Patent Publication Number: US-2023136199-A1

Title: Systems and methods for treating gi tract dysbiosis

Description:
RELATED APPLICATION 
     This is a non-provisional application of U.S. provisional application No. 63/263,392 filed on Nov. 2, 2021, the entirety of which is incorporated by reference herein. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to systems and methods for the treatment or prevention of dysbiosis in the gastrointestinal tract of an individual and includes implantable devices adapted to release therapeutic or restorative microbiota to an individual&#39;s GI tract as well as ablation systems that can ablate residing microbiota before administering the restorative microbiota. 
     BACKGROUND 
     The intestinal mucosa in a human is the largest body surface, approximately 200 m 2 , that is exposed to the external environment. At birth, the intestines and mucosa are thought to be sterile, but after birth, a large variety of maternal and environmental microbes rapidly colonize the intestinal mucosa to form a unique gastrointestinal (GI) tract microbiota population. Over time, the microbiota stabilizes, and its content is composed of many species of microorganisms, including bacteria, yeast, and viruses. In an adult individual, the gastrointestinal microbiota comprises about 10 14  bacteria, with a bacterial genome having from 200,000 to 800,000 genes per individual, i.e., 10 to 50 times the number of genes of the human genome. 
     Individuals may have quite similar bacterial species, but the exact microbiota composition in terms of bacterial species and proportions is, to a large extent, specific to the host. Thus, GI tract microbiota is a very diverse, complex ecosystem that is specific to each individual. 
     Taxonomically, the bacteria are classified according to phyla, classes, orders, families, genera, and species. While a few phyla are typically represented, these phyla may account for between 500 and 1000 discrete species in the individual&#39;s GI tract. The dominant microbial phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, with the two phyla Firmicutes and Bacteroidetes likely representing 90% of GI tract microbiota. The Firmicutes phylum is composed of more than 200 different genera, such as  Lactobacillus, Bacillus, Clostridium, Enterococcus,  and  Ruminicoccus. Clostridium  genera represent 95% of the Firmicutes phyla. Bacteroidetes consist of predominant genera such as Bacteroidetes and Prevotella. The Actinobacteria phylum is proportionally less abundant in a typical individual. Bacteria from the  Lactobacillus  family also may also be present in a GI tract microbiome. 
     Some GI tract microbiome activities are well understood, such as the ability of certain microbiota to break down carbohydrates that go undigested by the host&#39;s digestive system to provide energy in the form of short chain fatty acids and nutrition. In addition to providing energy, the complex, symbiotic microbiome ecosystem interacts within the gastrointestinal tract to provide many key metabolic end-products that are essential to the health of the host. The GI tract microbiome influences and yields a wide variety of functions, including metabolic function, immune function, gut integrity, bile and lipid metabolism, various organ functions (i.e., heart, liver, brain, etc.), and susceptibility to infections of the gastrointestinal tract. Recent investigations have found that GI tract microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between the intestinal microbiome and host regulatory systems are implicated in the development of psychiatric conditions and in the efficacy of common therapies. 
     It is essential for the health of an individual to maintain a stable, diverse microbiota that can return to its initial state after a change and is resistant to pathogen invasion. A rich and diverse GI tract microbiota is best adapted to withstand external threats. The GI tract microbiota represents a varying ecosystem that can be severely tested by unbalanced diets, stress, antibiotics, and diseases. Further, many pathologies and medical treatments can disrupt the microbiota, leading to GI tract dysbiosis. For example, inflammatory diseases, such as chronic intestinal inflammatory diseases, can limit intestinal microbiota diversity. Iatrogenic dysbiosis occurs when the imbalance is caused by a medical intervention or treatments, such as antibiotic treatments. A healthy host-microbiome balance is needed to optimally perform metabolic and immune functions and prevent disease development. 
     There is a clinical need for systems and methods for stabilizing, restoring and/or regulating the GI tract microbiome. 
     SUMMARY OF THE INVENTION 
     The present disclosure relates to methods of treating a gastrointestinal tract dysbiosis. For example, such a method can include delivering a condensable vapor to a targeted region of a lumen of a gastrointestinal tract to ablate a luminal surface and a mucous layer of a surface of the gastrointestinal tract without ablating a submucosal layer of the gastrointestinal tract such that a microbiome carried on or in the mucous layer is ablated. 
     In some aspects, the techniques described herein relate to a method further including delivering a catheter to the targeted region and expanding a first occlusion balloon and a second occlusion balloon to engage a wall of the gastrointestinal tract, where the first occlusion balloon is spaced apart from the second occlusion balloon, and delivering the condensable vapor through an inflow channel of the catheter to the targeted region between the first occlusion balloon and the second occlusion balloon. 
     The techniques described herein can relate to a method wherein the condensable vapor undergoes a vapor-to-liquid phase change that applies ablative thermal energy to the luminal surface and mucous layer. 
     In additional variations, the techniques described herein relate to a method wherein a portion of a liquid condensate resulting from the vapor-to-liquid phase change flows outward from the targeted region through an outflow channel and an outlet in the catheter. 
     The techniques described herein can relate to a method wherein the vapor-to-liquid phase change ablates villi that are immersed in the mucous layer. 
     The method can further include ablating the luminal surface and mucous layer sequentially in a plurality of locations by re-positioning the catheter and occlusion balloons. 
     In some aspects, the techniques described herein relate to a method wherein ablating the luminal surface and mucous layer is provided over a continuous length of the GI tract of at least 20 cm. 
     The methods described herein can further include administering a restorative microbiota to the region of the gastrointestinal tract in which the residing microbiota was ablated. 
     Additional variations include methods wherein at least one sensor of at least one occlusion balloon send a signal of balloon contact with the surface of the lumen. 
     In some aspects, the techniques described herein relate to methods of treating a gastrointestinal tract dysbiosis, the method including: administering a restorative microbiota to the gastrointestinal tract of a patient over a selected time interval from a time-release element, wherein the restorative microbiota includes an effective amount of bacteria from two or more different taxonomic families selected from the group of Bacteroidaceae, Acintobacter, Firmacutes, Protetobacter,  Lactobacillus, Fusibacter,  Ruminococcaceae, Rikenellaceae. Clostridiaceae and Lachnospiraceae. The techniques described herein can relate to a method wherein the restorative microbiota includes Anaerobutyricum Soehngenii. In some aspects, the techniques described herein relate to a method wherein the restorative microbiota includes a processed human fecal composition. The restorative microbiota can include a lyophilized composition. 
     The methods can include a time-release element that is an implantable element attached to the gastrointestinal tract. In some aspects, the implantable element includes biodegradable materials adapted to biodegrade to release the restorative microbiota to the gastrointestinal tract. Variations of the method include the implantable element including a tethered element that is attached to a wall of the gastrointestinal tract by a clip. 
     In some aspects, the techniques described herein relate to a system wherein the restorative microbiota includes Anaerobutyricum Soehngenii. 
     In some aspects, the techniques described herein relate to a system wherein the restorative microbiota is a lyophilized material. 
     In some aspects, the techniques described herein relate to a catheter for treating GI tract dysbiosis of a patient, including: a handle, a flexible catheter shaft extending from the handle having a proximal end and a working end carrying at least a proximal occlusion balloon and a distal occlusion balloon wherein the proximal occlusion balloon is at least 100 cm from the proximal end of the flexible catheter shaft, and a heating mechanism capable of converting a flow of liquid media to a flow of vapor media that exits the flexible catheter shaft at an outlet located between the proximal occlusion balloon and the distal occlusion balloons wherein the vapor media has a vapor quality of at least 80% vapor, 85% vapor or 90% vapor, and wherein the flow of vapor media from the outlet delivers at least 5 cal/sec to a GI tract lumen in which the proximal occlusion balloon and the distal occlusion balloon are expanded. 
     Variations of the methods can include treating a gastrointestinal (GI) tract dysbiosis by: acquiring a sample of microbiota existing in a patient&#39;s GI tract, creating a profile of existing microbiota corresponding to levels of selected microbial phyla and/or proportions of selected microbial phyla, wherein the microbial phyla are selected from phyla Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, and administering a therapeutic microbiota to the patient that includes levels and/or proportions selected to urge proliferation of existing microbiota toward a normal microbiota profile. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a sectional illustration of a portion of a wall of an individual&#39;s duodenum, showing the mucous layers of the surface of the lumen that carries the residing microbiota, the mucosa, submucosa, villi, and other anatomical layers of the intestinal wall. 
         FIG.  2    is an enlarged illustration of mucous layers, microbiota, mucosa, and submucosa of  FIG.  1   . 
         FIG.  3    is an illustration of a portion of an individual&#39;s gastrointestinal tract showing a method of using a gastroscope and ablation catheter to position the working end of the catheter in the duodenum of the individual. 
         FIG.  4    is an illustration of the handle of the gastroscope and the ablation catheter of  FIG.  3   . 
         FIG.  5    is an enlarged view of the working end of the catheter and spaced apart occlusion balloons. 
         FIG.  6    is a sectional view of a catheter shaft taken along line  6 - 6  of  FIG.  5   , showing the flow channels therein. 
         FIG.  7 A  is an enlarged view of the duodenum of  FIG.  3    showing the working end of the catheter and the occlusion balloons expanded in the individual&#39;s duodenum. 
         FIG.  7 B  is a view of the duodenum as in  FIG.  7 A  showing the working end of another variation of a catheter with a scalloped occlusion balloon expanded in the individual&#39;s duodenum. 
         FIG.  8    is an illustration of a portion of an individual&#39;s gastrointestinal tract showing a method of implanting an implantable device of the invention adapted to deliver restorative, therapeutic microbiota to the duodenum of the individual. 
         FIG.  9    is an illustration of the individual&#39;s gastrointestinal tract as in  FIG.  8   , showing a variation of an implantable device that carries a communication component for wireless communication with a smartphone or other device to operate a micropump in the implant or other mechanism for modulating the release of the restorative microbiota to the duodenum of the individual. 
         FIG.  10    is an illustration of an individual&#39;s colon showing a variation of a treatment device for performing a lavage to remove and eliminate the mucous and residing microbiota of a targeted region of the colon. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to systems and methods for the treatment or prevention of dysbiosis in the gastrointestinal (GI) tract of an individual. Such GI tract dysbiosis can be defined as a physiological state in which the microbiota profile of at least a portion of an individual&#39;s GI tract is not in a normal state or that the profile differs significantly from a corresponding GI tract microbiota profile that is typical of a normal, healthy individual. Such a profile of an individual&#39;s GI tract microbiota can be represented by quantities of various taxonomic groups and, ultimately, species, and also can be evaluated the relative levels of various groups of microbiota, as described further below. 
       FIGS.  1  and  2    are schematic sectional illustrations of a portion of small intestine and, more particularly, of an individual&#39;s duodenum  100 . In  FIG.  1   , the wall of the duodenum  100  includes the outer tunica serosa  101 , the mucularis  102  comprising an outer longitudinal layer  103  and an inner circular layer  104 , the submucosa  105 , the muscularis mucosae  108 , and the mucosa  110 . The duodenum, as shown in  FIGS.  3  and  7 A  has four sections with borders being delineated by angular course changes, commonly called the first part  111 A or superior part, the second part  111 A or descending part, the third part  111 C or horizontal part, and the fourth part  111 D or the ascending part. 
     The mucosal lining or mucosa  110  of the small intestine is well adapted for the function of nutrient absorption by anatomical structures that increase the surface area for trans-mucosal absorption at three levels. The inner surface of duodenum has plicae circulares or circular folds  112  (see  FIG.  7 A ) that increase the surface area by approximately 3-fold. The mucosa  110  projects from the circular folds  112  of the luminal surface  114  into the lumen  115  with villi  116  that, are finger-like structures approximately 1 mm in length ( FIGS.  1 ,  2 , and  7 A ). The villi  116  increase the surface area by an additional 10-fold. Finally, the surface of each villus is covered with epithelium  117  with epithelial cells ( FIG.  2   ) known as enterocytes where absorption takes place across the enterocyte barrier. Small hair-like filaments known as microvilli  118  project from the luminal surface villi into the lumen  115  ( FIG.  2   ). The microvilli  118  increase the surface area for absorption by an additional 20-fold. These three anatomical structures combine to increase the surface area of the small intestine by approximately 600-fold. 
       FIGS.  1  and  2    further illustrate the luminal surface  114  of lumen  115 , and contents of the luminal surface which includes a mucous layer  120  consisting with an outer mucous portion  122  and an inner mucous portion  124 . The residing microbiota  125  is on the luminal surface or partly in the mucous layer  120 . The inner mucous portion  124  descends around the villi  116  toward the crypts  128  at the base of the villi  116 . 
     An objective of the invention is to ablate the entirety of the residing microbiota  125  and at least a portion of the mucous layer  120  without ablation of the submucosa  105 . The ablation of the microbiota  125  and the mucous layer  120  can also ablate the villi  116  and endothelium that is immersed in the mucous layer  120 . Another objective of the invention is to administer to the patient a restorative or replacement microbiota which will re-populate the ablated region as a new mucosa regenerates over a period of 1 to 4 weeks in the methods described below. 
     In a variation, the introduction of the restorative microbiota can be accomplished over a time interval of 1 week to 180 days to return the patient to a more normal GI tract microbiota profile as described below. The divergence of a patient&#39;s GI microbiota profile away from a normal profile has been observed in many disorders, diseases, and pathological conditions. Thus, treating GI tract dysbiosis corresponding to the use of systems and methods of the invention can treat medical conditions selected from the group consisting of: gastrointestinal inflammation, metabolic syndrome, obesity, prediabetes, Type 2 diabetes, Type 1 diabetes, insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity and related disorders, gastroesophageal reflux disease, Barretts esophagus, irritable bowel syndrome, Crohn&#39;s disease, ulcerative colitis, celiac disease, constipation, diarrhea, colorectal cancer, polycystic ovarian syndrome, coronary artery disease, heart disease, stroke, cognitive decline, dementia, Alzheimer&#39;s Disease, fertility issues, menstrual dysfunction, cancers, eczema, sleep apnea, multiple sclerosis, arthritis, rheumatoid arthritis, asthma, chronic fatigue syndrome; autism, atopic dermatitis, psychiatric disorders (e.g., depression and anxiety) and combinations thereof. 
     Now turning to  FIGS.  3  to  7 A , a system and method of the invention for ablating the contents of the luminal surface  114 , the residing microbiota  125  and the mucous layer in a patient&#39;s duodenum  100  is illustrated.  FIG.  3    is a schematic illustration that shows a patient&#39;s esophagus  140 , stomach  142 , pylorus  144 , duodenum  100 , and jejunum  146  with a gastroscope or endoscope  150  being introduced into the patient&#39;s duodenum  100 . Further, an elongate catheter shaft  155  of a vapor delivery catheter  160  is introduced through a working channel  162  in the endoscope  150 . 
     The catheter  160  as shown in  FIGS.  4  and  5    is configured to deliver a condensable, thermal vapor media, such as sterile, condensable water vapor, to a targeted region of the gastrointestinal tract. Variations of probes and catheters of this type are described in commonly-owned U.S. Pat. Nos. 11,284,932; 11,284,931; 11,179,187; 11,141,210; 11,129,664; 10,548,653; 10,499,973; 9,943,353; and 8,579,892 and commonly-owned and co-pending U.S. Patent Applications Ser. Nos. 17/304,102; 17/457,501; 17/647,835 and 63/367, 293, all of which are incorporated herein by this reference. 
     In a variation as shown in  FIG.  4   , the catheter handle  164  carries a heating mechanism  165 , which is capable of instantaneously converting an inflow of sterile flowable liquid media LM, such as sterile water, into a flowable thermal vapor media VM, such as water vapor ( FIG.  4   ). More, in particular, a controller  170  is provided that when actuated causes a liquid media source  180  including a syringe pump to pump the sterile liquid media LM into the heating mechanism  165  wherein the liquid media is instantly converted to thermal vapor media, such as water vapor. The controller  170  operates the syringe pump to provide a very precise flow rate of the liquid media into the heating mechanism  165 . In a variation, the heating mechanism  165  comprises a helical tubing element  182  into which the liquid media is pumped. The material of the helical tubing element  182  is fabricated from an electrically resistive material, such as stainless steel, Inconel, or the like, that, when heated, will instantly convert the flow of sterile liquid media into water vapor. The helical tubing element  182  is suitable since it is axially compact and can be carried within the catheter handle  164  with electrical leads from an electrical source  185  coupled to opposing ends of the helical tubing element  182 . 
     The helical tubing element  182  has one or more temperature sensors  184  attached thereto that send temperature signals to the controller  170  to control or modulate either or both (i) electrical current delivered from the electrical source  185  to the heating mechanism  165  and (ii) the flow rate of liquid media into the heating mechanism  165  to thereby control the outflow of heated vapor media from the heating mechanism which then flows through a vapor inflow channel  188  to an outlet  190  in the working end  195  of the catheter shaft  155  ( FIGS.  4  to  6   ). In a variation, a temperature sensor  184  is coupled to both the proximal and distal ends of the helical tubing  182  to monitor the temperature of the helical tubing with the fluid flowing therethrough. In another variation, another temperature sensor,  184  is coupled to the middle portion of the helical tubing  182 , where the controller  170  is configured with algorithms that monitor signals from one to three temperature sensors. In response to the temperature signals, the controller  170  can modulate energy delivery to the helical tubing  182  to maintain the optimal temperature to instantly cause the liquid-to-vapor phase change. In a typical variation, the controller  170  and heating mechanism  165  can provide an outflow of vapor media VM from the vapor outlet  190 , having a vapor quality that is at least 80% water vapor, at least 85% water vapor, or at least 90% water vapor with less than a 10% variation in the vapor quality over a selected time interval of at least 5 seconds. 
     As can be seen in  FIGS.  4 ,  5 , and  6   , the working end  195  of the catheter shaft  155  carries proximal and distal occlusion balloons,  200 A and  200 B, that are configured for expansion in a gastrointestinal lumen  115 . The occlusion balloons  200 A,  200 B can be compliant or non-compliant and are configured to occlude a lumen  115  than can range from 18 mm to 24 mm in diameter. When the occlusion balloons are fabricated of a non-compliant material, a series of catheters can be manufactured with occlusion balloons that have selected different diameters, for example, a first catheter with 18-20 mm diameter occlusion balloons, a second catheter with 20-22 mm balloons, a third catheter with 22-24 mm balloons, etc. In the case of compliant occlusion balloons, it is possible that each occlusion balloon  200 A,  200 B can be expanded to a selected diameter within the range of 18 mm to 24 mm so that a single manufactured catheter  160  is suitable. Either type of occlusion balloon can be configured with a sensor  202  in the surface of either or both balloons to sense engagement of the balloon surface with the wall of the lumen  115  ( FIG.  5   ). Such a sensor  202  can comprise a capacitance sensor, an impedance sensor, another form of electrical contact sensor or a light energy contact sensor. 
     Referring to  FIGS.  5  and  6   , the axial length AA of the inter-balloon catheter shaft portion  205  between the occlusion balloons  200 A,  200 B can range from 2 cm to 25 cm and is typically between 5 cm to 10 cm. The vapor inflow channel  188  in the catheter shaft  155  has at least one vapor outlet  190  in the inter-balloon catheter shaft portion  205  that introduces the condensable vapor media VM into the luminal space  208  ( FIG.  7 A ) between the occlusion balloons  200 A,  200 B, wherein the targeted region of the GI tract comprises the luminal surface  114  of the lumen  115  between the expanded occlusion balloons. The luminal surface  114  of lumen  115  comprises the mucous layer  120  and microbiota  125  as shown in  FIGS.  1  and  2   . Often, there is a single vapor outlet  190  disposed in the inter-balloon catheter shaft portion  205 , as shown in  FIGS.  5  and  6   , but a plurality of vapor outlets may be provided axially and/or circumferentially around the shaft portion  205 . Additionally, at least one outflow port  210  is provided in the inter-balloon catheter shaft portion  205  that is adapted to extract condensate or water droplets (i.e., the condensed vapor) from the inter-balloon space  208  through outflow channel  212  in the catheter shaft  155  ( FIGS.  5  and  6   ). In a variation shown in  FIG.  5   , a vapor inflow outlet  190  is positioned in a first end of the intra-balloon catheter shaft portion  205  and a condensate outflow port  210  is in the opposing, second end of the inter-balloon catheter shaft  205  to create a circulating flow. Thus, the vapor inflows and the condensate outflows provide a form of circulating flow that can reduce the time interval needed for ablation of the targeted luminal surface  114 , mucosa  120  and microbiota  125  ( FIGS.  1  and  2   ). The circulating flow can function to extract a large portion of the condensate which in turn decreases the required energy delivery to the luminal surface  114  of lumen  115  to ablate to a selected depth because if the condensate were not extracted, the condensate (or liquid water) would otherwise need to be heated together with the targeted contents of the luminal surface  114  including the microbiota  125  of the lumen  115 . 
       FIG.  6    is a sectional view of the catheter shaft  155  showing a variation of an extrusion that carries the vapor inflow channel  188 , the condensate outflow channel  212  comprising dual passageways, and an independent inflation channel  214   a,    214   b  for the respective proximal and distal occlusion balloons  200 A and  200 B. In  FIG.  6   , it can be seen that the vapor inflow channel  188  is disposed of in the center of the catheter shaft  155 , with the other surrounding channels  212 ,  214   a,  and  214   b  having an arcuate shape around the central channel  188 . The surrounding channels  212 ,  214   a,  and  214   b  are filled with air or condensate during use which provides a thermally insulating layer around the central vapor inflow channel  188 , which is advantageous in helping maintain the quality of the vapor media VM flowing in the central inflow channel  188 . In another variation, the catheter shaft  155  can carry a single inflation channel (not shown) for inflating both occlusion balloons  200 A,  220 B contemporaneously rather than independently, wherein the catheter shaft  155  would then be configured with two or three arcuate channels instead of four arcuate channels as shown in  FIG.  6   . The occlusion balloons are inflated by an inflation source  215  that be controlled by the controller  170  or can Be manually inflated by a syringe. Electrical leads  218  are carried in the shaft  155  the extend to the contact sensors  202 . 
     Referring to  FIGS.  3  and  7 A , a method of the invention includes introducing the working end  195  of a vapor delivery catheter  160  catheter into the duodenum  145  to a targeted region of the lumen  115  thereof. The physician then, under endoscopic vision, expands the occlusion balloons  200 A,  200 B, which can be done sequentially or contemporaneously. In a variation, the physician positions the distal occlusion balloon  200 B in a desired location under endoscopic vision and then observes the inflation of this occlusion balloon  200 B within the lumen  115  of the duodenum  100 . Subsequently, the physician moves the endoscope  150  proximally and then observes the inflation of the proximal occlusion balloon  200 A. 
     Referring to  FIG.  7 A , after the occlusion balloons  200 A,  200 B are in position and expanded, the physician actuates the controller  170 , for example, by means of an actuator button  216  on the catheter handle  164  ( FIG.  4   ). A pre-set on the controller  170  is selected to deliver the thermal vapor media VM for a time interval ranging between 2 seconds and 20 seconds. The controller  170  also has pre-sets on its user interface to deliver a selected number of cal/sec, which is controlled by the flow rate of the sterile liquid media LM into and through the heating mechanism  165 . For any selected flow rate, controller  170  can control the electrical source  185  to apply the suitable electrical energy to the resistive heating mechanism  165  to convert the sterile liquid media inflow into high quality thermal vapor media, such as water vapor. As described above, at least one temperature sensor  184  coupled to the heating mechanism  165  sends temperature signals to the controller  170 , which then modulates the resistive heating of the heating mechanism  165  responsive to the temperature signals. 
     Referring to  FIG.  7 A , the inflow pressure from the liquid media source  180  and its syringe pump then further pumps the thermal vapor media VM through the inflow channel  188  in the catheter shaft  155  to the outlet  190  in the inter-balloon catheter shaft portion  205 . The thermal vapor then condenses in the lumen  115  to apply energy to the targeted luminal surface  114  of the lumen  115 , wherein the vapor-to-liquid phase change releases large amounts of energy and uniformly ablates a thin layer of the luminal surface  114  of the lumen  115 , which includes the residing microbiota  125  and the mucous layer ( FIGS.  1 - 2   ). The condensate or condensed vapor CV is at least in part removed from the inter-balloon space  208  in the lumen  115  through the outflow port  210  and outflow channel  212  in the catheter shaft  155 , as described above. The outflow port  210  and output channel  212  can be a passive channel where any pressure in the inter-balloon space  208  causes an outward flow of the condensate. In another variation, a negative pressure source  225  can communicate with the outflow channel  212  and be controlled by the controller  170  to extract condensate from the inter-balloon treatment space  208  ( FIGS.  4 ,  5 , and  7 A ). In a typical treatment, the delivery of vapor media VM to ablate the contents of the luminal surface  114  and microbiota  125  would be from 2 to 20 seconds of vapor delivery and often from 5 to 10 seconds. 
     As can be seen in  FIG.  7 A , the occlusion balloons  200 A,  200  engage the wall of the GI tract lumen  115  so that the targeted region of the luminal surface  114  between the occlusion balloons remains in its natural state with the circular folds  112  undisturbed. This is very advantageous as when the condensable vapor media VM is introduced through the outlet  190  in the inter-balloon catheter shaft portion  205 , the vapor-to-liquid phase change causes the release of energy, and ablation, at all exposed luminal surface  114  of the lumen  115 , where the condensation occurs. Thus, the vapor&#39;s phase change will ablate the contents of the luminal surface  114  comprising the microbiota, mucous layer  120  and mucosa  110  uniformly in and around the circular folds  112  in their natural state. The ability of vapor to ablate all luminal surfaces of the lumen  115  uniformly differs significantly from other potential forms of energy delivery that might be considered. For example, other means of delivering thermal energy or cryogenic freezing can consist of a hot water balloon, cryo-balloon or a balloon with a surface that is heated by RF electrodes, resistive heating elements, microwave energy, light energy, or the like, which could be expanded to engage the surface of the lumen  115  ( FIG.  7 A ). However, any expandable member such as a balloon would compress the circular folds  112  and villi  116  in the lumen  115  and prevent ablation to a uniform depth in the surface layers of the lumen  115 . 
     In another important aspect of a method of the invention, an entire selected length of the duodenum  100  and optionally a region of a jejunum  146  can be continuously and uniformly ablated by sequentially repositioning the working end  195  of the catheter  160 . In a variation, the physician typically would position the catheter working end  195  and occlusion balloons  200 A,  200 B in a distal location in the duodenum  100  or jejunum  146 . For an initial ablation, as described above, physician would observe the expansion of the distal balloon  200 B, then optionally relocate the endoscope and observe the expansion of the proximal balloon  200 A and then introduce the vapor media VM to complete the first ablation. Thereafter, the physician would collapse the occlusion balloons  200 A,  200 B and move that working end  195  in the proximal direction. The physician would then endoscopically observe the positioning of distal balloon  200 B in the lumen  115  so that the second ablation would slightly overlap the first ablation. The physician would then expand the proximal occlusion balloon  200 A and introduce vapor media VM to complete the second ablation. The physician would repeat this re-positioning of the working end  195  to provide a continuous ablation of the luminal surface  114  of the lumen  115 . In this sequential ablation method, in one of the re-positioning steps, either the proximal balloon  200 A or the distal balloon  200 B is positioned to cover the ampulla of Vater  230  so that the region around the ampulla would be protected from the ablation ( FIG.  7 A ). By this method, the physician can ablate luminal surface  114 , mucosa  120  and microbiota  125  continuously over a length of the small intestine that is at least 20 cm, at least 25 cm or at least 30 cm. It is believed to be important to ablate the residing microbiota  125  uniformly over such an extended length of the GI tract so that when restorative microbiota  425  is introduced as described below, there will be little or no residing microbiota  125  to compete with the progressive growth of the restorative microbiota  425 . 
     As can be understood, the method of sequential ablation allows for ablation of the residing microbiota  125  and mucous layer  120  in the first part  111 A, second part  111 B, third part  111 C, and fourth part  111 D of the duodenum  100  ( FIG.  7 A ). It should be appreciated that the sequential ablation can progress from a proximal position to a distal position which is the reverse of the above description. The number of sequential ablations can range from 2 to 8 depending on the length of treatment space  208  between the occlusion balloons  200 A,  200 B, which can be from 5 cm to 25 cm, as described above. 
     In a variation, the catheter shaft has a diameter of 2.8 mm or less so that it can be introduced through the working channel of a conventional, commercially available gastroscope  150  of the type shown in  FIGS.  3  and  4   . In a variation, the conventional gastroscope has a working channel length of approximately 100 centimeters. Thus, the length of the catheter shaft  155  extending from handle  164  is 100 cm from the proximal balloon, and often at least 110 cm, at least 120 cm, or at least 130 cm so that the working end  195  of the catheter  160  can be extended distally from the distal end of the gastroscope  150  a sufficient distance to observe the expansion of the occlusion balloons  200 A,  200 B. 
     In general, a catheter  160  of the invention for treating GI tract dysbiosis comprises a handle, a flexible catheter shaft extending from the handle having a proximal end and a working end carrying at least a proximal occlusion balloon and a distal occlusion balloon wherein the proximal occlusion balloon is spaced apart at least 100 cm from said proximal end of the catheter shaft, and a heating mechanism capable of converting a flow of liquid media to a flow of vapor media that exits the catheter shaft at an outlet located between the proximal and distal occlusion balloons wherein the vapor media has a vapor quality of at least 80% vapor, 85% vapor or 90% vapor and wherein the flow of vapor media from the outlet delivers at least 10 cal/sec to a GI tract lumen in which the proximal and distal occlusion balloons are expanded. In variations, the catheter  160  is capable of providing a flow of vapor media from the outlet that delivers at least 5 cal/sec, 25 cal/sec, or 50 cal/sec. 
     In another variation, the invention comprises a custom endoscope device that has a longer shaft than a conventional gastroscope  150 , with the custom endoscope having an increased shaft length. Often, a conventional gastroscope shaft is not long enough to reach the third part  111 C or fourth part  111 D of the duodenum  100  or the jejunum  146 . In a variation where it is deemed important to have in endoscopic viewing in the distal part of the duodenum  100  or in the jejunum  146 , an endoscope of the invention has a shaft with a length of at least 120 cm, at least 130 cm, or at least 140 cm. In a variation, such an endoscope device can comprise an integrated catheter that carries one or more image sensors and with a component or section of the working end carrying the occlusion balloons as disclosed in commonly-owned U.S. Patent Applications 63/367,293; Ser. Nos. 17/647,835; 17/457,501 and 17/304,102. In another variation, a single-use endoscope with a suitable length as described above can be provided with a 2.5 to 5 millimeter working channel for receiving the catheter, the type shown in  FIGS.  4  to  7 A  with an extended length to be used with the endoscope. 
     Referring to  FIG.  7 B , another variation catheter  240  with working end  245  that includes a scalloped occlusion balloon structure  250  that is configured to allow vapor ablation of the luminal surface  114  on a first side  255  of a gastrointestinal lumen  115  while preventing ablation of a second, opposing side  256  of the lumen  115 . In a variation, the occlusion balloon  250  comprises a proximate balloon portion  260   a  and distal balloon portion  260   b  that are configured to expand to engage the wall of the lumen as shown in  FIG.  7 B . As can be seen in  FIG.  7 B , the occlusion balloon  250  has a medial portion comprising an axially extending element  265  between the proximal balloon portion  260   a  and the distal balloon portion  260   b.  The axially extending element  265  can be inflatable or non-inflatable and is adapted to cover a side  256  of the lumen  115  when the proximal and distal balloon portions  260   a,    260   b  are expanded. The scalloped occlusion balloon  250  this is useful for protecting in ampulla of Vater  230  that was described above. A vapor inflow channel  270  and condensate outflow channel  272  are provided to function as described above. This type of occlusion balloon structure  250  of  FIG.  7 B  can be carried on an independent catheter  240  as shown in  FIG.  7 A  or can be carried on a type of catheter  160  as shown in  FIG.  7 A  that carries first and second occlusion balloons  200 A,  200 B as described previously. The scalloped occlusion balloon structure  250  can be positioned proximally or distally from the paired occlusion balloons  200 A,  200 B or ca replace either of the balloons  200 A,  200 B. In any event, such an occlusion balloon structure can be used in a situation where the objective is ablate the luminal surface  114  and residing microbiome  125  over a continuous length of a duodenum  100  only limited by a region around the ampulla of Vater  230  which is protected from ablation. 
     In another aspect of the invention,  FIG.  8    illustrates an implant device  400  that is implanted in the patient and adapted to deliver restorative microbiota  425  to the GI tract over a selected time interval. In  FIG.  8   , it can be seen that an endoscope  150  in phantom view has been introduced in a trans-esophageal approach. The implant device  400  can be delivered through a working channel in the conventional endoscope  150 , or a clip applier tool can be introduced through the working channel with the implant device  400  delivered outside of the endoscope. It should be appreciated that a nasogastric approach is also possible with a smaller diameter endoscope. In  FIG.  8   , the implant device  400  is shown as an elongated member that carries at least one reservoir  405  therein which carries the restorative microbiota  425  that is described further below. The microbiota  425  can be released over a time interval through an agent-release portion  428  of the implant device  400  which can consist of micropores or biodegradable surfaces overlying reservoirs carrying the restorative microbiota  425 . In a variation, the implant device  400  has proximal end  442  that is adapted for fixation to the wall of the stomach  142  with a clip  444  as is known in the art. A clip applier tool (not shown) is introduced through the working channel  162  of the endoscope  150  to affix the clip  444 . As indicated in  FIG.  8   , a proximal portion  442  of the implantable device  400  that is disposed in the stomach  142  may not carry micropores or reservoirs with biodegradable surfaces for releasing the microbiota  425  as the release of microbiota in the stomach may be degraded. In a variation, a distal portion  428  of the implant device  400  is positioned in the patient&#39;s duodenum  100 , which is the preferred site for releasing the restorative microbiota  425 . In another variation, the implant device  400  can be tethered in the duodenum  100 . 
     In a variation, the restorative microbiota  425  comprises an effective amount of bacteria from any gram positive family or from any gram negative family. The effective amount of bacteria can be selected from two or more different taxonomic families selected from the group of Bacteroidaceae, Acintobacter, Firmacutes, Protetobacter,  Lactobacillus, Fusibacter,  Ruminococcaceae, Rikenellaceae. Clostridiaceae and Lachnospiraceae. Typically, such bacteria comprise a processed fecal composition wherein such processing is known in the art. On a species level, the restorative microbiota  425  can include an effective amount of Anaerobutyricum Soehngenii, an anaerobic Gram-positive, catalase-negative bacterium as described in Gilijamse, P. W., Hartstra, A., Levin, E. et al. “Treatment with Anaerobutyricum soehngenii: a pilot study of safety and dose-response effects on glucose metabolism in human subjects with metabolic syndrome”; npj Biofilms Microbiomes 6, 16 (2020), and (https://doi.org/10.1038/s41522-020-0127-0) and Koopen A, Witjes J, Wortelboer K, et al. titled “Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production.” Gut Epub Oct. 25, 2021, which articles are incorporated herein by this reference. In a variation, the restorative microbiota  425  includes a processed human fecal composition. Typically, the restorative microbiota  425  comprises a lyophilized composition that is processed and fabricated as is known in the art. Research companies such as Creative BioLabs Inc, at 17 Ramsey Road Ste. 202, Shirley, N.Y. 11967 can be engaged to produce some or all types of restorative microbiota  425 . Other companies that can provide tools for profiling the residing microbiota and/or providing restorative microbiota are Diversigen Inc., 600 County Road D West, Suite 8, New Brighton, Minn. 55112; Rebiotix Inc., 2660 Patton Road. Roseville, Minn. 55113; DNA Genotek, 3000-500 Palladium Drive, Ottawa, Ontario, Canada K2V1C2; and Compound Solutions, Inc., 1930 Palomar Point Way, Suite 105, Carlsbad, Calif. 92008. The NIH Human Microbiome Project (https://hmpdacc.org/) has characterized the microbiota from healthy individuals across the gastrointestinal tract for comparison and also has data relating to the GI tract microbial enrichments, depletions, and dysbioses in microbial metabolic activities. 
     In the variation shown in  FIG.  8   , it should be appreciated that the implanted device  400  is adapted for temporary implantation, wherein the clip  444  is intended to maintain the implant  400  in position for a period of time ranging from one week to six months. The clip  444  is designed to eventually slough off the stomach lining and, together with the remainder, if any, of the biodegrading implant  400  and pass through the patient&#39;s gastrointestinal tract. 
     In a variation, the implant device  400  may be substantially short in length and be adapted to release the microbiota into the first part  111 A of the duodenum  100 , or the device can have length ranging from 10 cm to 50 cm to extend through the entire length of the duodenum  100  and the jejunum  146 . 
     In another variation, the implant device  100  can be adapted for temporary fixation with a clip or other fastener to a wall of the patient&#39;s pylorus  144  or a wall of the duodenum  100 . In another variation (not shown), the implant device may carry a larger reservoir and be configured with a proximal implant portion that resides in the patient&#39;s stomach  142 . In such a variation, the implant may carry a donut-shaped element for positioning proximal to the pylorus  144 . Such an implant variation would typically be adapted for introduction and retrieval through a trans-esophageal approach using an endoscope. In a variation, such a semi-permanent implant can include a refillable reservoir for carrying restorative microbiota  425 . 
     In a variation, the implant device  400  can consist of an elongated sleeve, tubular member, ribbon, or filament of a flexible polymeric material, as shown in  FIG.  8   , with an interior chamber or reservoir carrying the restorative microbiota  425 . At least a portion of the surface of the polymeric material overlying the interior chamber is configured with micropores that allow for the release of the microbiota therethrough. The implant may also comprise a plurality of elongated members tethered by a clip  444 . 
     In another variation, an implant device configured as in  FIG.  8    can comprise a biodegradable member with a plurality of chambers therein that carry restorative microbiota  425 . In this variation and other variations above, the polymer surfaces overlying the restorative microbiota  425  can be configured to biodegrade or bio-erode at different rates to allow for the release of the microbiota  425  over an extended time interval. Such bioabsorbable, biodegradable, or bio-erodible polymers have been widely used medical devices or for the delivery of drugs. Suitable the polymers are Poly-L-lactic acid (PLLA), polyglycolic acid (PGA), poly (D, L-lactide/glycolide) copolymer (PDLA), and polycaprolactone (PCL). Various degradation rates for such polymers can be designed. 
     In a variation, the implant device  400  can be designed to release the restorative microbiota  425  over a selected time interval, where the implant  400  can commence the release within 1 hour of the time of implanting the device, and the selected time interval for ending the release of said microbiota can be between 1 day and 180 days from the time of implanting the device  400 . 
     In general, a method corresponding to the invention for treating GI tract dysbiosis comprises ablating the residing microbiota of a targeted portion of a GI tract of a patient with a GI tract dysbiosis and administering a restorative microbiota to the patient comprising an effective amount of bacteria from two or more different taxonomic families selected from the group of Bacteroidaceae, Acintobacter, Firmacutes, Protetobacter,  Lactobacillus, Fusibacter,  Ruminococcaceae, Rikenellaceae. Clostridiaceae and Lachnospiraceae. The method can include administering the restorative microbiota comprising Anaerobutyricum Soehngenii. The effective amount or dose of restorative microbiota is the amount necessary to re-colonize or re-populate the targeted region of the GI tract, which will be in competition with the residing microbiota in portions of the GI tract adjacent to the ablated region that will also be migrating and attempting to re-colonize the targeted region. For this reason, the timed release and continuous release of restorative microbiota  425  over a time interval may be optimal, or a continuous release from the daily ingestion of capsules may be adequate. 
     Now turning to  FIG.  9   , another variation of implant device  450  is shown where a proximal region  456  of the implant carries a communication component  460  for wireless communication with a remote device  465  such as a smartphone or tablet. This variation includes a micropump that is adapted to pump restorative microbiota  425  from a reservoir in the device to outlets therein in response to signals from the remote device  465 . Such a remote device  465  can also communicate with the cloud  470  which can provide access to remote physicians to allow adjustment or modulation of dosimetry or agent release in response to questionnaires or responses from the individuals concerning his or her state of health. 
     Another aspect of the invention includes profiling the residing GI tract microbiota  125   
     ( FIGS.  1 - 2   ) prior to ablation thereof or the administration of restorative microbiota  425 . Such a profile of a residing microbiota may involve any convenient means by which the levels of microorganisms or groups of microorganisms in the GI tract of the patient can be identified and/or quantified. Such a microbiota profile would be prepared with in vitro methods using a sample taken from the GI tract. In a variation relevant to this disclosure, the sample would be acquired by a swab, rinse, aspirate, scrape or biopsy of a small intestine surface. Other treatments using the methods of the invention in other regions of the GI tract would acquire microbiota samples in the targeted region. For example, the human GI tract can be subdivided into the upper GI tract consisting of the esophagus and stomach, and the lower GI tract or the intestinal tract consisting of the duodenum, jejunum, ileum, cecum, colon, and rectum. Treatments of the esophagus and colon are possible using the methods of the invention, in which case profiles would be prepared for the targeted region from samples acquired from that region. For example, microbiota and mucous would be collected from the esophagus for evaluating the treatment of esophageal disorders. For potential treatments of the colon, fecal samples would be collected for profiling the residing microbiota therein. 
     In a method of the invention, in the event a profile of the residing microbiota  125  as described above shows that the profile is not highly differentiated from a normal profile, a method of the invention is to provide the timed release of restorative microbiota  425  from an implant device of  FIGS.  8 - 9    without the ablation of the residing microbiota  125 . In such a case where the profile of residing microbiota is not highly differentiated from normal, a method of the invention can include administering the restorative microbiota  425  by means of liquid compositions taken orally or introduced through an endoscope, capsules, aerosols, enemas, suppositoriesor the like rather than using an implant device  400 ,  450  as shown in  FIGS.  8 - 9   . 
       FIG.  4    illustrates the heating mechanism  165  carried in the handle  164  of the catheter  160 . It should be appreciated that a heating mechanism comprising helical or spaced apart, resistively heated elements can also be carried in a medial portion of the catheter shaft  155  or in a distal region of the catheter shaft  155 . In another variation, a primary resistive heating mechanism  165  can be carried in the catheter handle  164 , and a supplementary heating mechanism can be carried in a distal region of the catheter shaft to optimize vapor quality (cf.  FIG.  4   ). A heating mechanism  165  carried in a medial or distal region of the catheter shaft  155  can consist of a flexible helical element exposed to the vapor inflow channel  188  or can consist of a series of ring-like resistively heated elements with exposed surfaces in the vapor inflow channel  188  which again allows for flexibility of the catheter shaft  155 . Any of these variations with one or more heating mechanisms can provide high-quality vapor as described above. 
     The above methods of ablating the luminal surface  114 , mucous  120  and residing microbiota  125  of a patient&#39;s GI tract describe the advantages of using the condensable vapor CV ( FIG.  7 A ), where the vapor-to-liquid phase change applies an enormous amount of energy uniformly over a luminal surface. It can be understood that sterile liquid vapor is an optimal liquid media LM to vaporize, but other fluids can be used or added to liquid water, such as alcohol or other chemical compositions, to provide the ablative effect. Also, it should be appreciated that the scope of the invention includes using alternative forms of energy delivery, both thermal and cryogenic, such as heated or cooled balloons that engage the luminal surface  114 , as well as energy applicators that do not engage the luminal surface, all of which are followed by administration of restorative microbiota  425 . Such other forms of energy delivery can include RF devices, microwave devices, ultrasound devices, light energy devices, and the delivery of ablative liquids delivered to, and extracted from, a GI lumen. 
       FIG.  10    illustrates another aspect of the invention wherein mechanical means are provided in a catheter  480  for removing and substantially eliminating th residing microbiota and mucous from a targeted region of a GI tract.  FIG.  10    illustrates a patient&#39;s colon  482  with the distal end of catheter  480  introduced into the lumen  484  thereof. In a variation, the catheter  480  again has a proximal occlusion balloon  485 A and a distal occlusion balloon  485 B that are expanded in the lumen  484 . As can be understood, a large diameter shaft  488  is possible for introducing into a colon,  842  when treating a patient, for example, from 10 to 15 millimeters in diameter or larger. The catheter shaft  488  can be introduced with or without endoscopic vision, and in a variation, an image sensor can be carried at the distal end of the catheter shaft  488 . In a large diameter shaft  488 , a larger fluid inflow channel with a series of fluid inflow ports  490  can be provided for high rates of fluid inflows adapted for lavage of a targeted region of the lumen  484 . Also, one or more outflow ports  495  communicating with a large outflow channel in the shaft  488  can be provided, which is coupled to a negative pressure source. With a catheter of this type, a circulatory flow can be created with high-pressure inflows to wash and lavage the targeted region of the colon  482  to remove and eliminate the microbiota  125  and mucous layer  120  ( FIGS.  1 - 2   ) from the targeted region. Lavage may further include bactericides, other pharmaceutical agents, or ablative agents such as ethanol to eliminate the residing microbiota  125 . Such a lavage may be carried out for one to  5  minutes or more which is believed will remove and eliminate the mucus  120  and microbiota  125  from the targeted region. Thereafter, a restorative microbiota  425  of the types described above can be introduced in a liquid composition through the catheter  480  or by means of suppositories, an implant as described in  FIGS.  8 - 9    above that is tethered in the colon or by orally ingested capsules, tablets, and the like. In general, a method of treating a gastrointestinal (GI) tract dysbiosis comprises eliminating the mucous layers and residing microbiota therein within a targeted region of a GI tract without damaging a submucosal layer of the targeted region and administering a restorative microbiota to the targeted region. The targeted region for such a lavage in a patient can be the colon, esophagus, or small intestine. 
     Although particular embodiments of the present invention have been described above in detail, it will be understood that this description is merely for purposes of illustration and the above description of the invention is not exhaustive. Specific features of the invention are shown in some drawings and not in others, and this is for convenience only, and any feature may be combined with another in accordance with the invention. A number of variations and alternatives will be apparent to one having ordinary skills in the art. Such alternatives and variations are intended to be included within the scope of the claims. Particular features that are presented in dependent claims can be combined and fall within the scope of the invention. The invention also encompasses embodiments as if dependent claims were alternatively written in a multiple dependent claim format with reference to other independent claims. 
     All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.