Behavioral Changes Resulting From Microbiome Restoration

Assignment Task

Introduction

Modern medicine, both human and animal, acknowledges the need for a well-functioning microbiome to help maintain effective immune response and overall health for all body systems as a variety of medical abnormalities located in multiple body systems can arise from a compromised gut flora, specifically unstable microbiome diversity (1-13). Considering this claim, recent clinical studies support that a viable solution to ameliorating various medical conditions that span over the whole body is the “Fecal Microbiota Transplantation” (29, 22). This therapy, while still in its infancy, is receiving more acknowledgement in both human and animal medicine (19-28). In the near future, this efficacious treatment that replenishes the diversity of microbiome within the gastrointestinal tract with beneficial symbiotic gut flora of a healthy, supported donor has strong potential to become a standard of care in the treatment of many diseases.

In 2012, Dr. Roman coined the term “Microbiome Restorative Therapy” (MBRT) as opposed to the customary term “Fecal Microbiota Transplantation” (FMT), which more accurately captures what the therapy accomplishes, which is microbiome stability restoration as defined and practiced by Dr. Roman’s clinic. The process of the MBRT was developed at Dr. Roman’s clinic, Main St. Animal Services of Hopkinton (MASH), for small animals and involves an explicit, prescribed, holistic protocol not found in descriptions of the FMT (22, 29). While fecal microbiota transplants have been administered to humans and farm animals, until the development of the MBRT, this therapy had not been applied in small animal medical care. The MBRT has since expanded to being utilized by other holistic small animal medicine practices including Peak Animal Health Center, The Barn Door Vet, The Whole Pet, Animal Healing Center, and Wilmington Animal Hospital. Furthermore, the term “Microbiome Restorative Therapy” is increasingly referenced in veterinary information blog posts, YouTube presentations, in two peer-reviewed veterinary publications, microbiome conference lectures, and in various veterinary contexts (b) (30-36,58). The terminology and philosophy surrounding this therapy is progressively becoming accepted as standard nomenclature and care.

The overall restoration of health the clinic has observed in its patients after receiving the MBRT is among the numerous positive possible outcomes of the therapy. Based on hundreds of testimonials and credible reports shared by clients who have observed distinct physiological, behavioral, or personality changes in their pet(s) after receiving the MBRT, the clinic posits that microbiome restoration, a result of the therapy, is in part responsible for those changes.

To explore this claim, this paper will attempt to explore why these physiological and behavioral changes occur as a result of restoring microbiome stability. Specifically, this paper will explore this claim by offering a viewpoint based on clinical observations gathered through a survey and the personal testimonials of clients. Apart from clinical observations, this will additionally provide tangible research evidence that supports the efficacy of the MBRT and a wide range of physiological and behavioral changes that can occur as a result of restoring microbiome diversity and stability.

This therapy is worth researching further, not only for its physical healing qualities, but also for wider observation and documentation of accompanying behavior and personality changes. A better understanding of the role the gut plays in emotional and psychological well-being is timely and needed, and can inform the possibility of incorporating fecal transplants in behavioral therapeutic approaches for animals as well as humans. 

MBRT Procedure

The MBRT is a therapy that reboots the immune system of an animal. When there is an imbalance of the gut microbiome, and the depletion or overgrowth of a microbiome species due to medical conditions, multiple courses of antibiotics, or the consumption of harmful pesticides, a MBRT will reintroduce a healthy biome including the hundreds of species that is required for optimal microbial stability.

MRBT Donors

The donors utilized for preparing the transplantation satisfy a strict criteria that ensures the optimal stability of their microbiome and overall health. These donors are healthy dogs or cats who have received limited vaccinations, are titered regularly, are screened for intestinal parasites, are holistically treated with herbs, homeopathy, ozone, chiropractic, and other safe, alternative treatments (for more on vaccines, see Appendix I). Furthermore, these donors have been vaginally born, which introduces them to an inoculation of microbes at birth (such as the species Lactobacillus) that are otherwise absent in animals delivered cesarean section (43, 44). Lastly, these donors are fed a raw fresh organic balanced diet and have never consumed any substances with chemicals, pesticides, or antibiotics. Many harmful chemicals, such as glyphosate, a potential carcinogen found in the herbicide RoundUp, is common in many processed foods including commercial pet food, and especially in non-organic food made with genetically modified products (14-18). Additionally, this herbicide RoundUp damages mitochondria, chelates minerals, and disrupts the detoxification pathways of the body (14). It also becomes a synergistic agent, making combinations of low-level toxins more damaging (49). Therefore, because antibiotics, drugs, pesticides, herbicides, preservatives, and even chlorine and fluoride in water can affect the diversity of the gut microbiota, it is indispensable that such chemicals are eliminated from the fecal donor’s diet. Ensuring that the donors are on a raw or plant based diet with fresh, organically raised food without preservatives can increase the health of the gut flora. Organic fresh plant based foods as well as wild venison obtained during the hunting season are important components of the donors’ diet. Nutraceuticals that provide vitamins, Omega 3s, and amino acids are additionally given to the donors to increase their health. Likewise, it is important for the patients to be on high quality nutrition, probiotics, digestive enzymes, and additional nutraceuticals as well as avoid harmful chemicals to enable the new microbiome to have a healthy habitat (Appendix II).

While identification of the approximately 500 species and 1,000 subspecies or organisms that exist in a healthy human gastrointestinal tract is still underway, enough is known about the microbiome and predictable clinical treatment outcomes to recognize the vital importance of utilizing, healthy, happy, un-contaminated, varied, and pre-screened donors for chronic medical conditions, intestinal parasites such as hookworms, roundworms, whipworms, and tapeworms, and consider checking a PCR test for Giardia, C. difficile, C. perfringens, E. coli, and Salmonella when preparing an MBRT for a compromised patient.

SURVEY

To assess the efficacy of the MBRT treatment on patients as well as their physical and behavioral changes, a comprehensive survey was distributed to a large portion of the owners whose pet(s) received the treatment. Synthesizing these results and data revealed the beneficial factors of the MBRT and the philosophy of rebalancing the microbiome with a holistic and natural approach that builds the gut rather than subsequently damaging the epistatic environment.

This survey was opened to clients on August 10, 2019 and closed February 24, 2020. Criteria for inclusion included all patients who have received one or more MBRTs from when the treatment first began administration. This survey assessed 50 clients' observations of their pet(s) who received the treatment spanning from when the MBRT treatment began to be offered as a treatment at the clinic, which is more than a decade ago, to the most recent MBRT given.

Methods of Administering MBRT to Patients

The MBRT can be administered to the patient in multiple methods that the clinic offers. Traditionally, the MBRT is administered through a slurry enema involving a rectal fecal transplant with a catheter placed up the patients’ rectum. 79.59% of patients received the MBRT in office with this method. For clients who would like to continually administer the MBRT to their pet(s), the take-home option involves oral fecal infusion/capsules, which 69.39% of the patients receive, and oral fecal nuggets, which 46.94% patients received.

MBRT Patients

The MBRT treats patients with a wide range of underlying conditions, which the survey results reflect. Expectedly, a majority (60%) of the medical conditions patients had include, but are not limited to, a range of gastronomic intestinal disorders including Giardia and inflammatory bowel disease (IBD). Apart from gastronomic intestinal disorders, 50% of clients reported that their pet(s) received the MBRT treatment because they were diagnosed with Plechner Syndrome. 28.0% of clients reported that their pet(s) received the MBRT treatment upon being diagnosed with a chronic skin disorder. A minority of other medical conditions the MBRT was administered to treat include seasonal allergies, Lyme disease, and urinary infections.

The clinic believed it would be important to assess various health factors that can affect the stability of the microbiome in each patient. All clients came to MASH upon hearing other prognoses from another veterinarians that offered conventional treatments including prescriptions to antibiotics as 52% of the patients who received the MBRT were in the course of taking antibiotics for their respective medical conditions including steroids, allergy medications and shots (example: prednisolone). 42% of patients were in the course of taking supplements, and 16% were in the course of receiving medications and treatment for the Plechner syndrome. About half (48.0%) of patients were taking heartworm medication, including common brands such as Interceptor, Heartgard, and Ivermectin; inversely, about half (52%) of patients were not taking heartworm medication. In reference to vaccinations, 96% of the patients had received the rabies vaccine, 83% received distemper, 72% received parvo, and 34% received Leptospirosis. A minority of patients received a lyme disease vaccine and a Kennel cough vaccine. In reference to fluoride/chlorine/pesticides exposure, 14% of clients knowingly reported that their pet(s) had been previously exposed to fluoride/chlorine/pesticides in water and lawn products while 30.61% of clients reported that their pet(s) had never been exposed to pesticides/herbicides/chemicals in water and lawn products. In reference to diet, 38% of the patients were on a dry food or kibble diet, 48% were on a raw food diet, and 46% were taking dietary supplements.

In addition to MBRT, an overall integrative therapy approach is provided to each animal, which includes several other holistic treatments and supplements. These combined treatment modalities appear to provide significant, healing synergistic effects in conjunction with the MBRT; therefore, their administration is crucial in the treatment process (Appendix II). One of these additionally therapies includes ozone insufflation, which is typically administered with MBRT in order to support the process by removing biofilm from the gut, stimulating stem cells in the crypts of the colon’s columnar cells, and increasing oxidative hormetic reaction to support the mitochondria of the liver. Furthermore, the clinic offers other therapies including acupuncture, Ultraviolet Blood Therapy, and nutritional support in the form of dietary supplements: 73.47% of the patients started taking additional probiotics, 46.94% were taking essential fatty acids/herbal formulas, and 36.73% were taking homeopathics and other nutraceuticals (Appendix II) (a). However, it is clearly only after receiving MBRT in particular, that animals show distinct physiological and behavioral changes

Physical/Behavioral Changes

Physical Changes

The most common reported medical condition of patients included gastrointestinal infections, thus producing symptoms including significant vomiting, dry skin, diarrhea, constipation, and producing poor behaviors including drowsiness, lethargy, anxiety, and decreased activity/mobility. Post treatment, clients unilaterally reported the severity of the medical condition to decrease. For example, stool consistency returned to its normal, healthy consistency, either looser if previously constipated or more firm if the patient was previously experiencing diarrhea. Furthermore, clients reported that chronic skin conditions improved, vomiting ceased, and appetite level increased post MBRT.

Behavioral Changes

Moreover, clients reported that the behavior of their pet(s) significantly improved. These changes primarily included a significant increase in energy level and animated temperaments including animals becoming livelier, more positive, and happy.

Onset of MBRT: When MBRT Results Became Observable

From the documented cases of MBRTs this survey reflects, a majority of clients (68.88%) reported that they observed a noticeable change in health and/or in behavior within 1-2 weeks post MBRT. More specifically, 33.33% of the clients reported these positive physical and behavioral changes within 1 to 2 days post treatment, 22.22% of clients reported these observable changes within 3 to 5 days post treatment, and 31.11% of clients reported these observable changes within 7 to 14 days post treatment.

Frequency of Distributing MBRT & Duration of MRBT Results

In some transplants, after only one treatment, the clinic has seen animals completely healed; 34.04% of patients reported that physical/behavioral changes lasted permanently. However, there are other patients that need more than one. To completely treat the respective medical condition, 32.65% patients received (or are receiving) 5 or more MBRT treatments both in office and at home, and 16.33% of patients received 2 MBRT treatments. The criterion for re-inoculation is a recurrence of symptoms. However, some clients elect to give their pet(s) MBRT orally on a weekly, bi-weekly, or monthly basis as they observe their health to be better with maintaining the stability of the microbiome along with the addition of nutraceuticals allows the microbes to thrive within the gut (see Appendix II).

The survey demonstrated a trend of more MBRT administration to animals with ACEIS or Plechner Syndrome. It is important to evaluate the IGA, IgG, IgM, total estrogen, cortisol, and T3 and T4 values of an animal to determine if they have this disorder so as to predict the success of MBRT treatments (see Appendix III).

Client Assessed Efficacy

Overall, 66% of clients reported that the MBRT was not only effective in making a change, but additionally beneficial to improving their pet(s)’ health and behavior. 85.71% of clients reported that the MBRT treatment had no negative effect on their pet(s), and 14% of clients reported that the MBRT had little or no significant change. No clients reported any negative observable effects of their pet(s) post treatment. 

Testimonials: Animal Cases Observed at Main Street Animal Services of Hopkinton (MASH), Dr. Roman’s Animal Clinic

The following are eleven detailed accounts describing chief physical, behavior, and personality changes in patients who received the MBRT reported by clients.

1. Baxter, a 14 year old 85lb Labrador/Shepherd mix, was diagnosed with a liver tumor, a suspected hemangiosarcoma, and subsequent complications. When he came to the clinic in August 2016, he demonstrated weakness to a great extent that he had a hard time standing; euthanasia was recommended by his oncologist. The clinic put him on an aggressive holistic program, and he progressed very positively: he gained more strength in his back legs and appeared to be feeling stronger. In the first week of November 2016, he had a massive bleed in his abdomen and was taken to an emergency clinic where they diagnosed that his mass had ruptured, and he was hemorrhaging in the abdomen. The recommendation of euthanization was again given. The clinic decided to try intraperitoneal ozone gas in the upper flank area as well as other aggressive holistic therapies, and his lab results started to markedly improve. Baxter still demonstrated lethargy likely attributed to his age. He was given a MBRT from a 2 ½ year-old female poodle in heat. The next day he was acting like a puppy, playing in the yard and sexually mounting on his bed, which he had not done since he was 5 years old. His owner continued administering MBRTs, and each time he received a fecal transplant of youthful microbiome, he demonstrated youthful vigor and played like a young dog; several years had passed since his expected demise. Baxter finally passed at 16½ years.

2. Dudley, a 10 year old neutered male Shih-Tzu/Poodle mix, was diagnosed with multicentric, high-grade, T-cell lymphoma. He experienced two complete remissions after surgery, chemotherapy, autologous lymphoma vaccines, and integrative therapies. For the duration of his treatment period, Dudley received multiple MBRTs and other holistic therapies. The incidence of adverse effects during chemotherapy was low, and his overall quality of life was excellent with his survival of 2 ½ years post diagnosis far outlasting the prognosis of his oncology veterinarian and most dogs with T-cell lymphoma (40, 41). The most impressive behavioral outcome his owners observed after each fecal transplant from a young donor was his youthful energy; he would play with a ball like a puppy for long periods of time, a behavior he had not exhibited for years. He was also the recipient of “Microbiome Mixology,” in which he received the microbiome from a fecal donor who survived cancer for 7 ½ years and lived to 15 years, as well as from the donor’s 6 month old grandson.

3. Archie, a 7 year old neutered Wire-Haired Fox Terrier, presented aggressive behavior and was experiencing digestive issues. Archie was given a very stringent diet including nutritional support and many other integrative approaches, but he still remained very aggressive and was involved in an incident where he almost tried to kill his sister. Archie was additionally given pharmaceutical medications for his aggressive behavior that failed. 

Archie received an MBRT; about 30 hours after his first MBRT, Archie was grooming and kissing his sister, and was consuming foods he previously could not eat without them inducing diarrhea. This remarkable behavioral change stopped when Archie was given the heartworm preventive medication milbemycin oxime (Interceptor). About 30 hours after this dosage, he attacked his sister, and his aggressive behavior returned. Archie was given a second MBRT, and his improved behaviors resumed. It is logical that an anthelmintic, an antiparasitic drug, could have the same side effect of destroying the gut microbiome as an antibiotic. Archie’s suggests that damaging the microbiome with any antimicrobial could induce poor behavior and immune system issues. Because Archie showed symptoms of ACEIS, he was given multiple fecal transplants about every two weeks, and was taken off the heartworm preventative (Appendix III).  After eighteen fecal transplants and receiving microbiome from a pregnant donor, his chronic issues resolved completely.

4. Kaylee, a 7 year old Beagle, was scheduled in 2017 for euthanasia by two veterinarians, including a board-certified veterinary oncologist, as she was dying from what he determined to be a hemangiosarcoma in her abdomen and leg. Kaylee did not have a positive biopsy; therefore, this diagnosis was never confirmed. She had a swollen abdomen, had been on pain medication and antibiotics for 2 weeks, and was unable to stand. She received one MBRT along with other holistic therapies. In 5 days, she had a complete reversal of these symptoms as well as a complete behavior change. Her owner reported that Kaylee had always demonstrated insecure, afraid behavior, including aquaphobia and of leaving her owner’s side. Furthermore, Kaylee did not exhibit normal hunting Beagle behaviors. Two days after receiving her first MBRT, she started demonstrating typical Beagle behaviors of sniffing, digging holes to chase rodents, chasing other wild animals, and jumping into water. The owner was shocked as she failed to bring Kaylee near water or even through a puddle, nor ever witnessed other normal Beagle behaviors. Kaylee exhibited behavior very similar to what the donor dog’s behavior had been. Four years later, Kaylee is still thriving and acting like a puppy. 

5: Mojo, a 7 year old neutered male Maine Coon cat exhibited a mangy coat from years of atopic dermatitis and a severe skin condition, which had been treated with multiple courses of antibiotics, cyclosporine, antihistamines, and steroids. As a result, the owner reported that Mojo demonstrated poor skin condition, poor energy level, and poor behavior. Mojo received a MBRT from a 1 year old neutered Siamese male kitten. Within two days post MBRT, Mojo stopped scratching his face, and he was able to be relieved of his Elizabethan collar. In 2 weeks, his hair started growing back. Mojo exhibited a much happier behavior than he had prior. 6 weeks later, the owner requested a second MBRT. Because Mojo’s health demonstrated improvement after his second fecal transplant, Mojo was given a third MBRT 6 weeks later. Soon after, Mojo began sexually mounting his owner’s arm, behavior likely attributed to the (still present) hormones and youthful vigor of the 1 year old Siamese fecal donor microbiome. Furthermore, the owner reported much less hair pulling and penis licking. Mojo continues to improve and now has a healthy coat of hair. At age 15, Mojo demonstrated another medical condition including consistent itching of his ears. After receiving an oral MBRT, his symptoms ceased within 2 days.

6. Tober, an 11 year old spayed Calico cat, suffered constant diarrhea for over 18 months with up to 10-20 stools a day. She endured multiple ultrasounds, blood work, fecal exams, and years of intermittent metronidazole, an antibiotic medication. As a result of these treatments, Tober had a very thin and fragile appearance. Less than 2 days after her first MBRT, Tober’s stools were normal. Furthermore, previous behaviors including hiding in the basement and avoiding the additional dog in the house ceased; Tober began to sit confidently on the couch and play with the dog. Her owner described her previous weight as “a piece of paper”; however, after the MBRT, she regained some of her body strength and appeared “much happier.”  To have this radical improvement in less than 48 hours with both her stool consistency and behavior after years of illness is uncommon even if an animal is treated with standard holistic care for IBD. Tober continues to exhibit content behavior, has gained weight, and has no diarrhea. She is being maintained on a high quality, protein-specific raw diet, and occasionally receives MBRTs as she has also tested positive for ACEIS (Appendix III). 

7. Rozzi, a 6 year old female Golden Retriever, had chronic urinary tract issues that were treated with antibiotics for multiple years. Due to Rozzi’s significant lack of energy resulting in poor behavior, particularly lethargy, along with demonstrating poor stool consistency, skin sensitivities that were treated with steroids, and a poor appetite level, the owner was contemplating euthanization. However, once Rozzi received her first MBRT, she regained her energy. As with others, the clinic observed in Rozzi that when she was treated with fecal matter from a donor in estrus, she would mount other animals. Furthermore, the owner reported that Rozzi’s previously observed poor behavior and negative symptoms dissipated after the MBRT, and they noticed Rozzi’s quality of life to significantly increase 5 to 7 days after receiving the first MBRT. Rozzi tested positive for ACEIS, so began to receive MBRTs as oral fecal nuggets weekly to maintain her strength for about a year until she started to take two dietary supplements: Restore Now and Gut ION (Appendix III) (d). When Rozzi started Gut ION, a supplement that promotes an optimal gut environment, she held onto the benefits of the MBRT longer than without the Gut ION after each transplantation. The owner reports that Rozzi’s physical and behavioral changes are seemingly permanent.

8. Lola, a 4 year old Corgi mix, was spayed as a 6 week old puppy, and never showed any signs of female traits. Lola received an MBRT orally from a dog who was in heat to replenish a full range of microbiome as she had been depleted in her earlier life due to receiving several antibiotics and other pharmaceutical medications. Within a day of receiving her first MBRT, she started sexually mounting and thrusting for the first time in her life. Lola began to exhibit a happy temperament for 2 years, until she was attacked by Pit Bulls. As a result of this incident, Lola underwent multiple doses of antibiotics, and became very fearful. After another MBRT, Lola’s positive temperament was restored as she exhibited loving and trusting behavior.

9. Norton, an 18 month Black Labrador, had been raised and trained as a dog assistant. Although Norton underwent extensive training, he was coprophagic and had some anxiety (45). His performance as a dog assistant was satisfactory; however, his habit of eating his stool after each defecation was unacceptable to the organization (46). For over 6 months, this otherwise well-behaved dog still had some anxiety and his owners could not break his habit of eating his stool. After receiving an MBRT, his anxiety and habit of eating his stool ceased.

10. Zorro, a Bouvier, and Shelby, a Black Russian Terrier, were experiencing  constant technicolor diarrhea with mucus and blood. Frustrated with their local vet’s inability to suggest efficacious treatments that would return their stools to normal, Zorro and Shelby were brought to see Dr. Roman in 2009 who administered MBRTs for them. After their first MBRT treatment, their stools became normal, and they never had issues with their gastrointestinal chronic diarrhea that was medicated for years. Shelby lived to be over 10 and Zorro is still alive at 13 years of age in 2021. Neither dog ever had a problem with diarrhea since having received the MBRT.

11. Ludwig, a Lhasa Apso/Dandi Dimont/Cocker mix, received holistic care for a majority of his life. When he was about 12 years old, he developed a grade VI/VI holosystolic heart murmur. For treatment, he received both conventional heart and blood pressure medications as well as  nutraceuticals, herbs, and homeopathy. When he began to exhibit a poor energy level and weakness, he was brought to the clinic where he received Ozone, Ultraviolet Blood Therapy, vitamin shots, and an MBRT with the fecal matter of a young puppy (a). Within a day of receiving the MBRT, his owner reported that he had the capacity to endure long walks. His breathing became better, his energy level was restored, and he inhibited puppy-like behaviors. He passed at 16 ½ years of age. 

OUTSIDE RESEARCH

Gut Axes: Healthy Body Systems’ Dependant on the Stability of the Microbiome

The high diversity of the microbiota defines its “health” within the gut, whereas reduction of this diversity is therefore associated with dysbiosis, an imbalance in the microbiome structure that results from an abnormal ratio of commensal and pathogenic bacterial species (59). The term gut dysbiosis specifically refers to the imbalance of the microbiota and is the underlying, and yet commonly unseen determiner, of various diseases and disorders that span over many body systems, which was unilaterally observed within the patients who received MBRTs at the clinic. These bidirectional communication systems within the body are referred to as axes. There are a series of gut axes connected to multiple body systems, and the stability/health of the body system is largely dependent on the stability of the microbiome and gut health.

Connection Between the Brain and the Gut: Brain-Gut Axis

The gut-brain axis is one common example of the system of communication the gut has with an organ in the body. Research into the microbiome continues to expand into emerging concepts concerning the gut/brain connection that offer some explanation for some of our observations.  For instance, in the case above of Kaylee, the Beagle who had no interest in normal Beagle behaviors until after receiving MBRT, this may have been enabled by stimulation of neural sensory (olfactory) circuits after the donor’s microbiome restored some normalcy to the Beagle’s.

The stability of microbiota affects various functions of the brain due to a system called the gut-brain axis. The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive areas of the brain with peripheral intestinal functions. In this axis, also referred to as the enteric nervous system, it communicates back and forth with the control system or the brain to carry out bodily functions, such as controlling digestion, from swallowing to the release of enzymes that break down food to the control of blood flow that helps with nutrient absorption to elimination. When the gastrointestinal system is imbalanced, in cases of various intestinal disorders such as irritable bowel syndrome (IBS), this axis also becomes imbalanced, and the brain begins to produce actions in response to this imbalance or dysbiosis (59). It is for this reason that, for example, gastroenterologists may prescribe certain antidepressants for IBS, for example—not because they think the problem is all in a patient’s head, but because these medications calm symptoms in some cases by acting on nerve cells in the gut.

Research has shown the intestinal microbiome to specifically have a clear connection with the body’s neuroendocrine hypothalamic–pituitary–adrenal axis, or the HPA axis. The HPA is a dynamic intertwining of the central nervous system and endocrine system of which its end result releases cortisol in response to situational or internal stressors (60). The HPA axis is responsible for the neuroendocrine adaptation component of the stress response. This response is characterized by the hypothalamic release of corticotropin-releasing factor (CRF) (60). When CRF binds to CRF receptors on the anterior pituitary gland, adrenocorticotropic hormone (ACTH) is released. ACTH binds to receptors on the adrenal cortex and stimulates the adrenal release of cortisol. The HPA’s connection to the stability of the microbiome was hypothesized and tested in a 2004 test that demonstrated that the function of the microbiota in the brain-gut axis on behavior was ambiguous; however, a subsequent study conducted in 2011 released several experimental findings in mice revealing how a “lack of conventional (normal/healthy) microbiota” affects behavior, gene expression in the brain, and the development of the nervous system (61). Along with behavioral differences, Altered gut microbiota can manifest in various molecular differences within the brain. These include brain-region-specific changes in levels of brain-derived neurotrophic factor (BDNF), which are differences in the expression of various neurotransmitter receptors, and alterations in the turnover of certain neurotransmitters, including serotonin (62).

Due to the direct correlation of the gut-brain axis, gut dysbiosis can negatively affect behavior. The most common example of gut dysbiosis is associated with Irritable bowel syndrome (IBS), a disorder characterized by altered gut function often accompanied by comorbid anxiety (63). IBS is characterized by one of its most common symptoms in compromised patients, diarrhea. Observed instability in feces or observed pain in defecation can be an indicator of further internal and external symptoms accompanied by IBS such as rectal bleeding, iron deficiency anemia, spontaneous vomiting, or weight loss. While IBS is commonly treated with various supplements, antibiotics, and encouraged management in diet or alteration of specific habits, conducting a fecal transplant is also a viable and effective treatment. Accordingly, a fecal transplant was utilized to examine the developed changes the stool, specifically the microbiome, of an IBS patient induced in a normal organism, including the colonization of compromised microbiome on intestinal motility, immune activation, along with alteration in gut permeability, and behavior. An increase in negative behavior associated with patients diagnosed with IBS was the clearest developed change post-fecal transplant. Mice colonized with fecal microbiota from IBS-D patients “exhibited changes in behavior” as there was an “apparent transfer of the behavioral phenotype of the IBS-D patients with anxiety to mice” post the fecal microbiota transfer (64). The four IBS patients fecal samples were extracted from displayed “moderate anxiety,” as assessed by the Hospital Anxiety and Depression Scale (HADS) questionnaire (HAD-A score, ≥11), which was passed onto the mice, as assessed through sensory tests, through the IBS fecal sample. While the microbiome within the administered fecal sample is anatomically directed through the anus to the gastrointestinal tract, IBS has a number of “underlying etiologies” including the development of stress and anxiety, and these negative behaviors affected patients on a cellular level, as these disturbed behaviors were observed in the group of mice that received specifically the IBS stool post fecal transplant. This unbalanced microbiome in fecal samples administered within the organism induced the negative behavioral symptoms of IBS, not only revealing the explicit connection between the stability of the microbiome and behavior, but also the importance of administering the right fecal samples in a fecal translating.

In this regard, reestablishing the healthy microbiome and bacteria can result in positive behavioral responses in an individual. One study with SPF mice, “mice that are demonstrated to be free of a specific list of pathogens by routine testing” examined the behavioral response to the administration of the probiotic, Lactobacillus rhamnosus (JB-1) (65). Lactobacillus rhamnosus is a type of bacteria found within the intestine belonging to the genus Lactobacillus that produces the enzyme lactase, an enzyme that breaks down lactose. Accordingly, the administration of this probiotic not only assists in the production of the enzyme lactase, but it also reduces anxiety- and depression-like behavior in the SPF mice (61).

This correlation between the expression of behavior and the microbiome is used as a great advantage in clinical practice with humans. For example, the administration of a fecal transplant has been utilized in an effort to avoid post-operative trauma by rebalancing the microbiome depleted of its diversity due to antibiotics or stress. A recent study conducted in 2020 observed the effects of administering fecal transplants as a postoperative treatment. After a thoracic spinal contusion, a spinal cord injury (SCI), one study, through a series of sensory assessments, revealed that a group of rats displayed various depressive-like behaviors. These depressive-like behaviors following SCI have been associated with the traumatic nature of the operation, which is increased inflammation (66). One of these sensory assessments, the elevated plus-maze, utilized this obstacle with motion tracking software to analyze the moving patterns of mice on the elevated plus-maze. The motion tracking software revealed that the healthy control group and SCI-FMT mice traveled significantly further than the SCI group, and SCI rats spent significantly less time in the open arms compared to SCI-FMT treated and healthy rats. Reduced time spent on these elevated planes reveals anxiety-like behavior, a behavior observed in the SCI mice. Therefore, the increased time spent on these elevated planes, compared to SCT mice, reveals that anxiety levels were minimal in SCT mice who received the fecal transplant. All sensory post-operative assessments indicated that an incomplete unilateral cervical spinal cord injury can cause affective disorders and intestinal dysbiosis and that both of these post-operative manifestations can be successfully and fully prevented with the fecal transplant (66).

Poor diets that cause inflammation within the gut therefore inducing gut dysbiosis is also a variable that can affect gut microbiome composition, bacterial diversity, and behavioral responses. New research finds more evidence of the microbiome’s role regarding inflammation and unstable gut flora in the body and effects on the brain. Specifically, certain food substances  such as gluten and casein, can cause inflammation, and are now seen as probable culprits in some cases of depression. For example, assessment of psychiatric pathology in celiac patients has supported a statistically significant incidence of anxiety (panic), depression (21% in this study), bipolar patients, and schizophrenia (27% in this study) (3).Conversely, improved diets are found to directly and indirectly lead to better mental health (3,47,48).

Connection Between the Kidney and the Gut: Gut-Kidney Axis

Next to gastrointestinal disorders, the etiology of renal disorders in connection with the gut through the Gut-Kidney Axis have been researched. The gut-kidney axis can be subdivided into metabolism-dependent and immune pathways. First, the metabolism-dependent pathway is primarily mediated by metabolites produced by the gut microbiota that have the capability to regulate host physiological functions (67). Secondly, in the immune pathway, components of the immune system (for example, lymphocytes, monocytes, and cytokines) have a critical role in communication between the gut and the kidney. Crosstalk between the metabolism-dependent and immune pathway also has an important role in maintaining the balance of the gut-kidney axis (67). Studies demonstrate that changing the microbiome of an organism through fecal transplants decreases the frequency of UTIs associated with multidrug-resistant organisms, through gut decolonization and the reestablishment of colonization resistance (68). A previous study assessed the effect of a fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection by evaluating urinary, fecal, and vaginal microbiota samples of the participant post administration of the feces. As a result of the fecal transplant, the patient “remained without (urinary tract infection) symptoms,” revealing that rebalancing the microbiota in the gut additionally alters the state of kidney function and strongly corroborates the existence of the gut-kidney axis (69).

Connection Between the Heart and the Gut: Gut-Heart Axis

The intestinal microbiome plays a role in the pathogenesis of atherosclerosis, hypertension, and heart failure attributed to the Gut-Heart Axis. Even though studies in rodents suggest that the composition of the gut microbiome may affect the risk of heart disease, this link has not been shown in humans (70). Accordingly, the modulation of the gut microbiota as a mechanism for altering the pathogenesis of disorders in humans is an area of growing interest. For example, cardiovascular diseases (CVD) including coronary heart disease (CHD) are leading causes of mortality in the Western world affecting about one-third of the population. Studies suggest the role for the gut microbiome in the pathogenesis of atherosclerosis, CVD and heart failure. Imbalances in the composition and function of gut microbiota, gut dysbiosis, are associated with a wide spectrum of host disorders including cardiovascular diseases and heart failure. For example, one study recently used 16S ribosomal RNA gene sequencing to analyze fecal samples from HF patients and determined that gut microbial dysbiosis is associated with HF. This result is suggestive of the potential impact that the gut microbiota may have on the pathophysiological processes and treatments involved in HF (71). In this regard, alteration of the gut microbiota is being explored as a method of reducing risk factors associated with cardiac diseases.

One heart condition that has been treated with the fecal transplant is Myocarditis, an inflammation of the heart muscle (myocardium). Myocarditis can affect the heart muscle and the heart's electrical system, reducing its ability to pump and causing rapid or abnormal heart rhythms (arrhythmias) (72). Generally, treatment for myocarditis is still a difficult task in clinical practice. However, the gut microbiota's association with cardiovascular diseases such as atherosclerosis and hypertension is giving clinicians an upper hand in treating this type of heart failure (73). Accordingly, one study was conducted to evaluate the efficacy of the fecal transplant as a method of treatment of myocarditis. Experimental autoimmune myocarditis (EAM) mouse guts were repopulated with fecal contents from an untreated male mouse donor, and the study found that myocardial injury was improved by diminished inflammatory infiltration, showing that IFN-γ gene expression in the heart tissue and CD4+IFN-γ+ cells in the spleen were decreased after the fecal transplant in EAM mice (74). Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition (75). The study also found that the fecal transplant was able to rebalance the gut microbiota by restoring the Bacteroidetes population and reshaping the microbiota composition.

Connection Between the Liver and the Gut: Gut-Liver Axis

Gut dysbiosis is identified as an important factor in the pathogenesis of liver diseases. While the relationship between gut microbiota and the liver is still not well understood; many studies reveal that dysfunction of the gut mucosal barrier (“leaky gut”) and increased bacterial translocation into the liver via the gut–liver axis probably play crucial roles in liver disease development and progression. A better understanding of the pathophysiological links among gut dysbiosis, the integrity of the gut barrier, and the hepatic immune response to gut-derived factors are essential for the development of new therapies to treat chronic liver diseases, from liver cirrhosis to alcoholic and nonalcoholic liver disease, and hepatocarcinogenesis (76).

Improvement of the dysbiosis through the use of prebiotics, probiotics, and fecal microbiota transplantation improves the gut-barrier function and appears to be a promising new approach for managing chronic liver diseases. A study from Lawson Health Research Institute and Western University that evaluated the efficacy of fecal transplants as a method of treatment for liver diseases and specifically non-alcoholic fatty liver disease (NAFLD). A control based clinical trial with NAFLD patients as the positive control group receiving the fecal transplant revealed no changes in the percentage of liver fat or insulin resistance, most likely attributed to a source of error (77). However, the study revealed a significant reduction in intestinal permeability in patients who had elevated intestinal permeability at the study's start (seven patients in total) was observed. Changes to the gut microbiome in all patients who received a fecal transplant from a healthy donor were additionally observed (77).

Connection Between the Liver-Bone and the Gut: Gut-Liver-Bone Axis

Another means of communication between the microbiome and the liver has been identified, and it is called the gut-liver-bone axis. The microbiome has shown to have a connection with bone marrow, and unstable microbiome has shown to induce bone deterioration. In mouse experiments, exposing the animals to bacterial infections of the intestine or to a detergent that causes breaks in the gut’s epithelial barrier could lead to bone erosion (78). From studies such as this, it is well established that there is a correlation with the stability of the microbiome and bone health. In consideration of this, it is generally observed that patients diagnosed with inflammatory bowel diseases also experience bone loss and conditions such as osteoporosis. In an attempt to alleviate this issue, a probiotic was tested, and this probiotic was the bacterium Lactobacillus reuteri. In an in vivo study, this bacterium reduced intestinal inflammation while also causing the mice to gain bone mass, a reverse of bacterial infection symptoms (78).  To further affirm this finding, researchers tested L. reuter estrogen-deficient mice, a model of the post-menopausal period during which women lose bone density, and found that the treatment again prevented mice from losing bone mass; therefore supporting that bone health is specifically correlated with a strong gut barrier (79). Breaches in the gut lumen can allow for bacterial endotoxins, metabolites, or vitamins to spill out and trigger inflammatory signaling that can lead to bone erosion (78).

In reference to the connection between gut microbiome, bone health, and the liver, one study in which healthy, young adult mice with specific pathogens removed from their gut flora had less bone than germ-free mice and also enhanced immune activity in the liver (78). From a plethora of experiments looking at the differences between these two mouse types, researchers concluded that gut microbes or metabolites they produce pass through the intestines’ mucosal barrier into circulation, where they travel to the liver and fire up innate and adaptive immune responses that suppress bone formation while enhancing bone resorption (79). While minimal research has been conducted about a direct gut-bone axis, there appears to be a communication between these two systems through liver function.

In humans, a clinical trial at Memorial Sloan Kettering is now showing that fecal transplants can reestablish the health-promoting bacteria in that gut that are often lost in people who have stem cell or bone marrow transplants for blood cancer (80). This procedure is also referred to as an Allo HSCT, where a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion (81). The instability of microbiome was assessed by analyzing fecal samples through 16S ribosomal RNA (rRNA) gene sequencing 3237 longitudinally collected fecal samples from 753 patients, obtained between day −25 (before hematopoietic cell infusion) and day +100 (after hematopoietic cell infusion) (82). The average allo-HSCT patient’s microbiota diversity was initially high but declined as they underwent treatment with antibiotics. Ultimately this study found that the FMT intervention reestablished the microbiota after gut disruption from the allo-HSCT.

Connection Between the Skin and the Gut: Gut-Skin Axis

The gut additionally shares an axis with the integumentary system called the gut-skin axis. The connection between the integumentary system and the gut is viable because both organs are essential to the maintenance of physiologic homeostasis; it is suggested that they therefore must be related or correlate in function within an organism. A couple ways in which the integumentary system and the neuroendocrine organs work together to carry out specific functions in the body includes the absorption of nutrients in the intestines that have a direct effect on the skin. This is primarily observed in the consumption of “Western” food. Furthermore, various nutrients that are ingested, digested, and absorbed into blood vessels can stimulate hormonal changes that impact the skin (83).

The gut microbiome also appears to influence skin microbiome. SCFAs resulting from fiber fermentation in the gut – propionate, acetate, and butyrate – are believed to play a pivotal role in determining the predominance of certain skin microbiomic profiles which subsequently influence cutaneous immune defense mechanisms. Accordingly, gastrointestinal disorders are often accompanied by cutaneous manifestations and the gastrointestinal system, particularly the gut microbiome, appears to participate in the pathophysiology of many inflammatory disorders, such as psoriasis, acne, and atopic dermatitis (84). The intestinal microbiome additionally contributes to skin allostasis, which is the restoration of homeostasis after a disturbance or stressor, through gut microbiota-mediated effects on both innate and adaptive immunity (85). Studies have demonstrated that gut bacteria/microbiome can positively impact the response to disturbed skin barrier function (86). One study showed the improved recovery of skin barrier function and decreased signs of reactive skin inflammation – including mast cell degranulation, vasodilation, edema, and tumor necrosis factor-alpha (TNF-α) release – following the administration of

Theorrelation between the integumentary system and the microbiome is a primary reason as to why patients who have chronic skin diseases can receive fecal transplants. Once compromised patients receive a healthy microbiota, this restoration will also correlate with restoring the health of the skin. A recent phase 1 clinical trial explored the utilization of microorganisms in stool to help treat various skin cancers, including melanoma, which was effective in changing the cancer itself along with stabilizing the gut microbiome (87).

Studis including but not limited to these regarding the direct relationship between the gut and multiple organ systems validate earlier clinical observations on the amelioration of various medical conditions post MBRT, and support the existence of a bidirectional connection between gastrointestinal health and the homeostasis of various organs within the body, thus supporting the previous claim that restoring the stability of gut microbiome is a viable and effective method of treating infections and diseases by equipping the microbiota to be at its optimal diversity so that other body systems can function accordingly.

Conclusion

Recognizing the value of maintaining a stable microbiome is a viable, potential next step in the treatment and healing of both animals and humans in health crises. For example, the brain-gut axis is a viable physiological explanation for why in a majority of recorded fecal transplant cases there has been a significant improvement in behavior as animals become livelier, more positive, and seem happy as a result of restbalizing the microbiome of the gut flora. As the National Institute of Health and other researchers continue to acknowledge the value of the microbiome and how it influences neurotransmitters, serotonin, growth factors, and many other aspects of cellular communication and survival, this knowledge can be employed to help the body correct poor behavior and further repair itself (50).

From observations of the physiological and behavioral effects as a result of the MBRT as well as other types of transplants, future directions and questions in this area of study include if there is a cellular memory that works within cells and stem cells, possibly even in the microbial DNA, projecting not only just the functioning of those particular organs or microbes, but also that of the personality traits of the organ or fecal donor, and the mechanisms that make this communication or projection possible; along with if part of an explanation could be a holographic framework within each cellular or microorganism DNA. Also, as each organ has its own unique microbiome in addition to the host cells, could each of these microbiome populations have inputs that affect responses in emotional or other ways? Furthermore, while this paper highlights the presence of microbiota in the gut and the integumentary system, there are microbes in every organ system. Medical science does not currently understand the full significance of microbiota throughout the body; however more observation and scientific research can lead to continued understanding of this primordial creation basic to all life.

The physiological and behavioral outcomes of patients who received the MBRT at the clinic along with research and experiments about bidirectional communication systems within the body offer more validation on the strong influence of the microbiome supporting the health of an individual. Therefore, paying attention to the emerging science of these axes may bring medical science into a new and fruitful paradigm of mental health care for animals as well as humans.

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