostridium difficile. The latter is an anaerobic Gram-positive bacterium which, in some predisposed individuals or after exposure to risk factors such as hospitalization or antibiotic therapies, can produce toxins, triggering diarrhea with inflammation.”
Also in chronic inflammatory bowel diseases, the hypothesis of a contribution from intestinal dysbiosis to the development of these conditions is gaining ground, promoting relapses, the onset of specific pathology, or in predisposed individuals. Recently, an association with colorectal cancer has emerged, particularly in younger subjects under 50. Some studies observe that certain Escherichia coli strains that produce colibactin, a genotoxic toxin, may increase the risk of developing this malignancy. “Defining a causal relationship among all these factors is not easy since we still lack adequate tools,” continues Zilli, “although it is recognized that inflammatory bowel diseases share the same inflammatory trigger, responsible for the alteration of the intestinal flora. This would define a synergy between gastrointestinal diseases and dysbiosis and vice versa, amplified by other factors such as genetic predisposition and environmental exposure, suggesting that dysbiosis is not sufficient by itself to spark the cascade that leads to disease, but it is an integrated and essential part.”
Inflammation
Chronic low-grade inflammation, altered production of short-chain fatty acids (SCFAs), and immunological imbalances such as Th17 activation (a subgroup of white blood cells specialized in defending the body against bacterial and fungal infections) or a reduction in regulatory T cells (Tregs) that shut down immune responses to protect tissues and prevent autoimmune diseases, are factors that contribute to gastrointestinal clinical pictures.
“Butyrate, one SCFA, represents the main energy source for the colon’s epithelial cells. When it rises—continues the gastroenterologist—it reduces mitochondrial oxidation in intestinal cells, resulting in thinning of the mucus layer that normally coats the surface of colonocytes and serves as a barrier. This process can partially favor intestinal permeability, but also the luminal bioavailability of nitrate and oxygen: a synergy of factors that promotes the expansion of certain bacterial strains such as anaerobes and Escherichia coli, contributing to dysbiosis. Furthermore, butyrate appears to play an important role in the differentiation of regulatory T lymphocytes that, at the intestinal level, govern the immune response.” Studies in the literature show, for example, that in drug-induced colitis, the reduction of butyrate decreases the performance and efficacy of these lymphocytes, lowers immune tolerance, and thus amplifies the response to certain antigens: the imbalance between Th17 and regulatory T cells would promote the production of inflammatory cytokines, such as Interleukin-17, implicated in the inflammatory cascade.
The Leaky Gut
Intestinal permeability, i.e., the access of bacteria and various antigens that manage to cross into the gut due to gaps between intestinal cells, is another trigger for intestinal inflammation. A Canadian study on subjects with a family history of Crohn’s disease, followed for seven years, shows that intestinal permeability can precede the development of this condition, which then self-maintains with the ignition of inflammation. “To date,” explains Zilli, “there are few tools to assess intestinal permeability, including the zonulin test, a protein related to haptoglobin that modulates the permeability of tight junctions between the cells lining the digestive tract, and the ELISA kit, unfortunately not always reliable due to varying reference parameters. Therefore, permeability is largely studied for research purposes, for example in the endoscopic setting. In addition to dysbiosis, the use of anti-inflammatory drugs can also increase intestinal permeability in chronic diseases. There are several strategies to reduce permeability, and among the conservative options are specific probiotics or SCFAs, even in drug form.”
Therapeutic Approach
Robust evidence, including in the literature, supports the use of prebiotics, especially in certain clinical conditions. For example, in pouchitis, De Simone formulations, with high concentrations of specific strains, demonstrate the ability to reduce inflammation. In the presence of Clostridium difficile infection, the recommendation is fecal microbiota transplantation (FMT), in immunocompetent patients who have already undergone first-line antibiotic therapies without eradication or with recurrent relapses. In pediatrics, the most effective strategy is diet. “Before resorting to drugs in young patients with inflammatory bowel disease,” emphasizes the gastroenterologist, “we rely on exclusive enteral nutrition, sometimes combined with an exclusion diet free of foods with pro-inflammatory action that helps modify the microbiota to some extent.”
Regardless of the clinical picture and patient age, therapy must be tailored from the start by addressing lifestyle, primarily diet. The Mediterranean diet is preferred, as it promotes the production of butyrate-producing bacteria; in specific cases, such as patients with Irritable Bowel Syndrome (IBS), a low-FODMAP diet—temporarily reducing highly fermentable foods—may be used. On other fronts, at present there are no new molecules with robust clinical evidence, while in the future the microbiota may become a “therapeutic tool” in the treatment of chronic inflammatory gastrointestinal diseases.
Scientific Evidence
It is now established that alteration of the intestinal microbiota is strongly implicated in the development of many diseases, not only of the gastrointestinal tract. However, to date it is not yet clear whether this alteration is the cause or the consequence of a particular disease.
“Some preclinical models,” says Maria Rescigno, professor of General Pathology at Humanitas University, Group Leader of the Mucosal Immunology and Microbiota Unit at Humanitas Research Hospital IRCCS in Rozzano (Milano), “suggest that microbiota variation precedes the disease’s development, representing a co-cause. A key triggering factor is often increased intestinal permeability with dysbiosis, a condition that facilitates the entry of substances that would normally be blocked by a healthy, eubiotic gut barrier. Dysbiosis alters not only the intestinal epithelial barrier but also the vascular barrier, making vessels more permeable to substances of bacterial origin that translocate through the intestine to other sites, potentially fueling systemic inflammation. This could help explain why many diseases, even distant from the gut, such as cardiovascular or metabolic diseases, may be associated with dysbiosis.”
It is increasingly clear that changes in intestinal permeability are both dependent on and a consequence of lifestyle. For example, a diet rich in animal fats and simple sugars or highly processed foods can “inflame” the microbiota, fueling a leaky gut. “The evidence on the microbiota’s capacity to influence the effectiveness of a therapy, including oncologic therapy, is highly significant,” Rescigno continues. “New directions in research and care are considering the composition of the intestinal microbiota as a possible factor to predict a patient’s response to a treatment, thereby improving benefits and efficacy by acting on the microbiota itself. Examples of innovative, still experimental oncologic research include studies showing that a patient refractory to a specific therapy who receives a fecal transplant from a donor with good therapeutic outcomes may begin to show a response in about 40% of cases. These findings have driven the development of first studies using “super-donors”—people with highly diverse gut microbiota—to identify digital signatures that characterize the ideal donor for transplantation.”
This technique, requiring an individualized approach and thus not easily scalable, has led many companies to form consortiums of microorganisms, translating into the development of pills—some already on the market—with the aim of replacing FMT. The method has already been applied successfully to Clostridioides difficile infection, where a reduction in infection has been observed without needing a microbiota transplant, which in Italy is subject to the same strict rules as transplantation of any organ. “The idea in the future,” clarifies the expert, “is to develop similar tools for every kind of therapy, from oncology to more general treatments.”
Beyond transplantation, two other strategies have proven effective in improving the microbiota: a proper, varied diet rich in fiber in the Mediterranean style—whose effects are markedly superior to carnivore, ketogenic, or other diets that may show initial positive effects (reduction in bloating, weight loss, improved well-being) but can stress the microbiota in the long run—or supplements. Among these, probiotics, prebiotics, and postbiotics are the focus of ongoing research to identify the best approaches for modulation and maintenance of a healthy microbiota.
Microbiota and Cancer
While in Rome, at the Center for Digestive Diseases of the Gemelli Irccs University Catholic Foundation, researchers are conducting interesting studies to better understand the relationship between an altered microbiota and cancer, particularly colon cancer and treatment-responsive forms to immune checkpoint inhibitors. “Our studies,” explains Gianluca Ianiro, gastroenterologist and researcher at the Rome center, “are aimed at understanding whether it is possible to effectively exploit the microbiota in both diagnostic and therapeutic approaches. We are conducting a large cohort study to identify a microbial signature that could predict the onset of early colon cancer, thus enabling prevention and timely initiation of specific strategies. It is now well documented and reproducible across geographies—Western and Eastern—that subjects with colon cancer harbor bacteria from the oral cavity. This site is rich in bacteria because the oral cavity is the first line of defense against external agents and bacteria, but it is also the first to be attacked by insults such as tobacco and alcohol. This makes oral bacteria, for a portion, more aggressive than others, and some have been found across colon cancer.”
Based on this, the Rome group is investigating whether this set of bacteria can be detected in patients with precancerous polyps removed endoscopically with a manageable burden for the patient and the health system, or in very early-stage cancer. Such an approach could potentially be applied to any pathology: a GI or neurological disease or others. “In diagnostic terms,” continues Ianiro, “the microbiota should be considered as part of any diagnostic tool, on par with stool culture, a complete blood count, or a CT scan.”
The second research strand the Rome group is pursuing concerns the therapeutic aspect, specifically FMT, taken from a healthy person and purified fecal matter transplanted into the recipient’s intestine who suffers from the disease. “This practice is already approved in several national guidelines for Clostridioides difficile infection and is being studied for other diseases, such as neurological, gastrointestinal, infectious diseases, and cancer. Our research has shown that transplanting the fecal microbiota from a patient who responded very well to checkpoint inhibitor therapy into a patient about to begin immunotherapy yields a better treatment response in the latter than when treated with a placebo. In kidney cancer, in particular, we observed a nearly threefold increase in Progression-Free Survival: from about 9 months in the placebo group to about 24 months in the treated group.”
Impact on Healthful Aging
There are several ongoing research programs studying the relationship between the microbiota and longevity, aiming to increase not just the length but the quality of life. “Our focus,” says Rescigno, “is particularly on the microbiota composition and intestinal permeability, often associated with a subtle, systemic inflammation that, if not diagnosed and properly treated, can in the long term significantly affect quality of life, leading to the development of aging-associated diseases. Among these, cardiometabolic and neurodegenerative diseases drastically impact longevity.”
Precision Medicine
Microbiota, immunity, and aging form a fundamental trio for precision medicine. “The gut microbiota, in this trinity, is not a mere spectator of aging but an active modulator of metabolic and immune processes that determine quality of life over the years,” explains Mauro Minelli, the South Italy representative of the Foundation for Personalized Medicine (FMP). “Within the gut, in the Gut-Associated Lymphoid Tissue (GALT), more than 70% of immune cells reside, and their function—both innate and adaptive immunity—is governed by three main mechanisms. The first is tolerance dynamics and immune education, in which commensal bacteria and especially their metabolites train immune cells, particularly dendritic cells and regulatory T cells (Tregs), to prevent inflammatory or hyperinflammatory responses and autoimmune manifestations. The second mechanism concerns the integrity of the mucosal barrier, a fundamental but still underappreciated aspect of medical practice. Here, the synergy between mucin production and the expression of tight junction or occludin proteins prevents the entry of bacterial toxins, mainly lipopolysaccharides (LPS), and highly inflammatory and immunostimulatory bacterial metabolites into the systemic circulation. Finally, the third mechanism is a metabolic signaling pathway in which SCFAs, including acetate, propionate, and especially butyrate, bind to G-protein-coupled receptors on immune cells, suppressing the production of pro-inflammatory cytokines responsible for inflammatory immune responses.”
Immunosenescence
Age is the trigger that pushes the immune system toward immunosenescence, causing the decline of adaptive responses and an increase in chronic low-grade systemic inflammation. Aging, in addition to cellular impact, alters microbiota composition, gradually promoting a state of dysbiosis. Aging and dysbiosis, acting in synergy, cause the loss of mucosal barrier integrity (leaky gut). This condition allows the translocation into the systemic circulation of substances such as lipopolysaccharides (LPS) and bacterial antigens (PAMPs, Pathogen-Associated Molecular Patterns), normally absent in eubiotic contexts, maintaining the inflammasome constantly active, the molecular structure responsible for inflammaging, and fueling the chronic release of inflammatory mediators, including TNF-α, IL-1β, and IL-6. A vicious circle is thus triggered that, with age, promotes tissue deterioration typically associated with chronic-metabolic, cardiovascular, and neurodegenerative diseases.
The Microbial Signature
The patient-specific bacterial fingerprint governs not only the predisposition to particular clinical conditions but also the therapeutic choices, including prevention. This tailor-made rule also applies to probiotics: strains must be carefully selected and individualized according to the phenotype of each individual, determined by the holobiont—the fusion of roughly 23,000 human genome genes with millions of bacterial genome genes. The microbial signature thus characterizes the overall health status of every person.
“Metagenomic analysis of centenarians and supercentenarians,” Minelli continues, “reveals a microbial signature clearly different from that of frail elderly people. In this population, certain taxa associated with longevity have been identified: for example, the Christensenellaceae family, linked to a low BMI and therefore stable metabolism that supports healthy aging; Bifidobacteria, which in centenarians remain elevated to support mucosal immunity, unlike the normal decline seen in the elderly; and Akkermansia muciniphila, which preserves the mucus layer, improves insulin sensitivity, and reduces systemic inflammation. The microbiota composition that characterizes healthy longevity is not only a model to aim for, but also the guiding criterion on which to base a targeted therapeutic approach, extended to the use of probiotics tailored to the patient’s phenotype.”
Maintaining diversity and richness of the microbiota is crucial to slow down immunosenescence, together with proper nutrition, regular physical activity and precision eubiotic interventions. “To define these processes,” concludes Minelli, “we have developed methodologies based on machine learning and computational analyses that allow us to extract from the microbiota’s genomic data the strain or combination of strains targeted to the individual. Those strains, administered in personalized ways within a precision probiotic therapy, promote the restoration of the physiological gut microbiota, supporting healthy longevity and an improved quality of life.”
Eubiotic Balance
Prebiotic, probiotic, postbiotic supplements, and nutraceuticals are among the effective strategies to promote microbiota health. In fact, diet is the most important microbiota modulator. “Unlike probiotics, which are given cyclically or as needed,” explains Marco Cintoni, a nutrition science specialist at the UOC Clinical Nutrition of the Gemelli IRCCS Foundation in Rome, “a healthy diet with 3–5 meals per day provides continuous nutritional support, supplying an energy substrate for the viruses, bacteria, and microorganisms that comprise the intestinal barrier. This means that the diet can substantially modulate the microbiota, positively or negatively. For example, the Western Diet, low in fiber and high in animal proteins and fats, promotes the expansion of proteolytic strains—bacteria capable of digesting and breaking down proteins and tolerant to bile salts—shifting the microbiota toward producing certain metabolites, such as ammonia and hydrogen sulfide, which are strongly pro-inflammatory. In contrast, a healthy diet, balanced with fiber, simple and complex carbohydrates typical of the Mediterranean diet, helps select a range of bacteria that produce SCFAs, fostering a less pro-inflammatory microenvironment.”
The diet, moreover, exerts a competitive effect on harmful bacteria like Escherichia coli, which are kept in check by a healthy microbiota, whereas a pro-inflammatory microbiota or established dysbiosis promotes their overgrowth. Therefore, dysbiosis can trigger specific pathologies, including IBS, Crohn’s disease, ulcerative colitis, inflammatory bowel diseases (IBD), and cancers such as colorectal cancer, aided by the presence of particular bacterial species that damage cellular DNA. A dysbiotic microbiota can also influence primary gastrointestinal diseases such as celiac disease and lactose intolerance, or predispose to psychiatric conditions, including autism, for which there is substantial literature indicating a strong relationship.”
The Power of Diet
The demonstrated effectiveness of prebiotics, probiotics, and postbiotics, such as butyrate, is significantly reduced if diet is not normalized and/or corrected, though this is typically limited to the initial treatment period. “Crucial,” continues Cintoni, “is that a patient with microbiota alterations follows the guidance of a nutrition expert and does not attempt self-treatment, such as adopting a Low-FODMAP diet for severe dysbiosis or recurrent IBS, which, if sustained inappropriately, may cause more harm than good. Additionally, some microbiota analysis tools can detect absent or overexpressed strains in a given patient, allowing a personalized dietary plan based on the microbiota profile.”
Diet and Longevity
In a population that is increasingly aging, comorbid and multi-layered, it is essential to promote healthy aging by keeping low-grade inflammation under control, since it governs biological aging and has a significant impact on the microbiota. “Nutrition,” clarifies Cintoni, “can contribute substantially to lowering intestinal inflammation by selecting a subset of bacteria, such as SCFAs, capable of reducing proinflammatory cytokines and thus systemic inflammation. Therefore, treating the microbiota through diet is a primary objective that promotes longevity and better quality of life. This is demonstrated by studies on centenarians and Blue Zones, such as Sardinia or Japan, where diet and environment drive good health.” However, longevity is built from early life; it is essential to act proactively in the first thousand days of a child’s life, the period when a healthy microbiota forms. Breastfeeding, mode of delivery (natural or cesarean), and a family environment that can nurture and educate toward a correct lifestyle all contribute to longevity, including that of the microbiota. “We must counter the trend toward extreme industrialization that brings very unhealthy products to the table—starting with breakfast cereals for children containing a pool of ingredients like sweeteners, binders, and other substances that cause direct damage to the intestinal mucosa.” Protecting the microbiota of children means laying milestones for good health in adulthood and healthy, long lives.
Gut–Brain Axis
Good mental health and psychological balance promote longevity in both lifespan and well-being. Evidence shows that people with mental disorders live at least a decade less than those who are mentally healthy. Given the tight link between the brain and the second brain—the gut—protecting microbiota health supports a path toward healthier longevity. “An imbalanced microbiota negatively impacts serotonin, dopamine, and other precursors associated with the worsening of mental life and, secondarily, longevity,” says Fabio Piccini, physician and psychoanalyst, co-founder and director of the Italian Microbiome Project. “Moreover, numerous studies show microbiota alterations associated with a wide range of diseases: mental health disorders, respiratory conditions, cardiovascular diseases, endocrinological conditions. However, to date, the cause-effect relationship between a specific pathology and microbiota alteration is still assumed or not fully clarified. With a few exceptions—for example, autistic children who show GI problems and a 6–8 times higher predisposition to abdominal pain, diarrhea, flatulence, and constipation compared with typically developing children—this has led to elimination diets.”
The evidence, not always consistent or uniform, does not yet allow for a clear set of rules that can be modeled into clinical protocols. “Even in the absence of a standard approach,” continues Piccini, “in a patient with gastrointestinal disorders it is necessary to isolate symptoms and/or manifestations that could interact with the mind and emotions, such as sleep quality, vitamin D levels, and thyroid hormone values. Reversing the traditional paradigm, it becomes crucial to ask not whether a patient with intestinal dysbiosis has an increased risk for anxiety, depression, and stress, but whether emotional or mental disorders, or even neurologic conditions in which the patient is affected, can interact with gut health.”
The mistake current research is making is looking for correlations starting from the microbiota, but “navigating blindly,” without a goal or clear direction. “Whenever we confront a complex disease where a rapid therapeutic solution is not readily identified—perhaps because a treatment relieves the symptom but not the cause—the recommendation is to first evaluate gut health, which will guide correct history-taking and thus the setting of an effective therapy for the brain, the microbiota, and longevity.”
Abbonati a Karla Miller
